This paper is a primer on the current state of a biotechnology sub-sector focused on the category of medicinal compounds and interventions known as “psychedelics.” It is the story of re-emerging scientific, regulatory, and patient interest in therapeutic solutions that in several cases have been around informally for centuries and in a formal clinical setting since the mid-20th Century. Many of the interventions are based on naturally occurring plants and fungi and there are several parallels with the medicinal cannabis industry.

Lysergic acid Diethylamide (LSD)… was first synthesized in 1938 by the Swiss chemist Albert Hofmann in the Sandoz (now Novartis) laboratories in Switzerland. It was subsequently patented in the US as a medicine for analytical psychotherapy…,

History as a medicine
We know that plant-based psychedelics have been used for hundreds and probably thousands of years for mindful and spiritual purposes. It is the ‘mindful’ aspect that is now exciting modern-day researchers and clinicians. By combining the right natural extracts with the right setting, such as an accompanying ceremony, human consciousness could be altered in a beneficial manner. These traditions were brought into more mainstream medical science in the 20th century when serious, Big Pharma-backed, at scale scientific studies were undertaken into various psychedelic medicines from the end of the 1930s until their complete criminalization in the late 1960’s and early 1970’s as part of the well-documented “war on drugs”. Most prominent was Lysergic acid Diethylamide (LSD), which was first synthesized in 1938 by the Swiss chemist Albert Hofmann in the Sandoz (now Novartis) laboratories in Switzerland. It was subsequently patented in the US as a medicine for analytical psychotherapy and used in psychiatry to enhance psychotherapy through the 1950s and 1960s.

The term ‘psychedelic’ – meaning ‘mind manifesting’ – was coined by British psychiatrist Humphry Osmond who was a pioneer in the use of LSD as a treatment for alcoholism and various mental disorders in the early 1950s. It was through Osmond’s and colleague John Smythies’ study of the effects of another psychedelic, mescaline, on brain chemistry that it was postulated that schizophrenia was caused by a chemical imbalance in the brain, but this was not well received by their peers at the time. By the end of 1960s Osmond and another colleague, now in Canada, had treated around 2,000 patients for alcoholism with LSD with apparently strongly positive results. Other studies took place in the UK with similarly encouraging results.

By the end of the 1960’s, around 40,000 patients in total had received some version of treatment with LSD for mental disorders including substance use disorder (SUD), neurosis, schizophrenia and psychopathy. Many of the trials undertaken lacked the rigor that would be found today but with encouraging results and just as the discipline was gaining wider clinical credit, things were abruptly shut down when LSD slipped into the growing street ‘hippy’ counterculture resulting in a major conservative backlash. It still suffers from that association today.

An important thread running through the studies undertaken before prohibition, that differentiated the psychedelics from other pharmaceutical interventions, was the combination of the medicine with therapy, usually talking therapy together with careful control of the surrounding environment. This focus on ‘setting’ echoes the traditional use of plant-based psychedelics in indigenous ceremonies and it has been carried over to the modern approach to psychedelic therapy treatment today, along with careful attention to the starting mindset of the patient. Hence, today we talk about the importance of “set and setting” in psychedelic medicine therapy.

The US Food and Drug Administration (FDA) has designated both psilocybin for treatment-resistant depression (TRD) and MDMA-assisted psychotherapy for PTSD as Breakthrough Therapies

State of the science today
Interest in psychedelic medicine began renewing in the 1990s as more was learned of the underlying science at the molecular and neurotransmitter level despite the huge frictions to research from the legacy legislation. In fact, legislation is only now starting to loosen. In the US, where much research is now being planned and undertaken, major changes are underway. In November 2020 Oregon became the first US state to legalize psilocybin (extracted from certain varieties of mushrooms) for therapeutic use. In June this year Texas followed Connecticut in legalizing psilocybin for medical research. The same month New York State announced it was considering legislation and there are many more bills at various stages before local legislatures in the US. Perhaps most significantly, at the end of July 2021, the US House of Representatives passed a bill directing federal agencies to undertake and fund research into psychedelic-assisted therapies and the potential benefits of cannabis. This bill is now before the Senate. The fact that these solutions are being used to treat post-traumatic stress disorder (PTSD) within the military veterans community goes some way to explain growing support in the US among conservatives.

The US Food and Drug Administration (FDA) has designated both psilocybin for treatment-resistant depression (TRD) and MDMA-assisted psychotherapy for PTSD as Breakthrough Therapies. Worldwide there is an explosion of psychedelic drug studies with more research on-going than at any time in the past. Establishments such as Johns Hopkins University and Imperial College London have set up research facilities dedicated to psychedelic medicine. Others are appearing in respected research universities globally.

The psychedelic medicines that show the most clinical promise currently are as follows.

Psilocybin. This compound occurs naturally in dozens of varieties of mushrooms. Clinical trials and academic studies suggest that psilocybin has potential therapeutic benefit for: PTSD, depression, SUD (including alcohol, opioid, and nicotine), migraines, OCD, anxiety in terminally ill patients, anorexia nervosa and social anxiety for autistic patients. . Exactly how psilocybin works is still being uncovered but recent evidence suggests that the mechanism involves the repair of neural connections. In a study by academics at Yale University published in scientific journal Neuron in July 2021, one dose of psilocybin was shown to increase the number of neuronal connections in mice by 10% and also the size and strength of the connections to a similar extent.

LSD. This infamous compound has shown promise in the treatment of anxiety, depression, SUD, cluster headaches, Tourette’s syndrome, and Alzheimer’s.

Ketamine. Ketamine is a non-naturally occurring synthetic compound that was approved by the FDA for anesthetic use in 1970 and has been available as a medicine since then including as a tranquilizer in animals. It is currently in limited use in academic-established ketamine infusion therapy clinics in the US, Canada, the UK, and Australia (among other places) for various conditions including depression, anxiety, bi-polar disorder, PTSD, OCD, suicidal ideation, chronic pain, fibromyalgia, and reflex sympathetic dystrophy.

Ibogaine. Ibogaine is a compound extracted from the root of an African rainforest shrub Tabernanthe Iboga native to Gabon. It has been studied mostly for potential treatment of SUD including alcohol, opiates, and methadone and private Ibogaine therapy clinics focused on SUD treatment have appeared in countries where it is legal or unregulated, largely in Latin America.

MDMA. MDMA (3,4-methylenedioxy-methamphetamine) is a synthetic compound that stimulates the central nervous system. It is not viewed as a traditional psychedelic compound in that it does not induce hallucinations. One of its classic side effects is that it can generate empathy and it has high potential for misuse. However, as a medicine it has been designated by the FDA as a Breakthrough Therapy for the treatment of PTSD via MDMA-assisted psychotherapy with Phase III clinical trials currently underway in the US and Europe, with interim findings encouraging. It is also being studied as a potential intervention for anxiety in terminal ill patients and social anxiety in autistic adults.

In addition, the compound DMT (N,N-Dimethyltryptamine), most commonly experienced through consumption of an Amazonian ‘tea’ known as Ayahuasca comprising a combination of plants, is being studied for its treatment of many of the psychological problems identified above. It is in widespread informal use across the Americas for such purposes along with spiritual and recreational practices.

The attraction of psychedelic medicines is not merely a function of their potential value as therapeutics. It is also true that many existing pharmaceutical medications such as anti-depressants can have numerous negative side effects. Patients and, to an extent, regulators are receptive to new treatments that avoid these side effects. A similar narrative exists with cannabis, particularly in the area of chronic pain management where heavy-duty opioids are increasingly unpopular with both those stakeholder groups and also for general anxiety indications.

Psilocybin for example cannot be patented and owned by a company.

The role of intellectual property
The bedrock of the pharmaceutical industry, of biotech innovation and of drug development is intellectual property, primarily patents. The rationale for drug development is clear: biotechs and big pharma companies don’t have the incentive or funds to invest tens, sometimes hundreds of millions of dollars in developing and testing a new formulation, drug or therapeutic, that will often – in practice, nearly always – fail in clinical trials or in the regulatory approval process if they receive no intellectual property (IP) protection in return, allowing others to piggy-back or leap-frog without incurring the capital expenditure and risk of failure. The grant of a patent is what draws capital into the biotech arena and what leads to important clinical breakthroughs, just as we have seen with COVID vaccines.

In the psychedelic medicine arena, as it is with cannabis and other natural therapeutics, the situation is complex. First of all, plants, fungi, and products in nature cannot be patented. Psilocybin for example cannot be patented and owned by a company. These naturally occurring compounds belong to the public already and indeed, in patent terminology, they effectively amount to “prior art” that predated the patent application. Secondly, many psychedelics such as psilocybin (from certain fungi), mescaline (from peyote cacti), ibogaine (from an African rainforest shrub) and DMT (the psychoactive ingredient in Ayahuasca) have been used either as therapeutics or in religious or other ceremonies by indigenous peoples for thousands of years, again creating prior art that is legally and ethically challenging for biotechs seeking patents even where that prior art is not written down in a medical journal but based on oral history and cultural evolution.

And yet, there is a patent goldrush on-going around psychedelics as the biotech companies that have entered the space – as many as 200 currently – jockey for protection around their solutions and to raise capital. Much of their IP activity focuses on new or altered molecular compounds or new formulations of the base compound that improve on the natural source drug. Others focus on novel uses, novel delivery mechanisms or on novel manufacturing methods. Patents have already been issued and it is raising a debate about the ethics of ring-fencing what many see as ‘Nature’s gift’.

Whilst it is hard to argue against the patent-R&D trade-off in the biotech arena, the area where the public have a very legitimate interest in allowing natural solutions to flourish is in pricing. As we have seen before, the end pricing of novel pharmaceuticals is often such that only insurers can afford to cover their cost. And in a not-so-virtuous circle, only FDA-approved drugs will typically be accepted by insurers, effectively locking out natural solutions even where the efficacy and safety have been proven over perhaps thousands of years. In the US this leads to super-high premia for healthcare cover. In other countries where drug price controls are more actively policed, or in single payer systems like the UK’s NHS, where budgetary concerns remain a constant political issue, regulators face a tough choice between allowing natural therapeutics to enter the mainstream clinical space without the same level of clinical trial rigor but keeping pricing low or only allowing highly tested, regulated and IP-protected but high-cost therapeutics to dominate. In virtually no other domain – with the possible exception of cannabis in the future, when big pharma inevitably steps in – is this debate going to color our field of vision more than psychedelic medicines.

There are several companies listed on NASDAQ and NYSE with Psychedelic medicine as their core solution…

Some commentators believe that the psychedelic market can be greater than US$100bn and/or bigger than medical cannabis.

Psychedelics as an investment opportunity
There are several companies listed on NASDAQ and NYSE with psychedelic medicine as their core solution including two, COMPASS Pathways and Atai Life Sciences, with billion-dollar market caps. With the experience of cannabis fresh in the memory, many investors have identified psychedelics as the next big thing. Some commentators believe that the psychedelic market can be greater than US$100bn and/or bigger than medical cannabis. They identify the vast and exponentially growing incidence of mental ill health, from PTSD in the military to TRD (with existing pharmaceutical solutions ineffective and/or unpopular with patients) to an epidemic of general anxiety and depression fueled by modern lifestyles and the recent pandemic. Clearly, the cost to society is vast and estimated to be north of US$1 trillion when reduced to economic factors. With all that in mind, there will be many winners. Equally, as we saw with cannabis, anytime there is a goldrush mentality among investors, not every company will succeed or provide investors with the reward their risk-taking required. Sub-sector and company selection, timing and luck will all have their say.

As it stands, a large proportion of the companies seeking funding are chasing the same patients through their own therapeutic solutions, many patent pending. Some are segregated by target jurisdiction, with competition held back pending international expansion through additional regulatory approvals and patents. It seems inevitable that there will be well-funded losers as well as winners as the competition plays out and product overlaps crystallize. New sub-sectors are emerging, as they did in cannabis before, focused on cultivation, production technology, testing, certification support, logistics and so on and only as the industry matures will it be evident where the innovation, IP, competition, and margins unlock most value in the entire value chain.

As far as discernible trends go for would-be investors to track, the following stand out.

Isolates vs Natural Compounds. As trailed in the IP section above, it’s not yet certain that patented synthesized molecular compounds (isolates) will achieve the efficacy, safety and regulatory approvals required to dominate the medicinal arena or whether the natural compounds, in combination with clinical psychotherapy approaches, will gain more traction with insurers, clinicians, therapists and ultimately patients. There is a parallel analysis with cannabis where, several years after legalization in more than 30 US States and close to 50 countries, the vast majority of expenditure on medicinal cannabis (perhaps over 99%) is on full spectrum (naturally occurring) solutions rather than isolates. Part of this is about pricing and part the absence of Big Pharma (to date) but there is also strong efficacy-related science potentially at play with studies suggesting that the so-called ‘entourage effect’ whereby the dozens of cannabinoids, terpenes, and other active ingredients of the entire plant act in concert to generate better results by contrast with the synthesized sub-molecular compounds that currently exist. For this situation to translate to psychedelics, there will need to be significant investment and innovation in industrial scale cultivation and production technology and infrastructure that can produce consistent, pharma-quality products from plants and fungi. Equally new regulatory frameworks will need to be established that accommodate the production, storage, transportation, and dispensing of these products and at the same time provide patients and the public generally with the safety standards expected of any medicine. Having seen this happen with cannabis, there should be no reason why those same regulations cannot be expanded to psychedelic compounds.

Treatable Conditions. As more research is completed the number of indications for which psychedelic medicines may be approved will determine the ultimate market potential. Tackling various forms of depression alone will render the sector of blockbuster potential. Equally, translating successful medication to the clinical setting may give rise to a paradox that tamps down the potential market size. Some studies have shown that single doses of psilocybin can provide long-term relief from anxiety and depression, echoing early work with LSD for alcoholics. This has also been seen with Ibogaine treatments for SUD. Such findings reduce the potential revenue opportunity for the medications at work.

Clinical Setting. An adjacent point relates to the overall delivery mechanism for treatment. Much research suggests that “set and setting” have a crucial role to play in the effective administration of psychedelic therapies. Set refers to the mindset of the patient entering the therapy and setting the physical environment where administration of the medicine and therapy occurs. Both emphasize the role of a holistic approach rather than a traditional pharmaceutical one. Collectively set and setting are likely to sustain the private clinic and therapy setting models that have traditionally favored natural compounds rather than pharmaceutical isolates, to an extent leveraging the scientific practices of the 20th century and even the original context of the use of psychedelics by indigenous peoples.

Regulatory Overhaul. Perhaps most significantly, the investable market is ultimately a function of the regulatory market. Although the legislative developments referenced earlier are deeply encouraging, as we have seen with cannabis in the US, which remains federally illegal even for medicinal purposes, until a jurisdiction rolls back its long-held conviction about the misuse of drugs, patients cannot become customers. Moreover, with some psychedelic biotech valuations already sky high, investors will wish to understand the extent to which regulatory relaxation is already priced in to some stocks.

One thing seems clear, the market is real, large, fulfils an important societal need and consequently is here to stay. It is investible today with the right guidance and opportunity and it is inevitable that significant returns will be made by many that have those factors covered.

In a May 2020 study conducted by Prohibition Partners of 1,000 adults from the US and UK (500 each) 51% agreed with the statement ‘I support the legalization of psychedelics for medicinal purposes’, and only 13% disagreed.

A note on stigma
Psychedelic compounds and their natural sources remain illegal in most jurisdictions around the world, primarily as a result of the US-led “war on drugs” from the late 1960’s and early 1970’s. In the US, the foundational legislation is the Controlled Substances Act of 1970, in the UK it is the Misuse of Drugs Act 1971 and internationally there is the UN Convention on Psychotropic Substances of 1971. Other countries have their own criminal frameworks, many extremely draconian. For many individuals, funders and indeed regulators and law-makers that is enough to turn away from this sector, as it has been with cannabis before. Even casual observers feel the stigma of association with mere intellectual enquiry. Yet this approach is both deeply unscientific and inconsistent with the legal status of many prescription-only drugs such as Fentanyl and other opioids that continue to be accepted within our pharmacopeia despite enormous abuse both within a regulated clinical environment and “on the street”. There are other startling inconsistencies to be found in some European countries where euthanasia is available to patients with certain psychological suffering conditions, but the use of psychedelic medicines is not!

Moreover, as with cannabis, the psychedelic medicine train has already left the station, driven by deep scientific study showing efficacy and safety. Public opinion in, for example, the US or UK is already and surprisingly in favor of greater loosening of restrictions, especially but not exclusively around clinical research. In a May 2020 study conducted by Prohibition Partners of 1,000 adults from the US and UK (500 each) 51% agreed with the statement “I support the legalization of psychedelics for medicinal purposes”, 36% were unsure or don’t know and only 13% disagreed. In the case of cannabis, the intellectual dishonesty still perpetuated among some interest groups as regards comparisons between cannabis-based medicine and opioid medicines for indications such as chronic pain management, especially of the related side effects, is palpable. In my opinion, and each has their own, we are now at the “wrong side of history” point for those seeking to deny access to these life-changing therapeutics or even those who merely fear engagement with the intellectual debate. Now is the time to educate ourselves on the opportunities psychedelics (and cannabis) offer for medical advancement and the issues that must be confronted to provide safe and reliable access for patients.

By Tom Speechley

Mounting research in the last two decades has uncovered the critical influence that the diverse microbes in our gut have on our overall health. Varied studies worldwide have linked a balanced gut microbiome to immune system competence, regulation of our metabolism and psychological wellbeing. Imbalances, by contrast, have been linked to the development of multiple inflammatory disorders, several other disease categories and ageing itself. In this article, we explore current scientific opinion on the integral role of gut microbiota in health, disease and longevity, the impact of lifestyle factors and furthermore, how in practical terms we can optimise the health and balance of our microbiome.

Imbalances… have been linked to the development of multiple inflammatory disorders, several other disease categories and ageing itself

Introduction

We commonly associate microbes, including bacteria and viruses, with disease. However, in contrast with the pathogenic microbes that can invade our bodies, a huge number and diversity of microbes live in and on our bodies, with a significant beneficial role in our health. In fact, the population of such organisms is thought to be just above our own cell count [Sender R., et al 2016].

These beneficial microbes are found in several locations including the skin, gut, oral cavities, vaginal lining and respiratory airways, and in turn, they help support our normal tissue and organ functions. By far the greatest number are housed in the lining of the intestines. Their collective name is the gut microbiota, and their combined genes are referred to commonly as the gut microbiome. They constitute a complex ecosystem dominated by bacteria, but also another type of prokaryote, known as archaea. In addition, there are yeasts, other fungi and viruses. Bacteriophages, viruses that specifically infect bacteria, make up most of the viral count.

Over the last two decades, there has been a significant increase in research focusing on the gut microbiome, much of it trying to understand the nature of the continual ‘cross-talk’ between the constituent organisms in the gut and us, as hosts. Studies have identified an essential function for this interaction in maintaining good health, coupling the gut microbiome to immunity, digestion, energy metabolism, and blood glucose regulation.

Research has also firmly implicated an imbalance in the gut microbiome in diverse diseases. These include, but are not confined to, allergic conditions, neurodegenerative disease, anxiety, depression, inflammatory bowel conditions, obesity, type 2 diabetes and several cancers.

As such, the gut microbiome has become a significant target for therapeutics.

What then is the gut microbiome’s role in immunity and disease?

…a perturbed gut microbiome has been linked to several diseases that exhibit pro-inflammatory effects or auto-immune states… including allergies, atopic disease such as asthma, eczema, and atopic dermatitis, irritable bowel syndrome, ulcerative colitis, obesity, type 2 diabetes and several cancers

 

Immune function
The gut forms a critical concentration point for many of our immune cells. In fact, a huge proportion of our immune system’s focus is aimed at controlling our body’s interaction with the gut microbiome. Immune cells congregate and work in conjunction with the linings of the intestine and a mucus layer to produce an effective ‘barrier’ against our microbiome. This is sometimes referred to as a ‘mucosal firewall’ and it acts to prevent an unintended immune response against beneficial microbes. The interactions and responses of our immune cells here are thought to have far-reaching beneficial consequences to our body’s immunity as a whole.

Hence, the constituents of our gut microbiota can control pathogenic invaders in diverse ways, including producing antimicrobial proteins and molecules that adversely affect the survival and virulence of pathogens or competing directly for nutrients. For example, short chain fatty acids, produced by our microbiome by a fermentation process in the colon (discussed further below) have an anti-inflammatory effect mediated via the immune system. Moreover, several beneficial or ‘commensal’ bacteria types in the gut are known to synthesise vitamins, including B2, B6 and B12 vitamins, known to be essential for immune functioning [Belkaid,Y 2014].

Chronic inflammation and auto-immune disease
There is a growing recognition that many of our major disease categories result from chronic inflammation caused by imbalances in the proper functioning of multiple bodily systems. Moreover, a perturbed gut microbiome has been linked in research studies to several diseases that exhibit pro-inflammatory effects or auto-immune states, where the immune system erroneously attacks non-pathogenic cells causing chronic inflammation. This implicates disease categories including allergies, atopic disease such as asthma, eczema, and atopic dermatitis, irritable bowel syndrome, ulcerative colitis, obesity, type 2 diabetes and several cancers.

Allergies and atopic disease
There has been a significant rise in the incidence of allergic and atopic diseases, specifically in developed countries, over the last few decades. Many research groups have hypothesised this may be due to excessive hygiene as part of a Western lifestyle, that reduce infant exposure to microbes, including the beneficial ones that populate our gut. Furthermore, this could go on to disrupt immune responses resulting in hypersensitivity and disease development [Noverr, MC et al., 2004]. This is an expansion on the original ‘hygiene hypothesis’ by Strachan in 1989, that attributed atopic diseases to a reduced exposure to infections in infancy.

A host of clinical research studies suggest a strong link between changes in the gut microbiota, as well as those of the skin and respiratory tract, to allergic and atopic diseases [Huang, YJ. et al.,2017]. A large scale cohort study in The Netherlands examining nearly 1000 infants, concluded there were distinct differences in the guts of infants that went on to develop atopic diseases versus their healthy counterparts. An increased population of Escherichia Coli was present in those who developed eczema, with a direct correlation between the levels found and disease development. In addition, increased levels of Clostridium Difficile were associated with all atopic diseases (eczema, asthma, allergies and atopic dermatitis) [Penders, J. et al., 2006].

To summarise, the maintenance of a healthy gut microbiome could be critical to combatting cancer and a patient’s treatment success

 

Cancer
There is increasing evidence that the gut microbiome can significantly influence the development of certain cancers and a patient’s subsequent response to cancer therapies.

Several research studies have shown that dysbiosis in the gut microbiome can be a risk factor for developing colorectal cancer. An increased inflammatory state, altered immunity and the production of toxins from unhealthy bacteria are thought to contribute to the disease process. On the contrary, increased amounts of short-chain fatty acids (SCFAs), a metabolite produced by certain types of commensal bacteria in the gut have been shown to have a protective effect [Rowland L, et al 2018; Zou S., et al 2018]. We discuss SCFAs further below in the section on diet.

A cancer treatment known as immunotherapy, (covered in our previous paper), manipulates a patient’s own immune system so that it attacks and targets tumour cells. A recent study, showed that patients with a disrupted gut microbiome due to antibiotic consumption, had a poor response to cancer immunotherapy. The patients in the study were being treated for lung and kidney cancers, by a class of drugs known as immune checkpoint inhibitors (ICIs). All non-responding individuals were found to have low levels of a specific healthy bacterium Akkermansia muciniphila in their gut [Routy et al 2019].

In two other studies in melanoma patients, the best responses to immunotherapy were seen in those with a healthy gut microbiome. Conversely, non-responding patients had a disrupted or imbalanced gut microbiome [Matson et al., 2018].

Other research studies, that focussed on stem cell transplants for haematologic cancers (also known as blood cancers), showed patients with the best survival and response rates had a higher level of microbiome diversity when treatment started [Taur et al., 2014]. Some studies also showed the presence of known beneficial bacterial species in patients was associated with a reduced risk of relapse [Peled et al., 2017].

To summarise, the maintenance of a healthy gut microbiome could be critical to combatting cancer and a patient’s treatment success. The manipulation of gut microbiota through probiotics, prebiotics or fecal transplantation is currently under investigation through a number of ongoing clinical trials in cancer patients. The outcomes could prove critical in helping to improve outcomes and reduce the toxic effects of cancer therapies [Gopalakrishnan et al., 2018].

Obesity
Several studies have shown that differences in gut microbiota are intrinsically linked with obesity and metabolic syndrome. A study in 2018 showed that fecal microbiota transfer (FMT) – literally a transfusion of fecal matter from one host to another* – from an obese mouse to populate the gut of a germ-free mouse resulted in rapid weight gain [Turnbaugh, P et al., 2006]. What’s more, other studies have shown that the microbiota from obese individuals have an increased capacity for energy harvest from nutrients, and may increase intestinal permeability and endotoxin levels in the blood.

* Fecal microbiota transfer is an infusion through the colon, or delivery through the upper gastrointestinal tract, of stool from a healthy donor to a recipient with a disease believed to be related to an unhealthy gut microbiome

There has been increased reference in the last 5 years of the potential application of FMT, to treat diseases beyond gastrointestinal disorders where a perturbed gut microbiome is implicated.
There have been several clinical trials for the treatment of atopic disease and allergies, and obesity with inconclusive results. Some preliminary success has been observed for inflammatory bowel disease (IBD), irritable bowel syndrome, ulcerative colitis and metabolic syndrome, but further research is needed before wider use in patients [König, J et al., 2017; Zeng, W. et al 2019]

The ‘leaky gut’ hypothesis

The leaky gut hypothesis has been touted in many lay and scientific publications as a mechanism for disease development. The assertion underlying the hypothesis is that physiologic stressors such as dietary components, anxiety, or intense exercise can enhance the permeability of the intestinal mucosal membrane, specifically the ‘tight junctions’ between cells, thereby increasing entry of pathogenic bacteria, bacterial toxins and even food matter into the body’s circulation, causing inflammation and triggering numerous diseases or allergic reactions. However, whilst some continue to support this hypothesis [Bischoff, SC. et al., 2014; Mu, Q et al., 2017; Chakaroun RM et al 2020], other groups argue that there is a distinct lack of high quality scientific data to support this theory at present [Hollander, D. et al., 2020].

The gut is therefore a new and emerging target for health interventions in the field of psychiatric disease

 

The relationship between the gut microbiome and the brain

There are many pathways elucidated by researchers that connect the gut and the brain. The latter is referred to as the ‘gut-brain-axis’. For example, some neurotransmitters and metabolites that affect the brain are synthesised in the gut.

The role of gut bacteria in mood disorders has been investigated in a number of studies showing that individuals suffering from depression had altered gut microbiome diversity and composition compared to healthy individuals [Zheng, P. et al., 2016; Jiang, H et al., 2015]. Furthermore, these changes were also related to depression-like symptoms seen in rodent models [Kelly JR, et al., 2015]. The gut is therefore a new and emerging target for health interventions in the field of psychiatric disease.

Animal studies have bolstered the idea that gut microbes can influence the brain. Rats given fecal transplants from people with depression went on to develop the rodent equivalents of those problems. Conversely, giving those animals fecal transplants from healthy people sometimes relieved their symptoms [Kelly JR, et al., 2016]. Similar studies have been carried out for other diseases affecting the nervous system, including Parkinson’s disease and schizophrenia with varied and inconclusive outcomes [Bastiaanssen, TSF. et al., 2019].

Having considered the critical importance of a healthy gut microbiome for good health and prevention of disease, what constitutes a healthy gut microbiome and how is it created and fostered?

…a dominance of beneficial microbial categories coupled with a high-degree of diversity is what constitutes a healthy gut microbiome

 

What constitutes a healthy adult gut microbiome?

It is interesting to note that whilst the function of the gut microbiota is conserved between individuals, the make-up of a healthy adult’s microbe population varies greatly. Therefore, there is no single blueprint. However, we do know that certain microbiota categories have beneficial effects in the gut, whilst others are detrimental.

Additionally, microbial diversity in the context of the gut microbiome is seen as beneficial — as when one population of commensal bacteria is affected, another similar strain can step into its role, minimising any disruption to health. Diet is a significant contributory factor to increasing microbial diversity, and the prevalent microbe populations in our gut, as we will discuss further below.

Simply put, a dominance of beneficial microbial categories coupled with a high-degree of diversity is what constitutes a healthy gut microbiome.

How is our gut microbiome populated?

There is increasing evidence that the gut is not sterile when we are born, and its population with microbes actually starts in the womb, possibly sourced from the amniotic fluid and the placenta [Walker, RW. et al., 2017]. However, studies indicate that the gut of infants only becomes more densely populated with microbes during and after birth. Mother-to-baby transmission of microbes is often observed, with a newborn’s gut flora being different based on delivery method. Vaginal delivery results in a transfer of Lactobacillus and Prevotella, whereas those children born via Caesarean section acquire more Staphylococcus, which are more characteristic of the skin microbiome [Korpela, K. et al 2018].

Infants have been shown to share up to 30% of their gut microbiome with their mothers, further supporting the notion of maternal transmission of the gut microbiome to infant [Palmer, C, 2007]. However, some bacterial strains that are present in a mother’s gut, like Clostridia are not seen in the infant, suggesting there is some degree of selection. Subsequent to delivery, the intake of colostrum, breast-feeding, and environmental exposure go on to further influence the microbial composition.

Our gut flora starts to stabilise at the end of our first year of age. In later childhood, the similarity of our bacterial population to that of our mother declines, and is influenced more by more diverse lifestyle factors including the wider family members, and environment [Korpela, K. et al 2018].

In addition to such early-stage life factors, the adult gut microbiome is influenced by diet, body mass index (BMI), age, genetics, exercise frequency, lifestyle factors, medication, environmental stress and cultural habits. Perhaps not surprisingly, diet is seen as the most prominent lifestyle factor in shaping and modulating the human gut microbiota.

Numerous clinical trials and studies have shown that a high-fibre diet increases the microbial diversity of healthy bacteria in the gut

 

Can we change and optimise the gut microbiome through our diet?

Complex carbohydrates, dietary fibre and short chain fatty acids
Carbohydrate digestion happens in two principal ways. First, non-resistant starch and simple sugars are digested in the small intestine, where they become available for metabolism by the body. Secondly, more complex carbohydrates and resistant starches, that are indigestible in the small intestine, require bacterial fermentation in the large intestine to be broken down, in effect nourishing the commensal microbes present there. Complex carbohydrates that follow this secondary process are typically high in dietary fibre and include whole-grain cereal, fibrous vegetables and fruit.

A low F/B ratio is associated with a lean body type and a high F/B ratio is associated with an obese body type

 

Numerous clinical trials and studies have shown that a high-fibre diet increases the microbial diversity of healthy bacteria in the gut [Candela, M. et al., 2016; García-Peris, P. et al., 2012; Hoschler, HD. et al., 2014]. What’s more, high dietary fibre intake has been known to reduce the ratio between two key types of bacteria in the gut — Firmicutes and Bacteroidetes —referred to as the “F/B ratio.” A low F/B ratio is associated with a lean body type and a high F/B ratio is associated with an obese body type. Obese individuals commonly show a perturbed gut microbiome, as discussed earlier in this paper.

Another benefit of high fibre intake is that it encourages the growth of bacterial species that ferment fibre into short chain fatty acids (SCFAs). There are several documented positive health effects of SCFAs that include improved immunity, blood–brain barrier integrity, anti-inflammatory activity in the gut, an anti-cancer role in the colon and glucose and cholesterol regulation [Rowland, L., et al 2018]

Prebiotics and probiotics
Prebiotics are a sub-category of the complex carbohydrates that help feed our commensal gut bacteria and increase SCFA production. Common foods that contain prebiotics include raw garlic, leeks, chicory, onion, asparagus, banana and apples. Probiotics, on the other hand, directly introduce ‘live’ commensal bacteria into our gut and are present in live yoghurt cultures and fermented foods such as kimchi, sauerkraut and miso. They have also been shown to be beneficial for overall gut health [Markowiak, P., et al 2017; Sergeev, IN., et al 2020]

Detrimental effects of saturated fat
Diets high in saturated or total fat have consistently been shown to have detrimental effects on the gut microbiome composition and diversity [Wolters M., et al., 2019]. In particular, studies show saturated fats, such as animal-derived fats, lower the levels of microbes associated with good gut health, whereas unsaturated fats, such as olive oil, both increase the abundance of good bacteria and reduce harmful bacteria.

Further studies have also linked excesses of saturated fats sourced from milk or meat products with higher levels of anaerobic bacteria that have been implicated in inflammation in the gut and colorectal cancer [Peck, SC et al., 2019].

Negative influences of animal-derived protein
Several clinical and preclinical studies suggest that both the type and amount of protein in the diet have diverse and considerable effects on the gut microbiome. Studies in humans showed that individuals consuming large amounts of animal protein, mainly from beef, that incidentally also contains high levels of saturated fats, showed reduced bacterial diversity due to the loss of those groups required to digest plant derived carbohydrate [David, LA, et al., 2014].

Additionally, studies in animal models indicate that a diet dominated by animal based-protein results in an increase in detrimental gut microbiota and is linked to a pro-inflammatory gut profile. Conversely, one that is high in plant-protein and complex carbohydrate shows beneficial diversification of gut microbes [Yang, Q, et al., 2020].

Evidence also suggests that very high protein diets, including those supplemented with high protein drinks can have harmful effects. In a 70-day study that followed healthy athletes who supplemented with a protein drink, adverse effects were seen with a significant decrease in health beneficial microbiota [Moreno-Pérez, D., 2018].

Beneficial effects of polyphenols
Animal and human clinical trials have shown that polyphenols, like flavonoids, phenolic acids, stilbenes, and lignans (commonly found in fruits, vegetables, tea, coffee, and red wine) are thought to have prebiotic-like activities in the gut, imparting health benefits and reducing inflammation [Santino, A. et al 2017]. Furthermore, the intake of Vitamin A, C, D, and E have been shown to have a positive influence on health-beneficial microbes [Yang, Q, et al., 2020].

What other major factors influence the gut microbiome?

Getting a good night’s sleep
A recent study in 40 participants found that gut microbiome richness and diversity, are positively correlated with increased sleep efficiency and total sleep time. Conversely, there was a negative correlation with subjects who experience fragmented sleep [Smith, RP et al., 2019].

Another study, which focused solely on 37 older participants >65 yrs, noted increases in diversity in different groups of bacteria were associated with better sleep quality and cognitive function in advanced age [Anderson, JR. et al., 2017].

Exercise – keeping it regular and moderate
An increasing body of evidence indicates that regular aerobic exercise confers an independent beneficial influence over the human gut microbiome. In human models, moderate exercise, over a longer time scale of weeks rather than days, has been linked to notable positive changes.

Regular moderate exercise has been shown to decrease inflammation and its mediators in the gut. Indeed, several groups have suggested moderate exercise as an intervention for multiple inflammatory conditions. [O’Sullivan, O, et al., 2015 and references therein] .

Alcohol – a general disruptor
Alcohol is another dietary disruptor of the intestinal microbiota. Numerous studies have shown changes in alcoholic individuals, with or without liver disease, that result in a pathogenic disruption in the gut microbiome. A multitude of effects, reviewed in Engen et al., 2015, included bacterial overgrowth in the small intestine and a significant increase in potentially dangerous bacteria and toxins.

The only positive correlation for gut health and alcohol was seen with a limited intake of red wine, either a standard or de-alcoholised version (max of 272 ml/day) in a randomized control trial that resulted in an increase in certain healthy bacteria that has been linked to the polyphenol content of red wine providing beneficial prebiotic effects [Queipo-Ortuño MI, et al., 2012].

Smokers – a disrupted microbiome
Smoking was shown to induce imbalances in the gut microbiome in a small cohort study by Bidderman et al. in 2013. Furthermore, it has proven links to some chronic disease associated with the gut. For example, cigarette smoking is considered to be one of the most important lifestyle risk factors in developing inflammatory bowel disease [Danese et al., 2004].

A large scale study in Korea compared the gut microbiome of men who had never smoked, had quit smoking, or were current smokers, whilst controlling for all other variables. They observed that current smokers had a high F/B* ratio. This is something that’s normally associated with being predisposed to metabolic disease and obesity. Those who were former smokers or had never smoked had similar gut microbiota, suggesting that your microbiome returns to normal after smoking cessation [Lee et al., 2018]. Animal models of smoking have also shown increases in inflammatory markers in the gut.

(*Firmicutes and Bacteroidetes ratio —referred to above in the section on ‘Complex carbohydrates, dietary fibre and short chain fatty acids)

Stress – problematic over the long term
A number of research groups have linked an elevated stress response and stress-related disorders to dysregulation of the gut microbiome. Conversely, treatment with prebiotics and probiotics has been shown to attenuate the stress response in animal and in human studies [Foster, JA. et al., 2017]. A recent study showed that introducing certain bacterium into the diet through probiotics helped reduce anxiety and the stress response in healthy volunteers. [Allen AP et al., 2016].

Antibiotic depletion and the role of other drugs
The use of antibiotics is known to deplete the gut microbiome. Although antibiotics have had a vital medical role and are prescribed to help control and rid our bodies of pathogenic bacteria, they inadvertently also target the indigenous microbiota present in our gut. They can reduce bacterial diversity, and change or redistribute the microbe composition, in a transient or permanent manner. It should be noted that antibiotic treatment also selects for resistant bacteria in the long-run. For example, Clostridium Difficile infection (CDI) is often prevalent in patients continuously taking antibiotics [Modi, SR. et al., 2014].

The interaction between our gut microbes and other commonly prescribed non-antibiotic drugs is complex and bidirectional. The gut microbiome composition can be influenced by drugs, but, conversely, the microbiota can also impact our individual response to a drug by altering it enzymatically, and/or changing its bioavailability, bioactivity or toxicity. In studies, some routinely used drugs known to influence the microbiome include beta-blockers, ACE inhibitors, lipid-lowering statins, laxatives, metformin, and the antidepressants known as selective serotonin reuptake inhibitors [Vich Vila, A, et al., 2020]

Age factors
As we age, the gut microbiome is less diverse and unstable. It remains unknown whether this disruption of the microbiota is a cause or consequence of ageing. It has been linked in various studies to impaired sleep, changed lifestyle and dietary schedule, lesser mobility, weakened immune strength, chronic low-grade inflammation, recurrent infections and the increased use of medications [Nagpal, R. et al., 2018].

Although further studies are needed, some research has suggested that given that the gut microbiome composition is critical to healthy ageing, so its restoration can support longevity. Preliminary studies, in nematode worms nonetheless, have shown that genetically engineered probiotics could hold some promise as a new therapeutic to promote healthy ageing and longevity [Han, B et al 2017].

…strong evidence exists of the presence and diversity of specific beneficial microbes and how we as individuals can help support and promote their presence in our gut

 

Summary

Scientific reductionism has traditionally segregated the function of organs and systems in the human body. Health optimisations and interventions have often been siloed as a result. Increasing evidence supports the gut microbiome as a converging point and interface between our all our physiological systems. This favours a targeted approach, via the gut, to help maintain optimal health outcomes throughout our lifetimes and potentially protect against wide categories of disease.

Although no single blueprint of a healthy gut microbiome to attain exists, strong evidence exists of the presence and diversity of specific beneficial microbes and how we as individuals can help support and promote their presence in our gut. Dietary interventions, like consuming complex carbohydrates, fibre-rich foods, low levels of animal fats, plant-derived proteins, polyphenol-rich foods, probiotics and prebiotics can all contribute.

Other lifestyle factors, like optimising sleep, moderating alcohol, smoking cessation and maintaining regular levels of activity also have a role to play.

Whilst we cannot yet be sure of the causal or consequential relationship of the gut microbiome to disease development and ageing more generally, the disruption observed is recognised. This opens up the potential for ongoing clinical interventions, to help prevent and treat disease development and slow aspects of the ageing process. The targeted use of FMT, prebiotics and probiotics will no doubt have an ongoing role to play as new data emerges.

By Dr. Seema Sharma for SX2 Ventures © 2020

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“How do we feasibly adapt our lifestyle approaches to strengthen our immune system?”

Introduction

The immune system is critical for our overall health outcomes and well-being over a lifetime. It is integrated into all aspects of our physiology and operates to protect us from both infectious disease and non-communicable chronic illness. The idea of ‘boosting’ one’s immune system, therefore, presents an appealing focus for many to help maintain and improve health. In this article, we cover research-based strategies on how to give our immune system the upper hand.

“As a consequence, there is no magic bullet or single solution available to bolster our immunity”

 

Our immune function has evolved as a finely balanced and complex macrocosm of organs, circulating cells, proteins and regulatory molecules that protect us from all manner of invading pathogenic microbes, toxins and allergens. As a consequence, there is no magic bullet or single solution available to bolster our immunity. How do we then feasibly adapt our lifestyle to support it?

In the first instance, it’s important to recognise that the immune system operates through two complimentary functions, or responses, referred to as innate and adaptive immunity.

Innate immunity

Innate immunity includes physical barriers such as the epithelial cells that cover and line the surfaces of our bodies, the mucus that overlays them, and the microscopic hairs known as cilia that move to refresh the mucus and remove anything foreign that may have been inhaled or ingested.

Innate immunity is also provided by our white blood cells or leukocytes. Examples include dendritic cells, macrophages, mast cells and neutrophils — all with unique functions.

There are receptors on the surface of leukocytes that help produce a rapid non-specific immune response. They bind molecular patterns that are commonly expressed on a large number of foreign pathogens or toxins, and are not present in our own body [Chaplin DD. 2010]. This recognition of “non-self” is very important for an appropriate immune response. In addition, these cell types produce signalling molecules like cytokines, that cause inflammation and further increase white blood cell migration to a site of infection.

Other elements of innate immunity are circulating plasma proteins, known as the complement system. They bind to the surface of pathogens directly and mark them out for destruction.

The innate immune response is a rapid, first line of defence against an immune threat and is known to last between 4-7 days, before the synergistic adaptive immune response kicks in. [Janeway CA. 2001]

Adaptive immunity

Adaptive immune function is mediated by cells called lymphocytes, predominantly two types known as T-cells and B-cells. These cells are produced and activated by signals from the innate immune system. T-cells have different roles, including killing their target cells, or regulating the immune response. B-cells are most commonly known for their function as antibody producing cells, although they have other essential roles in the immune system [Chaplin DD. 2010].

One of the outcomes of an adaptive immune response is the creation of memory T-cells and B-cells. The other cells that have been involved in an immune reaction are cleared from the system. Memory cells carry an immunological recall and respond rapidly in the future if we suffer a repeat infection from the same pathogen. Adaptive immunity therefore is distinguished in having a memory [Chaplin DD. 2010].

Every stage of our immune response can be affected by a number of lifestyle factors. We discuss the impact of these individually, and approaches for optimisation in the rest of this article.

“Every stage of our immune response can be affected by a number of lifestyle factors”

 

The role of micronutrients for optimal immune function

We often hear reference to a study in the media of a particular mineral or vitamin being critical to the immune system, which may increase our propensity to reach for a supplement as a universal fix when we feel we’re succumbing to illness. However, the role of micronutrients is a varied and complex one. Indeed, there are numerous studies to show that vitamins A, C, D, E, B2, B6, B12, folic acid, and the minerals iron, copper, selenium, magnesium and zinc have all been found to be essential for immunocompetence [Maggini S. et al., 2018; Gombart AF. et al., 2020]. There is particularly strong evidence for an immune support function for vitamins C and D and zinc, which we will explore below. However, it’s important to note these act synergistically with multiple other micronutrients at every stage of the immune response.

Vitamin C is not, as sometimes purported, a one shot fix to all things immune, but undoubtedly has some central roles in immune function. These include, but are not limited to, acting as an antioxidant against damaging reactive oxygen and nitrite species produced when pathogens are killed, stimulating the production and movement of leukocytes, supporting the integrity of epithelial barriers, and key roles in the proliferation of lymphocytes and antibody production [Carr AC and Maggini S. 2017; Jacob RA. 2002].

Vitamin C RDA’s for adults are commonly 75mg for women and 90 mg for men [Institute for medicine US. 2000]. Although some suggest saturating plasma levels of vitamin C (100-200 mg) can be used prophylactically to reduce the risk of infection [Carr AC and Maggini S. 2017; Balz Frei et al., 2012 ]. Other peer-review suggests this may shorten the duration of infection, rather than preventing us catching it [Hemilä, H. 2013]. It’s important to note that at high doses, >1g per day, most of it will be excreted in our urine.

Vitamin D is known to have a key role in the regulation of immune function, with most immune cells possessing receptors for it. Some of its actions are an ability to promote differentiation and movement of the many white blood cells in the innate immune response, and inhibit aspects of adaptive immunity. It has also been identified as regulating antimicrobial proteins, that can help the gut in immune defence and protect the lungs from infection [Gombart, A.F. 2009].

Zinc helps maintain the integrity of skin and mucosal membranes. In addition, it has been shown to have a critical role in the function and survival of leukocytes of the innate immune system, T- cell proliferation and differentiation, the complement protein pathway and also antibody production. A decline in the functioning of the thymus (thymic atrophy) – a central organ to healthy immune function, is also seen in zinc deficiency [Gombart AF. 2020].

There is evidence to show that as we age, supplementation of key micronutrients may be beneficial as poor absorption reduces their bioavailability from a standard balanced diet [Maggini S. 2018]. This may be compounded by a less varied diet in some older individuals. So even though our overall required calorie intake reduces as we get older, our relative micronutrient requirements may increase.

In addition, individuals who smoke, have high levels of stress, or are subjected to high levels of pollution require higher micronutrient dietary intake, to counteract the deleterious effects of these factors on their stores [Gombart AF. 2020].

Our gut microbiome has a crucial role

As well as the pathogenic community of microbes we encounter during our lifetimes, many other beneficial ones exist, which use our body as a host in a commensal and mutualistic manner. They help support our normal tissue and organ functions in turn.

There are several such varieties of microbes including bacteria, archaea, yeast, fungi and viruses. Much of the viral count is made up from bacteriophages – viruses that infect bacteria. In totality, some estimates suggest that the human gut may be populated with as many as 100 trillion microbes, the majority of which are located in the colon, and whose collective genome is referred to as the microbiome.

Some microbes are ‘entrenched’ in that they are permanently housed on the gut wall, others are ingested. In addition to dietary roles like helping digestion, synthesising beneficial micronutrients and metabolising others in a useful way, our gut microbiome has been found to have a critical role in immunity.

The gut forms a central point of congregation for many immune cells. They work alongside an epithelial cell and mucus layer in an effort to produce an effective barrier against the microbiome, which is sometimes known as the ‘mucosal firewall,’ thus preventing an unintended immune response against beneficial microbes. The immune cell interactions and signalling responses here are thought to have several beneficial effects to our body’s immunity at large, such as by producing antimicrobial proteins and molecules that adversely affect the survival and virulence of pathogens.

As a result of the research into the role of our microbiome in immune system competence, it is increasingly recognised that fostering a healthy, diverse universe of microbes in our gut contributes substantially to our overall health and ability to fight disease. Not surprisingly, this also comes back to having a balanced diet of the kind referenced above. More specifically, pre-biotics – that help feed the microbiota in our gut, probiotics that include ‘live’ commensal bacteria like lactobacilli and bifidobacteria, and fermented foods have all come into favour in recent years to support microbes and maintain diversity. We will cover the gut microbiome in greater detail in our next paper, dedicated solely to this topic.

Ensure regular, high-quality sleep

The optimal sleep level according to recent research is between 7-8 hrs per night for adults [Daza EJ et al., 2019; Chaput J,P et al., 2018]. Sleep and the body’s circadian rhythm show an intrinsic link to immunity. Fluctuations are seen in the number of circulating immune cells, molecules and overall function of the immune system, during different stages of the sleep/wake cycle.

Specifically, sleep restriction has been shown to perturb immune function. In one study even a mild reduction in the amount of sleep, from 8 to 6 hrs a night for a period of 8 days, was shown to increase pro-inflammatory cytokines. Sustained levels of these pro-inflammatory markers are associated with a wide variety of medical illnesses, including type 2 diabetes and cardiovascular disease. In a separate study, sleep deprivation demonstrated an increased susceptibility to viruses like the common cold [Besedovsky, L. et al., 2012 Review].

The adaptive immune response, and associated immunological memory is thought to be initiated during sleep. For example, studies looking at the response to a Hepatitis A vaccination showed that sleep bolstered the reaction two-fold. Sleep restriction, on the other hand, reduced the response against vaccination to the influenza virus. Studies have also shown that some types of T-cells migrate to the lymph nodes during sleep, which may support the adaptive immune response. Conversely, immune cells of the innate immune system that have more immediate actions, are shown to peak during wakefulness [Besedovsky, L. et al., 2012. Review].

In summary, many research studies highlight that getting a good night’s sleep is essential for optimal immune function. Inversely, sleep restriction, or deprivation acts as a stressor to disrupt immunity, with the potential to act as a contributory factor in the development of chronic illness.

“chronic stress starts to suppress the adaptive and innate immune response by decreasing immune cell numbers and function”

 

Use techniques to minimise and manage stress

The major mediators of stress in our bodies are the neuroendocrine hormones adrenaline, noradrenaline, corticotropin-releasing factor (CRF), adrenocorticotropin hormone (ACTH), as well as the glucocorticoid — cortisol. Together these make up what’s known as the hypothalmic-pituitary-adrenal (HPA) axis — a feedback loop between the brain and adrenal gland that regulates stress. There are many pathways connecting the HPA axis and the immune system. For example, many white blood cells bind the hormone mediators of stress directly [Segerstrom SC. and Miller JE. 2004].

There are several studies examining the effects of stress on the immune system. A distinction is often drawn between short-term stress, of the ‘fight’ or ‘flight’ type — lasting minutes to hours, versus chronic or long-term stress. The latter being defined as lasting for several hours per day over weeks and months. Short-term stress can actually enhance the immune system to an extent, particularly the innate response, mobilising it against pathogens. In contrast, chronic stress starts to suppress the adaptive and innate immune response by decreasing immune cell numbers and function, in conjunction with an increase in inflammatory and autoimmune responses.

Using interventions designed to minimise the effects of long term stress in our daily lives, can therefore help maximally promote health and healing [Dharbar 2009, 2014].

Quit smoking

Smoking is known to cause cancer and increase the risk of stroke and cardiovascular diseases. In terms of the immune system, research has shown that smoking alters the development, cytokine release, and function of both innate and adaptive immune cells, with a potential to lead to pro-inflammatory responses and dysfunction in immunity. Several studies have linked smoking to auto-immune diseases including rheumatoid arthritis, Crohn’s disease and ulcerative colitis, amongst other conditions highlighted in a recent review [Qiu, F. et al in 2017].

Another study has implicated exposure to cigarette smoke (including second-hand smoke) directly to graft rejection [Wan F., et al 2012]. Whilst further research is needed to elucidate the precise mechanisms responsible for the many smoking-mediated immune effects, it is clear it has damaging outcomes. Therefore, smoking cessation should be considered to be crucial to any efforts to improve immune function.

Reduce your exposure to air pollution

Ambient pollution levels have reached concerning levels globally, with the World Health Organisation (WHO) stating that 91% of the world’s population live in areas of pollution above accepted levels. According to their estimates, outdoor and indoor (household) pollution is thought to contribute to as many as 8 million deaths combined a year. For context, this figure is comparable to the annual number of smoking-related deaths worldwide.

Air pollutants, including particulate matter, mainly deposit themselves on the respiratory airways and the cells that line them, which has been a focus for much of the research in the area. The common effects seen are increases in pro-inflammatory immune responses across multiple classes of immune cells at this location. This has been linked to exacerbations in asthma, allergy and chronic obstructive pulmonary disease (COPD), as well as reduced anti-viral responses. [Glencross, D.A., et al 2020].

Furthermore, studies have also linked air pollution to more diverse immune system problems, including effects on immune development in the neonate, and alterations in the gut microbiome in adults [Glencross, DA. et al., 2020; Dujardin, C et al 2020]

Avoid excessive alcohol consumption

Alcohol consumption has been shown to be detrimental to immune function in a dose dependent manner. Whilst low to moderate alcohol consumption does not show any significant effect, heavier drinking is shown to disrupt innate and adaptive immunity through multiple pathways.

Elevated blood concentrations of ethanol have been shown to interfere directly with the ability of white blood cells to recognise and bind endotoxin, a toxin released when bacteria are destroyed and a key marker of bacterial pathogens, resulting in an increased susceptibility to disease. Heavier drinking reduces the number of dendritic cells, that are key to activating the adaptive immune system into antibody production and pathogen destruction. Other studies have shown a reduced T-lymphocyte population, faster progression rates of viral infection, poor outcomes following injury and deficient wound healing [Molina, PE et al 2010]. Some sources suggest the gut may also become more ‘leaky’ to pathogens after chronic alcohol exposure, resulting in pathogenic molecules crossing into the blood stream [Barr, T. et al., 2017; Sureshchandra, S. et al., 2019].

To be safe, moderate or low risk alcohol consumption should be in line with current government guidelines, which in the UK are a maximum of 14 alcohol units a week or less, for both men and women – equivalent to a maximum of 6 glasses of 175ml wine, 6 pints of beer, or 10 X 25ml shots over 7 days – with designated drink free days across that period. The guidelines in the US are comparable.

Go for moderate, or vigorous, regular exercise <60 mins duration

Exercise has been shown to modulate the immune system in a complex way, dependent on the intensity and duration of the physical exertion. Some documented effects of moderate- and vigorous-intensity aerobic exercise, of less than 60 minutes duration, show a bolstering of the innate immune response. This includes the improved anti-pathogenic activity of macrophages, enhanced circulation of neutrophils and an anti-inflammatory effect. This occurs in parallel with an improved circulation of adaptive immune elements such as cytotoxic T-cells, and immature B-cells, all of which play critical roles in immune defence activity. Metabolically, this sort of exercise can also improve glucose and lipid metabolism over time [Gleeson, M. 2015].

Conversely, immune responses to the type of prolonged and intensive exercise undertaken by professional athletes, have been shown to result in transient immune dysfunction lasting from hours to days [Gleeson, M. 2015] although the long term effects are still being disputed amongst researchers [Campbell, J. 2018].

Ultimately, a lack of exercise and sedentary lifestyle can lead to obesity, that is associated with immune dysfunction, and increased risk to infections [Milner, J. 2012]. Exercise has also been shown to help mitigate the effects of ageing on immune function [Campbell, J. 2018].

A note on immunotherapy

The clear link between lifestyle adaptations and immune system competence is encouraging. We really are in control of much of our health. Moreover, medical advances have shown that our immune system can be manipulated to further help prevent and fight disease. Vaccines are a primary example of this. Here a small amount of altered or inactivated pathogen is injected that can’t in itself cause disease. It effectively hijacks our immune response so that we produce antibodies to protect us against future infection. Catastrophic and fatal diseases like Small Pox have been eradicated as a result.

Recent advances go further. Cancer immunotherapy uses several approaches to harness the power of an individual’s own immune system to attack tumour cells. For example, in chimeric antigen receptor (CAR) T-cell therapy some of a patient’s own immune cells (T-cells) are collected from their blood and modified so they specifically attack cancer cells when introduced back into the body. At present this therapy has shown to be effective in some specific blood cancers (childhood lymphoblastic leukaemia, and lymphoma) [Almåsbak H, et al 2016, Review].

Other types of cancer immunotherapies include monoclonal antibodies that specifically attach to tumour cells, identifying them for destruction by our own immune system. Vaccines are also in development, where components of different types of cancer cells are being used to try and elicit an immune response. Other approaches include administering specific signalling molecules in the immune system called cytokines. One of their mechanisms of action includes encouraging our killer T-cells to attack tumour cells.

Immunotherapies for the treatment of all types of cancer are at a preliminary stage, with applications in a limited number of tumour types. However, research and clinical trials are emerging at a fast pace, and targeted immunotherapy, annexing our own immune system offers much promise for combatting cancer in the future.

“…we can conclude that healthy-living strategies of the kinds outlined, will give our immune systems the best chance of fighting infection and much chronic disease”

 

Summary

Here we highlight that building and maintaining optimal immunocompetence requires a multi-faceted approach. The immune system is infinitely complex, with researchers still trying to decipher many aspects of its function. It is clear that immune system dysfunction can be problematic and is intrinsically linked to adverse health, including susceptibility to infection, the development of auto-immune diseases and co-morbidities, some of which can significantly reduce lifespan.

Avoiding exposure, and minimising the risk of infection sources through hygiene is very relevant in today’s climate. Furthermore, identifying the specific causes of a weakened immune system – for example nutrient deficiencies – requires clinical tests to ensure appropriate actions are be taken.

There are several lifestyle factors that we can optimise to bolster our innate and adaptive immunity. Studies to date indicate the influential effects of diet, age-related supplementation, gut health, sleep, psychological stress, air pollution, alcohol, smoking and exercise on the immune response. Whilst further research will provide further clarity, we can conclude that healthy-living strategies of the kinds outlined, will give our immune systems the best chance of fighting infection and much chronic disease.

Dr. Seema Sharma for SX2 Ventures © 2020

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“Can we feasibly optimise our lifestyles to minimise vulnerability and bolster our immune system against Covid-19, its resurgence and similar viruses?”

Introduction

Upon writing this paper, the world is in the midst of a significant health pandemic. Covid-19 appeared in China at the end of 2019, as a previously unknown disease and was declared a Public Health Emergency by the World Health Organisation (WHO) on 30th January 2020. Primary research has started to emerge from the hospitals and clinicians treating patients. So, what do we know about the implications of our current health on infection, disease prognosis and outcome? And, can we feasibly optimise our lifestyles to minimise vulnerability and bolster our immune system against Covid-19, its resurgence and similar viruses? Here, we explore some of the preliminary studies to help gain insights.

Covid-19 (also known as 2019-nCoV or SARS-Cov-2) has been identified as a novel betacoronavirus. Coronaviruses encompass a large family of pathogens that cause respiratory infections, including the common cold and more severe diseases such as Middle East Respiratory Syndrome (MERS) and a precursor to Covid-19 — Severe Acute Respiratory Syndrome (SARS). MERS, SARS and the currently circulating Covid-19 are zoonotic diseases, which means they have jumped from infecting animals to humans. [Zhang et al., 2020].

The first line of defence against viruses is to avoid contagion sources. This has resulted in affected countries introducing social distancing measures— to avert the spread of Covid-19 by the inhalation of infected respiratory droplets from others. The message for good hand hygiene and repeated, thorough hand washing using soap and water, to avoid picking up the virus through contact and transferring it to airways, has also been enforced.

“We need to glean insights from any research observations from the current pandemic to ensure precautions for our immediate health are taken, and in addition, take stock for future resurgences of the disease or related viruses.”

 

The body’s primary defence against viruses is innate immunity. This includes the physical and chemical barriers of the body, plasma proteins and a range of immune cells, which help elicit responses to protect tissues and attack any foreign invading pathogens. This is followed by an adaptive immune response, where highly specific antibodies are produced against a pathogen to provide immunity from re-infection long-term. Much of what we currently know about the innate and adaptive immune response to Covid-19 are from previous studies on SARS patients. There is evidence that some of the individuals infected with SARS produced antibodies that conferred them with immunity for up to 2 years [Wu LP, et al 2007].

Research on the novel virus is emerging. It is being expedited into the public domain, sometimes prior to peer-review by other scientists, in an effort to maximise help with global health responses. We need to glean insights from any research observations from the current pandemic to ensure precautions for our immediate health are taken, and in addition, take stock for future resurgences of the disease or related viruses.

A true halt to the pandemic would require a viable vaccine, or alternatively a successful drug treatment, fully validated as being effective through clinical trials. As of now, there are several commercial and academic research groups working on a combination of 115 vaccines against SARS-Cov-2. Human clinical trials are now underway for 5 vaccine candidates [Tung Thanh Le et al., 2020]. The drug treatment landscape has anecdotal evidence of efficacy from small cohorts of Covid-19 patients treated globally. These need validation and there are currently some 80 drug clinical trials in progress, as a result. Many companies have made their anti-viral drugs available for testing. It may be months of testing and optimisation before a vaccine or drug is available for the general population. [Rosa, Santos, 2020; Ekins et al 2020].

So what do we know about the implications of what an individual’s current health may have on infection, disease prognosis and outcome? Are there any lifestyle changes we can feasibly take as individuals to minimise vulnerabilities to both Covid-19, it’s resurgence or other coronaviruses? We explore some of the emerging research to help answer these questions below.
 

Emerging observations on co-morbidities and Covid-19

“Many [studies] have linked a number of underlying health conditions with the severity of illness and a risk of mortality in their observations. These include cardiovascular disease (CVD), obesity, hypertension, diabetes, chronic obstructive pulmonary disease (COPD), a weak or compromised immune system, and advanced age.”

As the pandemic has gripped the globe, primary data and observations have started to emerge from hospitals and clinicians at the forefront of treating patients suffering with Covid-19. At present, there are a limited number of studies, mainly done in China. Many have linked a number of underlying health conditions with the severity of illness and a risk of mortality in their observations. These include cardiovascular disease (CVD), hypertension, diabetes, chronic obstructive pulmonary disease (COPD), obesity, a weak or compromised immune system, and advanced age. Another observation is that more men than women are being treated in hospital from the severe form of the disease. The reasons for this are still not clear.
 

Cardiovascular disease

A meta-analysis from several studies, covering 1527 patients in Wuhan, China, where the outbreak first started, showed that those with pre-existing cardiovascular diseases (CVD), hypertension and diabetes had a much higher chance of having a severe form of Covid-19 requiring intensive care (ICU) treatment. These were two-fold of those of patients who didn’t have the condition, in the cases of diabetes and hypertension, and three-fold higher in individuals with CVD [Li et al., 2020]. Note that this study is a pre-publication and yet to be peer-reviewed by the scientific community.

Authors of a peer-reviewed, single centre study from 179 patients with Covid-19 induced pneumonia admitted to Wuhan Pulmonary Hospital, between Dec 2019 and Feb 2020, also identified pre-existing cardiovascular or cerebrovascular diseases as one of four predictors of mortality [Rong-Hui Du et al., 2020]. This was alongside an age >65 yrs, low levels of circulating CD3+CD8+ T lymphocytes (immune cells essential for killing infected cells and combatting viral replication, amongst many other essential roles) and cardiac damage (demonstrated by elevated levels of the protein troponin).

Another descriptive analysis published in the medical journal The Lancet noted the clinical observations, demographics and lab testing data of 99 patients who developed the severe form of Covid-19 in a single hospital in Wuhan [Chen, Nanshan et al., 2020]. They observed that 68% of these patients were men, the majority of whom were aged 50+, with underlying health conditions. The most prevalent of these illnesses was cardiovascular disease (40% of patients). Other major groups were digestive diseases (11%) and endocrine system diseases (11%). The latter encompassed diabetes. Immune disfunction was also recorded in these patients, including elevated levels of neutrophils (a type of white blood cell that is part of the innate immune response producing signalling proteins called cytokines) and a decrease in T-lymphocytes in many patients. We discuss the significance of some of the key components of the immune system later on in this paper.

It is important to acknowledge that the Covid-19 infection has been shown to produce pneumonia-like symptoms that aggravate damage to the lungs and heart, as the disease progresses. Elevated markers for inflammation, cardiac damage and low oxygen levels are observed in critically ill individuals, which therefore may be as a result of the disease [Petrilli et al 2020, Rong-Hui Du et al., 2020]. However, the emerging research suggests that several pre-existing conditions appear to be a distinct causal risk factor, rather than a disease consequence.

For additional context, it is relevant to note that CVD (cardiovascular disease) is a significant risk factor for mortality in itself. According to WHO figures, it is the number 1 cause of death globally, and accounts for just under a third (31%) of all reported deaths.
 

Obesity

“The outcomes from the current pandemic may help bolster the case in the wider global medical community to acknowledge obesity as a disease, and encourage individuals to seek treatment for this chronic condition.”

As the virus has spread globally, New York has emerged as an epicentre for COVID-19 cases in the US. In a letter sent to the New England Journal of Medicine, clinicians reviewing the first 393 Covid-19 patients admitted to two New York hospitals, identified obesity as an important risk factor [Goyal et al., 2020 ]. Over 35% of all those admitted were obese, (BMI>30). Patients who went on to require mechanical ventilation were also more likely to be obese, and have elevated liver function-values and inflammatory markers.

A separate, larger observational study, also in New York state, looked to identify risk factors for hospitalisations and adverse outcomes in 4,103 patients [Petrilli et al., 2020]. The strongest risk factors for patients for admission was also obesity (identified here as individuals with a BMI>40), alongside advanced age — individuals >65 yrs. The authors noted that low levels of oxygen (<88%) and elevated inflammatory markers upon admission (d-dimer>2500, ferritin >2500 and C-reactive protein >200) were also indicators of adverse outcomes for patients that included intensive care, mechanical ventilation, hospice admission and/or death.

Although obesity is not recognised as a disease in most countries outside of the US, there has been growing pressure globally to do so by prominent health organisations [Bray, G.A., et al 2017]. In theory, it was classified as a disease by the World Health Organisation at its establishment in 1948 [James, WPT. 2008]. The outcomes from the current pandemic may help bolster the case in the wider global medical community to acknowledge obesity as a disease, and encourage individuals to seek treatment for this chronic condition.
 

Age-related factors and immunity

Advanced age has been highlighted as a risk factor. Several of the studies cited in this paper [Petrilli et al., 2020; Rong Hui Du et al., 2020] show those >65 yrs of age have the highest risk. Increasingly, elevated death rates proportional to age have been documented in several studies globally. In a statement at the start of April 2020, the WHO European Director confirmed that 95% of deaths in Europe’s 30 member states occurred in those >60 yrs of age. In addition, 50% of all deaths were of individuals aged 80 yrs or older [Kluge H. 2020].

As an individual’s age advances their propensity to develop one or more underlying health conditions increases. This may be a contributory factor. For example in the UK, a national study published in 2019 on obesity, highlighted that the proportion of adults who were overweight or obese increased significantly with age, amongst both men and women. The highest levels were observed in men aged between 45 and 74 (78% across these age groups), and women aged between 65 and 74 (73%).

There is also significant evidence that immune function declines with age. The thymus, a critical organ for immunity is known to shrink with age (known as thymic involution in medical terms) [Palmer., 2013]. Since it has a critical role in helping the production of diverse T lymphocytes essential for immunity, this leaves an individual more susceptible to infection, with a reduced ability to generate what’s known as an adaptive (antigen-specific) response to pathogens.

A decrease in essential circulating macronutrients to maintain the immune system, is sometimes seen in those of advanced age. This may be caused by aging-related inefficiencies in absorption and utilization, or because the diet becomes less varied in some cases. In fact, although energy needs may be less as we age, some essential nutrients can be required in higher amounts, through diet or the use of supplements to compensate. [Rémond D et al., 2015,]
 

Smoking and Chronic Obstructive Pulmonary Disease (COPD)

The SARS-Cov-2 virus has been confirmed as gaining entry to cells in the respiratory system by binding to the Angiotensin-Converting Enzyme II (ACE-2) receptor [Zhou P, et al.]. Active smokers and those with chronic obstructive pulmonary disease (COPD) have been shown to express higher levels of this receptor, so may be at increased risk of the severe versions of the disease as a result. Conversely, there is some, yet to be fully verified evidence, that children and adolescents have low levels of expression, which may explain their reduced susceptibility [Skarstein Kolberg E. 2020].

Smokers have a reduced capacity for the blood to carry oxygen and are at increased risk of respiratory infection. There is damage observed to the microscopic hairs, called cilia, on cell surfaces in the airways and lungs in smokers. The vapour inhaled during vaping has a similar effect. Since cilia play a key role in removing debris, mucous and infectious agents, it is plausible that it could leave them more vulnerable. Furthermore, smokers are more likely to have pre-existing cardiovascular and respiratory disease.

This is backed by some clinical observations. A review published in Mar 2020 [Vardavas, C,I and Nikitara, 2020] identified five studies reporting data on the smoking status of patients infected with COVID-19 in China. While not all of the studies were conclusive, the data from the largest of these (1099 patients), showed that smokers were more likely to have severe symptoms of COVID-19, and be admitted to an ICU, need mechanical ventilation or die, compared to non-smokers. A critical limitation of the study was that results were unadjusted for other factors that may impact disease progression.

Indeed, the picture is far from clear cut. There is a research group in France that is currently exploring trialling nicotine patches to determine if they have a protective role, following their findings that smokers are under-represented in those being treated in a Parisian university hospital with coronavirus.

A retrospective analysis on critically ill patients admitted into intensive care in Lombardy, Italy, 1043 of whom had data available, showed 4% had COPD as an existing condition. Other notable outcomes of this analysis were that 82% of patients were male, the most prevalent co-morbidities were hypertension (49%), cardiovascular disease (22%), followed by hypercholesterolemia (18%) [Graselli, G et al., 2020]
 

Are there lifestyle adaptions that can improve our health defences?

“What we can conclude is that there are ongoing lifestyle optimisations, based on what we do know, that can stand us in good stead to fight infection more effectively, both in the case of this pandemic, or similar viruses that may emerge long term”

Given the current climate, with so much global data still to emerge, it would be naive to suggest there is a quick fix approach to our health that would mitigate the risk of contracting and developing Covid-19. Indeed, the entire learned scientific community is working towards this goal, a validated drug treatment and vaccine. However, what we can conclude is that there are ongoing lifestyle optimisations, based on what we do know, that can stand us in good stead to fight infection more effectively, both in the case of this pandemic, or similar viruses that may emerge long term.

There is a recurrent link emerging between CVD, hypertension, type 2 diabetes, obesity, elevated cholesterol and outcomes for the disease. These co-morbidities can be preventable and are often caused, or exacerbated by a choice of poor diet and lifestyle [Bodai B I, et al., 2018]. There are of course genetic components, and ethnic propensities. For example, CVD is thought to cluster in families. Also, those of South East Asian origin are thought to be pre-disposed to developing Type 2 diabetes at a lower BMI than other ethnicities, due in part to their predisposition to gain visceral fat. [Ma, R. C and Chan J.C. 2013]

However, maintaining a healthy weight, where BMI is 20-25, is a critical first step and one that can be achieved by reducing calorie and saturated fat intake to that recommended for your age and gender, whilst increasing your activity and level of exercise. Physical exercise and regular activity can help maintain a good level of cardiovascular fitness, keep weight under control and, in addition, improve circulation. The latter also allows improved accessibility of circulating immune defence cells to tissues and organs.

It’s important to identify if you’re classified as a borderline individual prior to developing cardiovascular disease, or type 2 diabetes to pre-empt their occurrence. This is sometimes referred to as having ‘metabolic syndrome’ or ‘syndrome X’. Individuals here show raised blood pressure, blood glucose, hypercholesterolemia (high overall levels of cholesterol), an elevated LDL to HDL ratio (bad to good cholesterol), excess abdominal fat and may be overweight (BMI 25+), but not necessarily obese (BMI 30+) [Pérez-Martínez P et al., 2017].

Early interventions, through regular health checks, consultations and blood tests can help pinpoint this, and is something that is sometimes missed in primary healthcare due to a lack of resource and manpower. In the meantime, an individual may have progressed to the preliminary stages of chronic disease development and may require clinical intervention. Alternatively, when metabolic syndrome is identified, ongoing support is often not provided to help instigate the lifestyle changes required longer term.
 

Can we bolster our immune system by healthy-living strategies?

“The idea of ‘boosting’ our immunity with a magic bullet agent is, therefore, far too simplistic. It’s actually a fine balance between multiple components.”

A healthy immune system is critical to fighting pathogens. Several emerging studies on Covid-19 discussed in this paper have identified lymphopenia (low levels of T lymphocytes), suggesting immune damage or compromise, as one of four risk factors for more severe forms of the Covid-19 disease. Many have also indicated high levels of immune cells, called neutrophils, that release molecules called cytokines — resulting in what is described as a ‘cytokine storm’ that causes inflammation and contribute to the damage to the lungs that is seen in severe cases [Shi, Y., et al 2020]

A good question to ask is — what actually constitutes healthy immunity and can you boost it? In reality, our immune system is an infinitely complex network of tissues, organs, millions of circulating cells of different functions, numerous protein pathways and regulatory molecules that are involved in its regulation. The idea of ‘boosting’ our immunity with a magic bullet agent is, therefore, far too simplistic. It’s actually a fine balance between multiple components.

However, there are some key micronutrients that we need for our immune function, and a healthy dietary intake can help us ensure we get those to a required level. Eating a balanced diet, rich in fruit and vegetables is beneficial to health. Vitamins A, C, D, E, B2, B6 and B12, folic acid, beta carotene, iron, selenium, and zinc have all been shown to have a role in immunocompetence [Alpert B, 2017], and there are daily recommendations on their intake.

As we get older, poor absorption can affect the bioavailability of such nutrients. Supplementation can be necessary in these cases. However, there is a difference between this and over-supplementing with one vitamin, without knowing whether we are deficient in the first place. [Maggini S et al., 2018]

Smoking cessation can improve immune function, leaving us less vulnerable to respiratory illness, improving our blood oxygen levels and overall fitness. Specifically with Covid-19, there’s evidence smoking may increase entry points for the virus in the lungs, as discussed previously.

In terms of other lifestyle factors, alcohol consumption has also been shown to be deleterious for immune function in a dose dependent manner. Whilst moderate alcohol consumption does not show detrimental effect, heavier drinking is shown to disrupt innate and adaptive immunity, and the ability to fight infectious disease [Barr T, et al 2017].

It’s important to note that in the UK the Chief Medical Officer recommends a maximum of 14 alcohol units a week, for both men and women with designated drink free days (equivalent to 6 glasses of 175ml wine, 6 pints of beer, or 10 X 25ml shots over 7 days). The dietary guidelines for Americans are comparable, recommending no more than 1 drink per day for women and up to 2 drinks per day for men (note that 1 drink here constitutes 150 ml of 12% wine, 350 ml of beer or 45 ml of 40% spirit).

Sleep and its accompanying circadian rhythm is intricately linked with activity in our immune system. Some immune processes, including the adaptive immune response are known to peak during a specific phase of nocturnal sleep. Chronic sleep loss can be correlated with an increase in inflammatory markers and immunodeficiency [Besedovsky et al., 2012]. For example, individuals show a diminished response to vaccination after 6 days of restricted sleep [Spiegel K., et al]. There has also been evidence for enhanced susceptibility to viruses like the common cold in the case of poor sleep efficiency.

The optimal sleep is between 7-8 hrs per night for adults [Daza EJ et al., 2019; Chaput J,P et al., 2018]

There have been a number of studies on the effects of stress on the human immune system. Research to date describes a critical distinction seen between short-term stress, lasting a maximum of minutes and hours that actually resulted in some immune enhancement, to chronic long-term stress that was very detrimental to immune function [Dhabhar, F.S. 2014]. Long-term stress was shown to suppress innate and adaptive immune responses, induce low-grade chronic inflammation, and decrease the function and amount of immunoprotective cells.
 

Summary

The epidemiology, and the potential for immunity to Covid-19 are emerging areas of research. We cannot definitively make any assumptions about individual immune response to the virus threat and risk of infection, or outcome yet. We need large scale epidemiological studies for that, which will be available in the coming year, once the peak of the virus has passed and it is under control globally. With the development of a vaccine months or possibly a year or more away, and larger scale clinical trials required to prove the efficacies of drug treatments and avert continued or resurgent infection, Covid-19 may pose a significant threat for the foreseeable future. However, this paper has set out to discuss how we can give our bodies the best fighting chance in the event of immune assaults like the current global pandemic, lower our risk of developing co-morbidities – a known risk factor, and adopt lifestyle adaptations to bolster our immune system.

Dr. Seema Sharma for SX2 Ventures

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Ultimately, the best use of an individual’s resources is perpetuating that individual’s existence. And whilst that might seem a little too selfish for some, it’s pretty close to the biological reality for most species. Humans however have a unique ability to influence our longevity through the choices we make for our own biological systems. This is true for humankind collectively – and it is entirely possible, if not likely, that the choices we make during this millennium will lead to the extinction of our species. It is also true on an individual basis. We can materially influence our longevity by the choices we make for ourselves. There is minimal room for fatalist philosophy when it comes to our individual biologies, genetic predispositions aside. Whilst there is still much of the inner workings of our bodies that we do not understand, we know enough to understand that the answers will be scientific.

And yet, medical science, for all of its genius invention and discovery, has strangely subordinated the science of prevention to the science of cure. It is systematic. The UK’s national health budget is divided up 97/8 in favour of treatment and cure versus prevention. A medical student in the UK will spend 5 or more years learning about the body, what goes wrong and how to fix it but only a few mornings worth of lectures on how human lifestyles and environmental factors cause us to become ill in the first place. It’s not meaningfully different in the US or, say, Germany with average tuition time on nutrition somewhere between 10 and 20 hours in total across the entire medical degree. Indeed, studies show that plenty of doctors in these ‘advanced’ countries don’t believe nutrition to be relevant to their work.

No surprise perhaps, with hindsight, that we spent the best part of a century concluding that smoking causes lung cancer despite the evidence in front of us from around the 1940s if not earlier.

Correlation Between Smoking and Lung Cancer in the USA

And we are still paying the price, in lives and dollars, for that wilful blindness. The American Cancer Society estimates that as recently as 2017, there were 222,500 new lung cancer cases diagnosed in the United States and 155,870 lung cancer deaths. Consider all of the resources we have spent finding cures and funding treatments and all we had to do, more or less, at a statistically irrefutable level, was persuade or legislate for people to give up smoking. The cost on lives is bad enough but for health services and insurers facing exploding costs for ageing populations, the monetary costs are ruinous. According to the National Institute of Health in the US, in 2017 the chemotherapy and radiation treatment costs for lung cancer patients enrolled in the federal Medicare system ranged from $4242 to $8287 per month during the initial six months of care and the cost for surgery was $30,096.

Thankfully, lung cancer cases are on the decline in those countries that have acted to educate their citizens of the risk that smoking brings. The bigger question now is whether we have really learned the lesson from smoking and lung cancer – that our lifestyles really do have a material impact on our longevity. Depressing data points on other diseases suggests that we have not. Many cancers, cardiovascular disease, stroke, dementia, and diabetes all have unhealthy lifestyles as a material risk factor, and some are rising as rapidly as lung cancer did in the 20^th Century.

For example, since 1996, the number of people diagnosed with diabetes in the UK has risen from 1.4 million to 3.5 million. With another 500,000 estimated to have the disease that remain undiagnosed, this amounts to around 1 in 16 of the population of the United Kingdom currently living with diabetes. Diabetes is a killer resulting in an overall reduction in life expectancy of more than 20 years for Type I and 10 years for Type II. It is also estimated that as much as 10% of the NHS annual budget is now utilised in the treatment of diabetes, equal to around £173 million per week. That’s more than the £8 billion the UK government spends annually on the police service. Type II diabetes makes up around 90% of all cases and there is irrefutable evidence that lifestyle factors summed up in the term ‘obesity’ are a material risk factor for developing Type II diabetes.

Moreover, epidemiologic evidence suggest that people with diabetes are at significantly higher risk of developing many forms of cancer and it is established that Type II diabetes and cancer share many risk factors. A recent study published in the Journal of the National Cancer Institute goes further in finding that new-onset diabetes may be an early indication of pancreatic cancer, the world’s toughest cancer, with survival rates often measured in months. Another clear indication that much cancer is lifestyle and environmentally driven is the rapid increase in incidence seen in the developing world where lifestyles, especially diet, have changed so rapidly over the last few decades. The WHO projects that the global cancer incidence will increase from 14 million in 2012 to 22 million in 2032, with more than 60% of incident cancers and 70% of cancer deaths occurring in central and south America, Africa, and Asia.

Other less well-known diseases are catching up and we have yet to allocate them to the ‘lifestyle disease’ category despite growing evidence. For example, the US Center for Disease Control & Prevention (CDC) estimated that between 1999 and 2015 the incidence of Inflammatory Bowel Syndrome (either Chrohn’s disease or ulcerative colitis) had increased from 2 million to 3 million US adults. The CDC also reports that the prevalence of food allergy in children increased by 50 percent between 1997 and 2011. Each year in the US, c.200,000 people require emergency medical care for allergic reactions to food and childhood hospitalizations for food allergy tripled between the late 1990s and the mid-2000s. Although researchers have yet to determine the precise reason for these major increases, evidence is emerging that our lifestyles and environmental factors including what we eat, where we live and the air we breathe are material risk factors.

Medical researchers currently investigating the human gut microbiome are perhaps closest to providing answers as to why this is the case. In simple terms, the gut microbiome is the collection of bacteria, viruses, microflora and other microbes in our intestinal tract and scientists at our top research centres have been studying its links to all manner of ailments for over a decade. Although much of this is emerging rather than settled science, researchers have already discovered a systemic link between the diversity and health of our gut microbiome and our susceptibility to many diseases including IBD, food allergy, cancers, Alzheimer’s, depression and several auto-immune diseases. The precise causal connection has not yet been fully established, and mainstream medicinal doctrine is yet to embrace it, but there is growing evidence that the microbial ecosystem in our gut is a major indicator of our propensity to many chronic illnesses. Researchers suggest that one of the mechanisms at work may be the interface between our gut lining and the body’s blood and lymphatic systems. A properly functioning gut lining will allow only the required nutrients through into our blood stream, for use around the body, whilst preventing absorption of all the other contents of our intestines. According to the ‘leaky gut’ theory, when this system fails, and we suffer from ‘increased intestinal permeability’ (‘leaky gut’), the body’s immune system is forced to deal with many ‘foreign bodies’ that have been released into the blood stream. This in turn results in increased inflammation which is at the core of many chronic illnesses. The theory remains controversial among many mainstream medical practitioners, who cite a lack of clinical trials, but many others are embracing it as a major reason behind the significant rise of many auto-immune diseases and severe allergies over the last few decades.

And what is it that impacts the health of our gut microbiome perhaps most of all? Naturally, what we consume. It seems entirely obvious that what we put into our bodies directly and significantly influences our health. We are exposing our internal workings to whatever it is we swallow or breath. If we eat, drink or breathe poison we become sick and maybe die. If we smoke, we eventually die, actuarially at least. If we eat a Mediterranean diet, we live longer. If we live like the Japanese we live longer. People from the country-side live longer than those who live in cities. Athletes follow a strict nutritional plan to elevate physical performance. Human space exploration requires strict nutritional planning. We know all of this because the data are incredibly clear. What we consume is a major determinant of our health. It is true that microbiome scientists today cannot say exactly why or how the diversity of our microbiome contributes to the incidence of disease, but they understand enough to know that there is a systemic link and most likely causality. Incidentally, the diversity of the microbiome is also significantly impacted at birth with vaginal births and breast-feeding transferring microbes from mother to baby.

And yet, despite these advances and all that our instinct tells us, our entire healthcare system is set up as if we didn’t know the connection between lifestyle and illness, as if each patient that arrives with the symptoms of a chronic lifestyle disease is just another patient with another disease.

Why is this? Much has been written about the role of nutrition in the beginnings of Western medicinal doctrine. The phrase “Let food be thy medicine and medicine be thy food” has been attributed to Hippocrates. Whether or not that is true, at a certain point Western medicinal doctrine became all about treating the sick rather than about prevention. Not surprisingly perhaps given the explosion in disease during the industrialisation of the planet but that is basically where medical science has been ever since. Big pharma is big business and spends billions convincing us through one method or another that all we really need is more pharmaceuticals. Just spend an hour watching TV in the US and marvel at the advertisements for complex pharmaceuticals aimed directly at individuals, some with side effects that “might include death”. It’s also quite obvious that prescribing clinicians can be brought on side. Read up on the opioid crisis in the US or to a lesser extent the UK.

Imagine, by contrast, if the ‘cure’ for many cancers, heart disease, stroke, Type II diabetes and Alzheimer’s was actually a proactive lifestyle change rather than a reactive pharmaceutical, radiation treatment or surgery. Hint: it is, and the public health data are irrefutable. According to the Lancet, it is possible to prevent or delay the onset of dementia in as many as 35% of people through modifications to risk factors including increased child education and reducing hypertension, hearing disability, obesity, smoking, depression, physical inactivity, diabetes and social isolation. Research and clinical studies show that adopting at least three positive life-style adaptations from not smoking, reduced alcohol, healthy diet and regular exercise makes a significant difference in our propensity to develop dementia versus adopting just one or two of these lifestyle changes. Many other studies show that regular physical exercise is a major contributor to longevity more generally.

Another part of the narrative here relates to the way we anoint medicinal solutions. In order to be approved for sale or prescription to the public, pharmaceuticals go through incredibly rigorous research studies and clinical trials that often cost more than US$100,000,000 and take over 15 years to complete. A new cancer drug could cost as much as US$2 billion to bring to market. What chance is there for a prescription of more vegetables, sleep and physical exercise? Food and most other naturally occurring products are not required to go through clinical trials. But that doesn’t mean they can’t have the equivalent impact on our health. A doctor in the UK or US is more likely to prescribe aspirin than omega-3 fish oil to reduce the risk of heart attack despite large scale trials that show fish oil to be more effective. Clearly, with many illnesses, at a certain point in the lifecycle of the illness, only a pharmaceutical or clinical intervention will yield the desired results. Rightly, significant medical research is devoted to finding cures for diseases or treating those affected. Yet it is abundantly clear that we are not doing enough to prevent the diseases developing in the first instance. The cost in lives and dollars of not doing more by way of prevention is monstrous.

What can be done? I see five avenues of attack. First, healthcare policy makers must devote many more resources to public education, just as we did eventually with smoking, or as we did when the AIDs epidemic first broke. Second, we must change the way that we educate our health professionals so that their studies include more of the science of prevention. That means embracing nutrition as a core medical science rather than a branch of ‘alternative medicine’. Third, we can go further in taxing unhealthy behaviour, extending what we do with smoking and alcohol to sugar-sweetened beverages (SSBs) for example. Certain cities, regions and countries around the world have implemented taxes on SSBs resulting in reduced consumption. Fourth, more funding should be allocated to research into the microbiome and mitochondrial health and how it is affected by, among other factors, antibiotics, additives and chemicals in the food supply chain. The Quadram Institute is a new research centre in the UK set up to do exactly that. And fifth, health insurers – including single payer systems such as the NHS – must incentive healthy living. Some insurers have already begun this by reducing premia for cyclists much in the same way that we can reduce our car insurance premia by using technology to show that we are safe drivers. The point is, it’s not difficult but the impact on public health would be massive.

This article has not touched on the contribution of genetics in the propensity for developing certain illnesses and it is clear from the enormous amount of research over the last decade or two that genetics can be a significant factor in our propensity to certain diseases. Yet, we must understand the implications of these statistics. It is not fate that you develop an illness that your genetics pre-dispose you to. All of us can tilt the odds in our favour by adopting a healthy diet, regular exercise, good sleep and reduced stress. Nor should an individual point to the outliers that smoke, drink, eat badly, don’t exercise and live to 90 plus. The statistics are the statistics. There will always be outliers but that provides no comfort to the vast majority of us that fall within the predictive range of outcomes. It is a high stakes gamble with our health pure and simple.

Would we bet the house on the turn of a roulette wheel? No and partly because the result of the gamble is instant. You can lose your house immediately. Should the fact that we don’t find out if the gamble worked for 30 years lead us to different conclusions? And therein lies the issue. As humans we are happy to defer judgment day for just one more roll of the lifestyle dice. Instead we should be investing in our futures by adopting extremely easy lifestyle choices, giving up smoking, selecting the right diet, taking regular physical and mental exercise, getting good sleep and reducing stress. If we do that we will definitively be extending the length and quality of our lives.

Nor is it an excuse to say that there seems to be constantly conflicting advice on what a good diet is and whether it includes meat or carbohydrates or fat etc. The reality is that avoiding certain elements of modern food is not in debate, especially refined sugar, salt, processed carbohydrates, and ‘bad’ fat. Debate around the benefits of say, polyphenols in wine and coffee, or the avoidance of animal protein and fats will continue to rage, not least given the extensive funding efforts the food and beverage lobby, like the smoking lobby in the past, is able to undertake. We know enough with certainty to be able to recommend diets that will materially increase our longevity. In years to come we will look back on the diets we adopted in the past 50 years, and the way we process food, in the same way we now look back on smoking. We are creating the public health graphs of the 21^st Century right now and we need to decide if we see that now or learn later.

Tom Speechley, SX2 Ventures, November 2019

At SX2 Ventures we invest in the business of human care.  One of the areas we are most interested in is longevity and innovations that can be made to the primary care model to refocus resources on preventive steps especially lifestyle factors and non-invasive interventions prior to the onset of chronic illness.

Over the last few years dementia as an illness has come out of the shadows. We recognise it more openly in society, the scientific research community is more focused on it and ultimately many more of us are exposed to it through elderly relatives. Here are the ten things we all need to know about dementia.

1. Dementia is not itself a specific disease
Dementia is not a specific disease but rather a medical term used to describe a set of neurological symptoms caused by a group of brain disorders including Alzheimer’s. The most common symptoms are memory loss, confusion, getting lost, difficulty with daily tasks and mood changes. It can reach the point where dementia sufferers don’t know they need to eat or drink and dehydration is a major concern for many people with dementia.

2. Alzheimer’s is the most common form of dementia but there are several others
Alzheimer’s disease is the most well-known cause of dementia, and the most common, but there are several other discrete pathologies of the brain that are dementia causing illnesses. These include vascular dementia, dementia with Lewy bodies, fronto-temporal dementia (also known as Pick’s disease), Parkinson’s disease dementia, Huntington disease dementia, amyotrophic lateral sclerosis and the recently identified LATE form of dementia that mimics Alzheimer’s. Although these different illnesses may affect different parts of the brain, all generally result in brain cell death and result in similar resultant symptoms. Dementia may also be caused, even developing many years later, by traumatic injury to the brain either from a single incident or through repetitive brain injury as is being increasingly recognised among certain sports players.

3. Dementia is not an inevitable outcome of old age
It was originally thought that dementia was merely a symptom of ageing, an inherent decline in cognitive capability that necessarily flows from old age like greying hair and the loss of physical strength. Indeed, old age remains the single biggest risk factor for developing dementia – probably because the changes in the brain that cause dementia appear to start in mid-life, even though caused by other factors – but it is not an inevitable outcome of ageing. This has now been disproven by research and we know that many people who live well into their 90s and beyond have brains that remain remarkably clear of any signs of dementia.

4. Dementia causing illnesses are now the leading cause of death in the UK
Dementia illnesses now result in more deaths in the UK than any other disease including heart disease, any individual cancer or strokes. Although all cancers combined still account for more deaths – and as recently as 2014, twice as many – dementia is projected to overtake all cancers combined in the next decade or two. The growth rate is staggering, with mortality rates from dementia effectively doubling in the last 10 years.

In fact, a major reason for this rapid increase is statistical. In 2011, the Office for National Statistics (ONS) made changes to the way deaths due to dementia are recorded to better reflect guidance from the World Health Organisation. Since then when a person dies with dementia, doctors can report it as the main cause of death on their death certificate. Previously, the immediate cause of death would be listed, such as a fall or an infection like pneumonia. But in many cases, these illnesses are a result of the underlying dementia causing increased frailty, a weakened immune system or problems with swallowing. The ONS also updated their coding system so that vascular dementia would be reflected in the dementia category instead of the stroke (cerebrovascular disease) category.

More fundamentally, the longer-term trend reflects our increasing longevity. Whilst not an inevitable outcome of ageing, as we live longer the risk of developing dementia increases.

5. We do not really know what causes dementia but we are unearthing clues
At the moment we can’t say with any precision why one person develops dementia while another person does not. However, it is becoming clear that a combination of genetic, lifestyle and environmental factors, together with age, are material risk factors. Research is on-going into certain identified genetic risk factors that indicate a predisposition to certain dementia causing illnesses. Many studies have also been published and continue to be undertaken showing the extent to which our lifestyle, especially our diet, physical exercise, sleep and stress levels, can increase (or decrease) the risk of developing dementia. And age continues to be the largest single risk factor, even though it is not the underlying cause per se. For example, in the US, the number of people with Alzheimer’s doubles every five years from age 65 and about one-third of all people age 85 and older may have Alzheimer’s.

6. There is no known cure for dementia
Dementia is the only major cause of death in humans not to have a known cure. As of today, if you develop dementia, absent another intervening cause of death, it will eventually lead to your death. Thus far, despite significantly increased funding and research activity over the last few years, a ‘cure’ remains elusive. Indeed, it is unlikely that there will ever be a ‘cure’ for ‘dementia’ given that it is caused by a range of underlying illnesses and the fact that dementia generally reflects brain cell death which cannot be reversed. Much of the research is focused on Alzheimer’s which is the most common cause of dementia and the state of the R&D is sometimes likened to the search for an HIV cure in the 1980s and 1990s. However, despite the increased focus, funding for Alzheimer’s research is still dwarfed by the amounts spent on cures for cancer.

While identifying a definitive cure is the ultimate goal, identifying drugs that merely slow the pace of onset of dementia is also seen as a major milestone. Analysis by Alzheimer’s Research UK argued that a drug that delayed the onset of dementia by five years would cut the number of people living with the disease by a third and alleviate the economic cost by 36%. As this article was being written, a US bio-tech company made the first announcement of launching such a drug on the market.

7. Despite the absence of a cure, prevention is still possible
It is becoming increasingly evident that lifestyle choices and environmental factors contribute materially to the risk of developing dementia later in life. According to the Lancet, it is possible to prevent or delay the onset of dementia in as many as 35% of people through modifications to risk factors including increased child education and reducing hypertension, hearing disability, obesity, smoking, depression, physical inactivity, diabetes and social isolation. There are now many studies showing that, as with so many other illnesses, regular physical exercise (of body and mind), improved nutrition, good sleep and reduced stress will materially reduce the risk of developing dementia. Research into the human gut microbiome suggests that enhancing the diversity of bacteria and other microbes in our intestinal tract may result in lowering the risk of developing Alzheimer’s or slowing its onset. Another important take-away from the research is that early diagnosis can help with mitigating the onset and impact of dementia by slowing the progress of the disease and at a minimum preparing for it with those around us.

8. The explosion in diagnosis and absence of a cure place a huge responsibility on care
A diagnosis of dementia is currently a lifetime diagnosis and the support of a caregiver will become inevitable at some point. The first line of caregiving support is usually a family member, which may be a life-partner or other immediate family member. The cruelty of the disease is often most acutely felt in this situation as a loved one changes from the closest of companions into a potentially antagonistic stranger, with no recognition for the past years spent together. Moreover, in the absence of control of bodily functions, carers are required to attend to the most basic needs of patients often to the immense embarrassment or shame of the sufferer. It is no surprise that family carers themselves are at a high risk of depression.

Caregiving is also a healthcare service delivered by private and public providers, either at the patient’s home or in a residential facility. However, public resources for dementia care are massively underfunded in the UK. Unlike virtually all other illnesses of aging, the UK’s NHS does not support treatment or long-term care for dementia sufferers. As a result, long term dementia care is primarily the responsibility of local authorities. If no cure is found, the dementia care crisis will swamp publicly available funding. And in the absence of a new national funding plan that supports benchmark care for all sufferers, much of the financial burden falls on the individual with the disease or their family.

9. In other countries euthanasia and assisted dying allow sufferers to elect a dignified death
In the UK the law does not permit euthanasia or assisted dying although there are signs that attitudes may be evolving, partly in response to the explosion of dementia diagnoses. In other countries, a person deemed legally capable of making the decision can elect to end their life in a dignified manner before, in their minds, it is too late and advanced dementia takes hold.

We do not really know the extent to which those with dementia suffer, despite some level of depression being a symptom for some, because no one returns to full health from a dementia diagnosis to describe the effects. However, we do know that dementia slowly robs a patient of their mental and physical faculties. This includes the ability to control bodily functions and cognitive abilities such as memory, mental agility, sight, hearing and speech.

10. What should I do, if anything, if I am concerned about developing dementia?
It is estimated that one in four people in the UK over the age of 55 has a close relative with dementia and that it affects one in 14 people over the age of 65 and one in six over 80. It is not surprising that it is the disease that people of these age groups fear the most. Some of the underlying risk factors such as genetics, gender (it affects more women than men) and possibly ethnicity (for example, South Asians appear to be more prone, especially to vascular dementia, although a major part this may prove to be a function of lifestyle factors such as diet) are beyond our control. However, there is also overwhelming evidence that lifestyle factors significantly increase our chances of developing dementia later in life. This can be detected through high blood pressure, high total cholesterol, obesity and Type 2 diabetes all of which are material risk factors for dementia. Steps we can take that will reduce the risk of developing dementia include giving up smoking even later in life, good diet especially to nourish our microbiome, reduced alcohol consumption, regular exercise for both body and mind, maintaining a healthy weight, being social, reducing stress factors, and getting good sleep. Research and clinical studies show that adopting at least three positive life-style adaptations from not smoking, reduced alcohol, healthy diet and regular exercise makes a significant difference versus adopting just one or two of these lifestyle changes. Such changes will also reduce the risk of other diseases including heart disease, type 2 diabetes, several cancers and stroke.

Tom Speechley, SX2 Ventures, October 2019

At SX2 Ventures we support innovation in the business of human care. One of the areas we are focused on is the design of “next generation dementia care facilities” that combine the very latest evidence-based practices and technologies to improve the quality of care residents receive. The innovations we seek include those that reduce the cost of providing care so that more citizens have access to benchmark quality care. Whilst all of our projects must generate a profit, this is only one metric of success alongside benefit to humankind and experiential value creation.