The organ we never realise we had. The sheer biomass of microbial life teeming within our gut is becoming widely recognised as an important influence on our health and, as research suggests, our predisposition to disease. But could shifting the balance of this mysterious microscopic community be a useful therapeutic strategy for disease?
Like any good promising therapeutic tagline, targeting the rogue 37 trillion microbes in our gut offers a left-wing and highly adaptable angle to targeting a wide range of diseases. Well, perhaps if we can get it right. But how could we perturb an entity that exceeds our own human cells at an estimated count of 3:1? And if so, could we change or disrupt our tiny denizen bugs (good or bad) in such a manner that we can prevent or treat a range of different diseases?
What is the biological purpose of our gut microbiota?
While bacteria inhabit nearly ever recess of our bodies; it is the special niche of the gut that really redefines a viable therapeutic target. The gastrointestinal microbiota is the largest and most diverse assembly of commensal and mutualistic bacterial species in our bodies. At such levels, in fact, that the entire totality of their genomes rivals ours at a thought provoking 100x – an entire other genome, just to blow your mind. Our enteric brethren, however, are widely regarded to play an important role in our normal physiology.
The normal flora of our gut (the beneficial microbial populations) colonise as early as 1 to 2 years after birth and ultimately aid in immune cell development and training, the production of fatty acids, food digestion and fibre breakdown; as well as other general roles in metabolism. Our volatile microbiome is essentially acting as an “exteriorized” endocrine organ and weighing as much as a human brain. And like other organs, this organismal bolus can extend its impact outside of the gut and exert its influence to the brain. It’s the topic of “microbially derived metabolites” influencing brain signals and behaviour that really spark the question of how many of our thoughts and impulsive behaviours are genuinely our own? Also, what kind of secret “Chinese whisper” style games are happening between our gut bugs and our brains.
Outnumbered at a cellular and genome level; what happens when our relationship with our microbes falls apart? Scientists have identified that getting the wrong bugs in the mix could predispose individuals to a whole suite of problems from type 2 diabetes to cardiovascular disease, cancer and as far wide as autism and obesity.
What happens when the balance shifts against our favour?
Recent studies have illuminated that in a lot of cases our microbiome landscape differs quite dramatically from healthy individuals to those afflicted with a disease. And it is really a change in who our friends are, in an already stabilised microbiome population, that is the problem.
Characterising these shifts has become a senior focus in some institutions, where the microbiome has been implicated as a significant trigger for many inflammatory, metabolic, neuropsychiatric, and other chronic conditions. Even our baseline mood may suffer from a skewed excess of opportunistic bad bugs, secreting and influencing our dopamine and serotonin levels (but that is up for debate). A report in Nature last year saw researchers at the Weizmann Institute of Science elegantly demonstrate for the first time that the microbiome may be a powerful contributor to post-dieting weight gain. The unique approach involved transferring the intestinal microbes from mice with a history of obesity into a germ-free, essentially microbiome-less, cohort of mice. Low and behold, the addition of a high fat/ high-calorie diet saw the rapid accumulation of those mice now toting the high-fat microbiome versus the microbiome of an obese-naïve, in all respects, skinny mouse.
In a very close link and slight jump to other metabolic syndromes; scientists from Broad Institute in the US and Seoul National University, South Korea published evidence in the journal Genome Medicine highlighting a potential link between our gut microbiota and the development of Type 2 diabetes (T2D) by studying the fecal metagenomes (otherwise known as microbial genomes) of 20 healthy Korean identical twins. The researchers were able to identify associations between T2D-related biomarkers, microbial species and host biochemical functions. What is interesting about this study is that it provides an unbiased view of microbial populations in individuals who share the same genetic traits and lack an already established disease. Minus these biases, the authors were able to confidently show that chronic, low-grade inflammation associated with obesity and metabolic syndromes, like T2D, may be the result of sub-clinical inflammation caused by a shift in microbial communities.
But what is exciting about our increasing curiosity in the microbiome, coupled with extraordinary leaps in technologies such as sequencing, our handling of big data and CRISPR; is the ability to look at a multitude of different diseases with our heads cocked at a completely different angle. Taking aside the metabolic syndromes such as obesity and T2D, we are now understanding that a stressed microbiome may be strongly associated with many gastrointestinal conditions, autoimmune disease, asthma, regulation of tumour growth and even contributing to the autism spectrum (it seems the pesky Clostridium and Sutterella genus might be to blame for this one).
A reader … may be surprised by my recommendation to absorb large quantities of microbes, as a general belief is that microbes are harmful. This belief is erroneous.
– Élie Metchnikoff, Nobel Laureate, 1907.
What are the therapeutic avenues being explored to target the microbiome?
The microbiome therapeutic market itself is set to gain traction itself – coined as the next big frontier in medicine. But how can we positively target the cocktail of microbes in our gastrointestinal tract? And if we can, is it precise enough to effectively treat disease? I guess the answer to those two questions remains quite challenging at this early phase. But I think a tentative yes is in order. While we have the precise and effective whole genome sequencing based library of the good and bad microorganisms associated with human habitation (courtesy of the Human Microbiome Project), we tend to be just bottling up those results, jamming them into a pill or throwing a probiotic at it. New approaches in microbiome-based therapeutics are currently being investigated under the guise of three strategic paradigms: additive, subtractive or modulatory therapies. What is attractive about each one is they can be used to specifically target our guts to modulate our balance back into the green.
Probiotics and prebiotics (additive and modulatory approaches, respectively) have been extensively reviewed as the first generation of microbial-based therapies. Indeed, we see this in our local supermarket when we pass the yoghurts rich in beneficial bacteria. Multiple clinical trials have also suggested a probiotic effect in the treatment of gastric infections of H. pylori – a powerful causative microbial agent in the aetiology of colorectal cancer. One viable way to balancing out our gut microbes is also getting a few heads turning. The Fecal Microbiota Transplantation (FMT) has had tremendous success in treating people who have failed typical antibiotic therapies. The idea itself is effectively a probiotic and an arguably practical one at that. Healthy individuals are able to donate donor stool to act as a reference microbiome to repopulate and balance out a sick individual. Recent studies have shown this to be an effective treatment for C. difficile infection.
Furthermore, researchers from multiple countries including China, Germany and the UK have found that obesity predisposed children with a rare genetic condition known as Prader-Willi syndrome (PWS) may be able to be treated with a prebiotic intervention to successfully shift their metabolism and microbiome to more favourable profiles. We can also subtract opportunistic microbes from our stomachs when they become pathogenic. Recent results from a Phase 2 clinical trial suggested that a synthetic oral enzyme known as ribaxamase may be able to help degrade certain antibiotics within the gastrointestinal tract and prevent an opportunistic Clostridium difficile (C.diff) infection.
However, we have yet to see any marketable translation into space; an unsurprising narrative is given that we are yet to fully grasp how these microbial populations work and tinker. But biotechnology companies are working on it and certainly making ground. Nevertheless, the jury is still out on the complete role that our microbiome plays on our general homoeostasis. In fact, one could ponder the role that gut bugs have played over the course of our entire evolution (and us unto them). While the symbiosis we both share becomes obvious, it is the dysbiosis that occurs with our complex lifelong relationship that has scientists looking down to their belly buttons and thinking, “what if?”. Currently, we are not at a stage that we can be prescribing prebiotics to children at risk of autism, or diabetes. Neither can we confidently say we have a faecal transplant therapeutic option for weight loss. But if we are not there now we are certainly close.
What has not been touched on yet is the positive ways we could harness these microbes for personal good. Is there a way to enhance our personal senses, eliminate depression or detoxify alcohol sooner? Think the midichlorians from Star Wars meets an energy drink. The over-dramatised reference to the “human super-organism”. And with that, I will conclude… except to say, long live our budding friendship with our gut biology. I’ll be off to eat some kimchee and yoghurt.
The opinions in The Freethink Tank’s Opinion category are those of the author and are no reflection of the views of the website or its owners