Gut health is a fascinating economy of research and health promotion. It has inspired and empowered leagues of ordinary people as they delve into the advice, regimes and products that promise healing and vitality via fixing the gut and bolstering the integrity and biodiversity of their gut microbiota – now framed as being a critical underpinning factor in all manner of chronic and autoimmune conditions. Commercial prebiotic and probiotic formulas are taking the market by storm, with heaps of anecdote to support their utility and therapeutic effect. But what’s the crack, do they work? Well yes, no, maybe… some of them and in unexpected ways. The science supporting microbiome modulation via probiotics is in its infancy and there are a great deal of other factors to consider in the quest for gut health. Here we put the rise of microbiome based therapeutics in context, recommend some discernment via a cursory glance at some of the science and try to think a bit more laterally about what true gut health might mean for everyone.
But what’s the crack, do they work? Well yes, no, maybe… some of them and in unexpected ways.
The groundswell in microbiome research and subsequent therapeutic intervention emerged out of the Human Genome Project (1990 – 2003) really – which inspired a great deal of hope and investment, both socially and economically. Infact, it was one of the most resourced areas of biomedical research in history.(1) The notion that a stable genome could be mapped across the human population, with any variance being an “indicator for human health, disease and difference”(2), inspired considerable public support and commercial investment. The opportunities for biotechnical intervention and therapeutic innovation through decoding and mapping the human genome provoked considerable hand wringing. However, despite the hype, the therapeutic application of genomic science has been scant (3) – In a fascinating plot twist, assumed an anti-climax for some and an ever expanding frontier of medical research for others, the potential of genomic science was detonated through the technological advancements catalysed by the HGP and segued into new realms of biological complexity vis a vis the human microbiome.
Compared to the 22,000 human genes sequenced through the Human Genome Project (HGP) defined as the mammalian genome, 3 million genes constituting a secondary genome belong to bacteria in the body which outweigh human cells by around 3:1. Advances in high-throughput sequencing technologies have extended research via the Human Microbiome Project (2007 – 2016) into this “microbial dark matter” (4) – promising new insights into health, susceptibility to specific diseases and “mechanisms of person to person variations in response to food, drugs, vaccines and other health interventions” (5). These research advancements are heralded as a “panacea for personalised medicine” (6) with the hope that developments in the scope of sequencing across diverse populations will produce biomarkers which can help “diagnose microbiome driven impacts on health and the necessary evolvement of therapeutics” (7). Non-communicable diseases without current clinical understanding and effective intervention, which have eroded the legitimacy of modern medicine since the 1970’s, have now become a “prevalent scope for microbiome modulation” (8).
Compared to the 22,000 human genes sequenced through the Human Genome Project (HGP) defined as the mammalian genome, 3 million genes constituting a secondary genome belong to bacteria in the body which outweigh human cells by around 3:1.
The research of The Human Microbiome Project (HMP) has instigated a paradigmatic shift in medicine as it becomes clear how heavily influenced human biology is by the microbiome; a body of research now explores how bacteria and their metabolites may affect everything from evolution (9), physiology, metabolism (10), immunity (11), neurology (12), susceptibility to infectious diseases and sleep & circadian rhythms. Whilst also underpinning, or at least being correlate to, the different disease processes and autoimmune conditions that have become such a mainstay of our contemporary medical landscape (13). The nascent field of microbiome biotherapeutics or microbiome modulators – a new class of phamacomicrobiomically engineered therapeutics aimed at having a corrective or healing effect on perceived abnormalities or dysbiosis in the human microbiome – are predicated on this new wave in medicine.
These insights have seen the HMP attract a similar amount of sensationalism and funding as witnessed with the HGP. Between 2007 – 16 $215m was “rapidly deployed as research resources” which supported over 35 different institutions and 50 research consortiums. A further $1BN in “extramural NIH funding” (14) has been extended to the project now in its second stage under the umbrella of The Integrative Human Microbiome Project. Overall the project has achieved quite a feat; creating an open source data bank which helps characterise the microbial communities from 300 healthy individuals and now in its second stage, of creating longitudinal data sets to properly understand the correlation between microbiome distributions and particular diseases.
The impact of social, cultural and environmental factors on the composition of gut microbiota and related pathogenesis are a critical indices in microbiome research.
The community of scientists involved in the project insist the findings are nascent and tentative. Telling the difference between the microbiome of healthy and sick people in tightly controlled studies is a very different thing to do in the general population (15). Further, whilst certain bacteria might be indicated in various disease states, it’s another leap to understanding their actual function and role in pathology. No doubt the HMP continues to provide fascinating “health-related associations” but rather like the fallout of the HGP, “the discovery of associations very rarely translates to direct interventions” (16). For instance, the impact of social, cultural and environmental factors on the composition of gut microbiota and related pathogenesis are a critical indices in microbiome research. Factors such as “diet, chemical exposure, and change in behaviour, which are thought to affect the composition of our microbiota, may be more predictive of disease than either human DNA or microbial DNA” (17).
However, despite being lambasted for too prematurely extrapolating the science of the HMP into therapeutic innovation (18,19), this hasn’t prevented a commercial bloom in microbiome biotherapeutic startups and the growth of microbiome technologies. Beyond improving the clinical efficacy of pharmaceuticals through assessing the impact of the potentially disruptive prism of the microbiome on bioavailability and effect (20), a whole new class of biotherapeutics is both anticipated and actively being generated. Of course on some level these are by no means a new class of therapeutics – the market for prebiotics and probiotics has been established and expanding rapidly for some years now. However, the research field is deepening and a number of pharmaceutical companies specifically aimed at biotherapeutics with a special interest in the microbiome are emerging. The market for microbiome modulators has grown exponentially, with an annual growth rate of approximately 6.08% with the global market for drugs “anticipated to grow at the fastest CAGR of 22.26% during the forecast period 2018-2023” (21).
There is no core human microbiome. Indeed, the variation and malleability of the microbiome between individuals is complicated and vast and the research aiming to disentangle and make sense of this phenomenon to create robust bioinformatics to enable effective intervention and therapeutics in microbiome related pathogenesis, is in its infancy.
For the health consumer this is an interesting time. Indeed, for anyone in the role of health advocacy around gut health there is enormous responsibility in making claims around the efficacy of probiotic products or other microbiome therapeutics. Whilst fecal matter transplant – taking stool from a healthy donor and using it as a way of repopulating the microbiota of a patient’s gut, has shown great promise particularly in cases of acute infection of clostridium difficile through microbiome modulation – commercial probiotics and other ‘gut friendly products’ just don’t carry the same proven legitimacy.
Ultimately, there is ‘no core human microbiome’ (22). Indeed, the variation and malleability of the microbiome between individuals is complicated and vast and the research aiming to disentangle and make sense of this phenomenon to create robust bioinformatics to enable effective intervention and therapeutics in microbiome related pathogenesis, is in its infancy.
The idea that probiotics can alter the gut microbiota is an attractive notion but one that needs more research (23). VSL#3 is a leading probiotic and stands out as one that has enjoyed some clinical research. In two papers, the application of VSL#3 showed efficacy in preventing the relapse of ulcerative colitis or in treating IBS, but not necessarily as a result of having any marked impact on the composition of gut microbiota overall; raising questions about the exact mechanisms of their therapeutic effect (24,25). In mice models after exposure to antibiotics, attempted re-population of the microbiota with VSL#3 led to significant enhancements in the regulation of immunity. But again, this was not necessarily owing to a direct impact on the composition of the microbiota but rather through the crosstalk and interaction of probiotics and their byproducts with host microbiota (26). The social enterprise “IBD Relief” does a good job at breaking down the clinical research applied (or not as the case may be) to a number of leading brands of probiotics (27). Many market formulas are without clinical evidence but support their marketing with public research carried out on specific strains – for instance such as through the utility of Saccharomyces boulardii to aid in the prevention of chron’s disease flare ups, which is supported by some preliminary research.
The theapeutic effect of probiotics does not necessarily owe to a direct impact on the composition of the microbiota but rather through the crosstalk and interaction of probiotics and their byproducts with host microbiota.
It’s clear that commercial probiotics hold promise but before buying a brand consider whether there is any underpinning or associated research to make your purchase worthwhile. The market for probiotics is expanding rapidly and there’s some serious money to be made – be discerning. Afterall, the human microbiome is as much a social and cultural organism as it is biological. One of the biggest factors impinging on microbiome composition is where an individual may live (urban vs rural / indigenous) and their associated cultural and lifestyle factors which extend to diet, behaviour and general relationship with the land. It seems that one of the most important things for microbiome health is where you are situated, the nature of your environment and how you live your life. Pragmatically, for microbiome health, this may mean avoiding environmental stressors on the microbiome related to a modern industrial lifestyle (pharmaceuticals, processed foods, stress) and embracing your nature as a creature of the outside. In that sense, probiotics can only ever be part of the picture in microbiome health and anyone or anything selling you something otherwise should be taken with a pinch of kraut. Fully appreciating the truly holistic nature of the human microbiome is perhaps the liberatory potential of this paradigmatic shift in medicine. Systemic change, which honours the environment that we are, is the medicine.
Pragmatically, for microbiome health, this may mean avoiding environmental stressors on the microbiome related to a modern industrial lifestyle (pharmaceuticals, processed foods, stress) and embracing your nature as a creature of the outside.
Of course, you might be wondering, what does this mean for the oft-told therapeutic effects of our beloved fermented foods? The good news is, they’re still healthy. Just perhaps not in the way we might think. Tune into our next segment as we drill down into their potency and effect.
Until next time!
Image Credit: Ideas.Ted.Com
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(2,15) Lappe, M. & Landecker, H. (2015). Sociology in an age of Genomic Instability: Copy Number Variation, Somatic Mosaicism, and the Fallen Genome. Genetics, Health and Society. Published online: 16th July 2015: 157-186 https://doi.org/10.1108/S1057-629020150000016006
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(8,21) PRNewswire. (2018). Global Human Microbiome Modulators Market: Focus on Non-Dairy Supplements, Drugs, Applications, 15 Countries Data, Pipeline Product Mapping, and Competitive Landscape – Analysis and Forecast, 2018-2023. Published online 12/12/2018 https://www.prnewswire.com/news-releases/global-human-microbiome-modulators-market-focus-on-non-dairy-supplements-drugs-applications-15-countries-data-pipeline-product-mapping-and-competitive-landscape–analysis-and-forecast-2018-2023-300764238.html
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(27) IBD Relief. Accessed online. https://www.ibdrelief.com/