Our gut microbes

In the previous post, I discussed our evolutionary connection with bacteria – all the cells in our bodies are evolved bacteria, and nearly all harbour evolved bacteria within them. Further, all the surfaces of our bodies are teaming with resident bacteria (and other microorganisms such as fungi or viruses). There are roughly ten times more microbes on us than there are cells in our bodies, and they contain at least 100 times more genes than we do (these numbers are constantly being revised). The more our microbes are studied, the more we realise how important our invisible companions are.

Our gut microbes are not inside us

All of our microbial colonies, whether on the skin, in the gut or elsewhere, are external to us. They are on us, not in us. I will explain using the gut as an example.

The digestive system, in total, from mouth to anus, is effectively a long and continuous tube that can be opened or closed to the outside world at either end. It’s contents, therefore, are external to us – the inside of our digestive system is outside of our bodies. We are like an elongated doughnut with an opening that runs down the middle – the dough is our ‘inside’ but the hole down the middle is outside the doughnut. Another analogy might be a tunnel through a mountain. A train going through is inside the tunnel but not inside the mountain, it is just surrounded by the mountain. If we put some food in our mouth and shut our mouth, the food is not inside us, it is in a cavity that we have created, but it is still outside our body. Likewise, bacteria on the gut wall are outside us too. If they crossed the wall into our bodies they would not be helpful anymore, they would cause us illness and be attacked by our immune system. The actual inside of our bodies is kept sterile by the immune system.

This gives a different way of thinking about our microbes – they are a living barrier that stands between us and the outside world, covering all external and internalised surfaces. Consequently, they curate our interaction with our environment, everywhere that we are exposed to it.

Microbiota

The term ’microbiota’ refers to the collection of all our microbes. The body region with the greatest density of microbes is the large intestine (colon), and these are often referred to as our gut microbiota. We also have skin microbiota, lung microbiota etc. The term ‘microbiome’ refers to the gene pool of the microbiota.

In 2012, the first comprehensive measurement of the human microbiome was published (it took 5 years to accomplish that feat). Samples were taken from the gut, skin, mouth and other regions (18 sites in all were sampled for women and 15 for men, the difference in numbers being genital). The study recruited 242 healthy Americans, but included different ethnicities, ages and other demographics. The results were a turning point in the understanding of our microbial partners – it had not generally been realised how diverse and potentially important these microbial colonies were, and now there were tools to investigate them (the number of publications related to our microbiota was in the hundreds before 2012 and >10,000 since).

However, this recency also means that many of the questions we might want to ask about our microbes do not yet have scientifically-settled answers.

What they do

Numerous studies have highlighted the roles performed by our gut microbiota. They include: resisting pathogens by competing for colonisation sites; maturation and regulation of the immune system; production of vitamins, such as B12, B5, and K, and amino acids; synthesis of some digestive enzymes (e.g. lactase); production of antibacterial and anti-fungal substances; fermentation of indigestible dietary fibres into short-chain fatty acids (such as acetate and butyrate) that fuel cells in the gut wall and elsewhere (or have signalling roles); fermentation of lactose, and; contributing to absorption of some minerals (e.g. zinc, iodine, selenium, cobalt). That’s an impressive list. Without our intestinal microbes, we would not survive well. We evolved together with our microbiota, and have outsourced these functions to them.

In return we offer them a safe haven: they populate the newborn (from the mother’s microbiota) at (or before) birth and immediately communicate with the infant’s fledgling immune system to instruct it to look after them and attack foreign species; our gut offers a regulated temperature environment (meanwhile, we freeze or sweat according to the weather); we feed them constantly – they don’t need to forage for food (we do); we use our brains to select and prepare food carefully so as to avoid pathogens that might harm them (and us) and; it’s possible we offer them a safe house when under attack – our appendix. There is speculation that in the presence of pathogens, a representative sample of our microbiota migrate there (a sort of intestinal Noah’s Ark) and wait out the infection as a back-up population.

So, it is a unique niche we offer, which perhaps explains why the density of microbes in our gut is greater than that in any other ecological environment that we know of. If there was a microbial nirvana, it would be our gut.

Epigenetics

There is another important role for our microbes that is just beginning to emerge – regulation of how we express our DNA (i.e. read our DNA to produce the proteins that make us up). One of the sobering outcomes of sequencing the human genome was that we had only about 23,000 genes. That’s about the same as a fruit-fly. An earthworm has three times that many. Our gene pool differs from that of a chimpanzee by only 400 genes (we share the other 22,600). How could we have evolved into something as complex as a human under these circumstances?

It turns out that evolution took a different turn with us. It seems that it became increasingly unwieldy to keep adding genes to our DNA to make us more adaptable. Instead, we developed the ability to use a smallish number of genes but to combine or express them in different circumstances and times to produce complexity (known as epigenetics).

It is a common way of creating complexity – think of how many books, with different stories, that have been written with the same 26 letters of the alphabet. Various factors, such as environmental, dietary, experience, career, lifestyle and mood can potentially influence our epigenetics. It makes good sense, we can use epigenetics to adapt rapidly to the circumstances and environment we find ourselves in, while our DNA evolves over millennia. It means that our DNA is not necessarily our destiny, an empowering realisation.

The astonishing thing is that our gut microbes can release signalling molecules that influence this epigenetic process. Our gut microbes have a say in what we are. As Ed Yong puts it: “…they don’t just go along for a ride; sometimes, they grab the wheel”.

They also have a say in who we are – there is much interest in what is called the ‘gut-brain axis’. These two organs can communicate (bidirectionally) via the vagus nerve. Gut microbes can release neurotransmitters (e.g. serotonin, dopamine) that can modulate gut-brain signalling (although they will not cross the blood-brain barrier) or release other molecules that have neuromodulatory behaviours (e.g. butyrate). Or, they can alter brain behaviour more indirectly, such as through the immune system or by influencing sleep or the circadian rhythm.

Some commonly-experienced examples of gut-brain signalling are: feeling nauseous when stressed; ‘butterflies in the stomach (gut)’ when nervous; a ‘gut feeling’ about something that our brain cannot resolve; even, perhaps, the satisfaction of a bowel movement. The gut microbiota are silently speaking to us, responding to us, and chattering among themselves in ways that are probably as old as biological time.

Before leaving this topic, I can’t resist mentioning the curious case of Toxoplasma gondii. This parasite is found worldwide, including in ~50% of humans globally (in whom it is mostly asymptomatic). Rodents are a favourite host for the parasite, however, it can only reproduce in the intestines of cats (or other felids). To achieve this, it’s strategy is to epigenetically modify the fear centre of the rodent’s brain (the amygdala) so that the rodent is no longer scared of cats or repelled by cat urine. This makes the unfortunate rodent more likely to end up as cat food. A dastardly way of completing its life cycle, but a remarkable example of gut-brain control. It may seem rather machiavellian, however, the prevalence of the parasite worldwide attests to the success of its strategy.

Manipulating our microbiota

So, there is an abundance of evidence that our gut microbiota influence many aspects of our biology, including brain function, and this evidence is only likely to get stronger with time. We also know that the gut microbiota are dysbiotic (imbalanced) in many clinical conditions. But, the question that is less clear is this – can we manipulate our gut microbiota to improve our health, reverse or cure certain clinical conditions or protect ourselves from developing those conditions? Unfortunately, while there is much promise, there is little evidence – there are few definitive studies in humans.

The methods we might use include: faecal microbiota transplant (FMT – just what it sounds like); prebiotics (feeding our resident microbiota); probiotics (adding transient microbes) and; antibiotics (sometimes there is ‘overgrowth’).

I. Faecal microbiota transplant

This has had the most clinical success so far. Faecal matter is collected from a thoroughly tested donor, mixed with saline, strained, and placed in a recipient’s large intestine by colonoscopy or enema. It has also been trialled in capsule form and taken by mouth (which is less invasive). However, there are dangers in playing with something as influential as our resident gut microbiota. For example, there is emerging anecdotal evidence that recipients can take on aspects of the donor (e.g. weight, mood), as would be expected from animal studies.

At least one company is at the clinical stage for supplying doses for FMT: 50 g of human stool with 150 mL of 0.9% saline/polyethylene glycol, containing 1 trillion live microbes in a single-dose enema bag. This delivery system is less risky than colonoscopy, and more easily managed, however the number of microbes migrating into the colon will be fewer. Phase 2 clinical trials have been completed (phase 3 underway) for treating Clostridium difficile infection (a bacterial overgrowth in the colon, usually arising after the use of antibiotics have undermined resident microbial colonies). FMT has an average success rate of ~85% in patients that have not responded to other therapies (as the name suggests C. difficile is difficult to treat in conventional ways). FMT is also being explored for other gut disorders, such as inflammatory bowel conditions.

II. Prebiotics

This is probably the most straightforward approach – consuming dietary fibre or resistant starches that our resident gut microbiota metabolise. This is a routine part of the diets of people eating whole (real) foods rather than processed ‘food-like substances’ (to quote M. Pollan). While I recommend ketogenic diets, there would be some benefit expected for anyone who moved away from processed food (even fibre-enriched processed food) on any diet. I am not sure there have been definitive studies of this though, as there are many confounds (is it the nutrients in the whole food, and not the fibre, that confers a benefit?). I addressed fibre as a health topic in a previous post, and I won’t expand on it here.

III. Probiotics

These usually come in capsule (or pill) form, and contain a curated selection of bacteria thought to be beneficial to, or typical of,  our resident microbiota. They contain billions of bacteria, mostly lactic acid bacteria (Lactobacillus acidophilus, L. brevis, L. bulgaricus, L. plantarum, and/or L. rhamnosus). Other common probiotics are the Bifidobacteria (B. Bifidum), Streptococcus thermophilus and Enterococcus faecium. Bear in mind, though, that our resident microbiota is measured in trillions, and a probiotic containing billions of microbes will be just adding about 0.1% to that.

Two issues to consider are whether these are delivered in sufficient numbers to make a difference, and whether they form colonies with our resident microbiota or whether they are transient.

It looks like species diversity is important for a well-functioning gut microbiota. With many microbial species resident, a certain functional outcome can be achieved in more than one way, giving us resilience. There were thought to be about 1,000 bacterial species in the human gut, however recently it has been suggested that it might be ~30,000. So, is it likely that adding a small number of bacteria from a few species to our resident microbiota will translate into a health benefit? Further, there will be significant probiotic death during transit of the stomach, reducing numbers and further reducing diversity as only the most acid-resistant microbes will survive. One advantage of FMT is that it preserves the microbial diversity of the donor and, depending on the delivery system, in vastly greater numbers.

Are probiotics resident or transient? They can be measured in stools, and the general consensus is that they are transient. A healthy gut microbiota would naturally resist foreign microbes or a pill of microbes in an unnatural combination. However, it normally takes 1-2 days for faeces to travel the length of the large intestine, and that gives probiotics the opportunity to interact (for good or bad) with resident microbes. It is the transience of probiotics that makes it necessary to take them daily.

The next consideration is whether probiotics confer a benefit on otherwise healthy individuals. This has not been answered, however there have been studies investigating whether probiotics can alter faecal microbe composition, a first step to potentially modifying health.

A recent review of available randomised control trials (the gold-standard) that addressed this question, concluded that there was insufficient evidence to draw a conclusion one way or the other. The problem was the lack of standardisation across studies. They highlighted these issues: small sample sizes (that’s number of participants by the way, in case you were thinking something else); low resolution-methods for assessing faecal microbiota composition; inter-individual differences in susceptibility to the probiotic; the use of different probiotic strains; variations in dosage; the administration mode; duration of intervention and; variation in the habitual diet of participants.

Likewise for psychological outcomes. A randomised control trial review concluded “Overall, there is very limited evidence for the efficacy of probiotic interventions in psychological outcomes. The evidence base is incomplete and lacks applicability.

What these studies show is that if there is an effect-size of probiotics, it is small and gets lost in the background ’noise’ (e.g. from inter-subject variability). This will mean that there is no detectable average effect across a group, which is what science looks for. It does not mean that there will not be an effect for some individuals. So, science doesn’t rule out trying probiotics for yourself, but it does lower expectations substantially. This is not fundamentally different to other nutraceutical products such as vitamin or mineral supplements, body-building supplements, fish oil etc. However, if manufacturers are making health claims for their probiotic, be aware that they are not science-based claims of a high order.

IV. Naturally-fermented foods

There are even more confounds in determining health effects of fermented foods, which include at least as many versions as there are human societies. Ferments may be thought of as another class of probiotics (although probiotic manufacturers might dispute that). Some ferments, such as sauerkraut, are both prebiotic and probiotic (referred to as synbiotic). My comments in the previous paragraph apply to ferments too – are there sufficient numbers of microbes, how well do they survive stomach acids (and small intestine bile), what is their interaction with our resident microbiota and so forth.

It may be thought that because ferments have been nurtured and maintained in so many societies for so long, they must be healthy. Perhaps they are, but it doesn’t follow that it’s because of their microbial inhabitants. This food survived for so many generations and in so many places because it was a way to store food for leaner times. Our forebears were not thinking how good eating this stuff is for their gut microbiota, they were thinking how good it was to have any food at all to eat in winter.

Before I go

This post has been about gut microbiota, because this is the largest single repository of microbes on our body. But, I don’t want to leave this post without commenting on a curious thing – many of us deliberately nurture our gut microbes (or try to), but we don’t have the same regard for our skin microbiota, even though they perform many of the same roles as those of the gut. Our resident skin microbiota have a key role in keeping our skin intact and healthy, they: communicate with our immune system and are a large reservoir for holding immune memory cells (T-cells); interact with other microbes and with human cells; are involved in wound healing and tissue repair; control inflammation, and; produce defensive anti-microbial molecules. The physical barrier of the skin is actually classified as part of our immune system, and the microbes on it are just as important.

Nevertheless, many of us scrub and shower with soaps and antibiotic washes on a daily basis. We use antiperspirants and deodorants, and rub on skin ’care’ products that may be detrimental to our helpful bacteria. In short, we disrupt our skin microbial colonies regularly, and without care. The irony is that we wash our bodies more than ever, even though our environment is more sanitised than ever.

As far as I can tell, most dermatologists recommend washing hands regularly, but showering only according to need, and probably no more than once or twice a week. Deal with problem areas with a damp sponge. Some adventurous souls have given up showering altogether, and are still able lead a social life. We didn’t evolve to shower and, after a transition period, our healthy skin microbiota get established and take care of everything for us, just as they do in the gut (even though some heroic people try to wash that out too).

Summary

Our microbiota are essential for our health. Many of the mechanisms whereby they do this have been identified. Many more are being discovered. However, our microbiota are evolved to suit us, and as adults our gut microbiota are normally stable and resilient. It seems to be a challenge to change that with probiotics or fermented foods in healthy people. Nurturing our resident microbiota prebiotically is likely to be a better strategy. Clinical research is still in its early phases. FMT may be the most promising strategy for serious clinical conditions.


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Further reading:

Animation – if we could see our skin microbiota… imagine that happening everywhere.

Systematic review of evidence to support the theory of psychobiotics

Diet, the Gut Microbiome, and Epigenetics

Structure and function of the human skin microbiome

Alterations in fecal microbiota composition by probiotic supplementation in healthy adults: a systematic review of randomized controlled trials.

Faecal Microbiota Transplantation (FMT) for Clostridium difficile Infection: A Systematic Review.

FMT requires comprehensive donor screening. The Phase 2 Clinical Trial, mentioned in the body of this post, did the following:

RBX2660 is a microbiota suspension prepared from donated human stool. Four donors were used to prepare the RBX2660 used in the study, and all completed a comprehensive initial health and lifestyle questionnaire and then provided blood and stool samples. Blood was tested for human immunodeficiency virus; hepatitis A, B, and C; and syphilis. Stool samples were tested for C. difficile toxin, norovirus, rotavirus, adenovirus, ova and parasites, vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, Vibrios, Listeria, and enteric pathogens. A questionnaire was completed at the time of every donation to confirm continued health. A sample was retained from each donation and then pooled with other samples from the same donor and subjected to repeat stool testing at 45-day intervals. Repeat donor blood testing was performed at a minimum of 14 days after the last donation in the cycle. If a donor passed the repeat screening, the unit manufactured from the donations within that donor cycle was released from quarantine. Each unit was identified by batch number and traceable to a specific donor and recipient. Good manufacturing processes and a standardized chain of custody were used.