A few weeks ago, I watched the recorded sessions from the Gut Microbiota for Health World Summit 2020. It’s been a great way to learn from researchers around the world while we are under the stay at home order.
In this article, I’m summarizing the main takeaways from the summit. If you’re interested in catching the full replay, you can watch all of the plenary sessions for free here.
1) The road to translating microbiome science is not always easy
Dr. Colin Hill from Cork, Ireland kicked off the conference with a stellar keynote discussing the major roadblocks that prevent us from getting developments from the laboratory into clinical practice. As the microbiome is much more malleable than our own human genome and involved in the pathology of a number of different diseases, it represents a rich source of options to intervene to influence human health. Probiotics, prebiotics, FMTs, diet and lifestyle interventions, and other targeted therapeutics all have great potential for treating human disease, but – he emphasized – they need to follow the defined path of clinical translation.
Collectively, researchers need to apply more rigorous standards. Dr. Hill argues that microbiome research has been plagued by sloppy language, imprecise numbers, and increasing complexity of data visualization at the expense of clear hypotheses and data-driven conclusions. The microbiome is a complex system that does not lend itself to simple, linear stories. Still, he remains optimistic that with these higher standards, many of these potential therapeutics will make their way into the clinic to prevent and treat disease.
2) Probiotics, prebiotics, and fermented foods: what’s the evidence?
Dr. Kevin Whelan from King’s College London gave a great overview of probiotics, prebiotics, and fermented foods, and the evidence for them in various conditions. Fermented foods are foods or beverages produced through controlled microbial growth and the conversion of food components through the action of microbial enzymes. These foods, including kefir, sauerkraut, and sourdough bread, have been consumed for centuries, but have remained a real challenge for microbiologists to formally study because of the high variation between different foods and even between batches of the same food inoculated with the same microbial culture. Most of the evidence thus far has been based on cell culture or animal studies.
He next discussed the evidence for probiotics, highlighting their lack of ability to colonize the gut and the possibility of delaying the return of the native microbiota after antibiotics. He highlighted several meta-analyses, suggesting that probiotics may be beneficial for managing constipation, irritable bowel syndrome, and even ulcerative colitis. Notably, the effects were both strain and disease-specific. Lastly, he mentioned prebiotics, specifically focusing on inulin-type fructans and fructo-oligosaccharides (FOS). Most interestingly, a recent study demonstrated that responses to a prebiotic fiber intervention are highly variable between individuals, irrespective of whether those individuals habitually consumed a high or low fiber diet. He also shared a recent meta-analysis of prebiotics in IBS, in which they found that low doses of prebiotics (≤6 grams per day) might reduce symptoms, while high doses of prebiotics (>6 grams per day) seemed to exacerbate symptoms.
3) The maternal microbiome shapes the infant immune system
Dr. Kathy McCoy from the University of Calgary discussed the impact of the microbiota on the development of the infant immune system. We’ve known for some time that a newborn acquires its microbiome through vertical transmission – that is, babies are colonized from their mom’s microbiota at birth. Dr. McCoy’s latest research has found that the maternal microbiota also helps in shaping the neonatal immune system.
Through a series of experiments, they demonstrated that maternal microbial products are loaded onto maternal antibodies, which can then pass to the baby through the placenta in utero, or through the breastmilk after birth! This is able to educate the baby’s developing immune system quite broadly. It also allows the infant to face its own onslaught of microbes during early life without excessive inflammation. This suggests that the maternal microbiota is not only important at birth, but is also already working to protect the baby and begin to shape its immune system during pregnancy. The group has preliminary data suggesting this may have long-lasting effects and is currently studying the implications for the development of diseases like type I diabetes.
4) A critical window exists for weaning to prevent inflammatory diseases later in life
Dr. Gérard Eberl of Institut Pasteur in Paris discussed the importance of weaning on the imprinting of the immune system. During weaning, a baby begins to eat solid foods and the gut microbiota begins to expand and diversify. This leads to an immune response called the weaning reaction. Dr. Eberl’s research group has shown that the timing of the weaning reaction and the proper signals during this period are critical for educating the immune system.
They discovered that bacteria, short-chain fatty acids from dietary fiber, and vitamin A were all required to support healthy imprinting of the immune system. Healthy imprinting led to low susceptibility to inflammation and immune-related diseases later in adulthood. On the other hand, antibiotics or a processed, Western diet during weaning resulted in pathological imprinting. Mice that had these exposures during the critical window had significantly increased susceptibility to inflammatory conditions like allergies, colitis, and cancer later in life.
5) Addressing the microbiome and inflammation in inflammatory bowel disease
Dr. Harry Sokol spoke about the pathogenesis of inflammatory bowel disease, highlighting the vicious cycle of inflammation and alterations in the gut microbiota. One strategy for targeting the microbiome, of course, is fecal microbiota transplant, or FMT. Dr. Sokol summarized four studies of FMT in ulcerative colitis, which were all performed in patients with active disease with the aim to induce remission. Three of the four trials had positive results, but with significant variability in individual responses.
Dr. Sokol believes that we likely need to target both the microbiome and the inflammation. To that end, his research group recently performed the first pilot clinical trial of FMT in Crohn’s disease patients. They enrolled patients with active disease but focused on inducing remission with steroids first. Once in remission, the patients were randomized to receive a donor FMT or a sham treatment, and then were slowly tapered off corticosteroid therapy. While this was a small study, those in the group receiving the donor FMT trended towards increased steroid-free clinical remission and had significantly reduced endoscopic scores after six months. Patients who had more stable engraftment of the donor microbiome seemed to have a greater likelihood of staying in remission. I was thrilled to see research targeting multiple aspects of the disease at once, and hope we see more and more researchers moving towards this more synergistic approach in studying gut therapeutics.
6) Spore-forming bacteria stimulate serotonin secretion in the gut and influence host physiology
Dr. Jonathan Lynch from Dr. Elaine Hsiao’s laboratory at UCLA presented on the interplay between serotonin and the gut microbiota. While we classically think of serotonin as a neurotransmitter, in many aspects it acts more like a hormone, with broad-acting effects throughout the body. Approximately 50-95 percent of our total body serotonin resides in gut tissues, primarily produced by specialized epithelial cells called enterochromaffin cells. Previous studies had demonstrated that the presence of gut microbes significantly affects gut and serum serotonin levels.
Most recently, Dr. Hsiao’s lab has found that spore-forming microbes are primarily responsible for stimulating serotonin release. Metabolomic analysis revealed that this was likely due to higher levels of the SCFAs butyrate and propionate and the bile acids cholate and deoxycholate. Notably, higher levels of gut serotonin also increased the abundance of these spore-formers in a sort of positive feedback loop. Using one particularly ubiquitous spore-forming microbe, Turicibacter sanguinis, they were able to identify a functional serotonin transporter. Amazingly, they found that fluoxetine, a commonly used SSRI drug, was able to inhibit serotonin uptake by T. sanguinus, and impair its growth in the gut. I found this topic fascinating and will be dedicating an entire blog post in the near future to serotonin in the gut.
7) Proton pump inhibitors negatively impact the gut microbiome
Dr. Rinse Weersma of the Netherlands presented on the detrimental effects of proton pump inhibitors (PPIs) on the gut microbiota. Upwards of 20 percent of the population may use these acid-reducing drugs, which are available for anyone to take without a prescription. Dr. Weersma acknowledged that there are several indications where PPI use may be warranted but emphasized that the majority of consumers have no evidence-based indication for their use.
PPIs have a number of reported side effects, including increased risk of Salmonella, Campylobacter, C. difficile¸ and other gut infections. They can also cause deficiencies in magnesium, calcium, and other minerals that require an acidic environment for absorption. Dr. Weersma’s lab has recently shown that PPIs increase levels of Enterobacteriaceae, a group of facultative anaerobes that has been shown to be highly abundant in a number of chronic disease states. He expressed concern that these drugs are available over the counter, especially when we don’t understand the long-term consequences of altering our long-evolved gut microbiome-host symbiosis on future generations. In my experience, these drugs do not address the root cause of disease, and typically make things worse in the long run.
8) Pharmaceuticals, both non-antibiotic and antibiotic, impact the gut microbiota
Dr. Athanasios Typas from Heidelberg, Germany gave a fascinating talk on the impact of other pharmaceuticals on the gut microbiota. A study from his lab published last year demonstrated that nearly a quarter (24 percent) of non-antibiotic drugs impact the gut microbiota. While I had seen the study before, I didn’t know just how conservative this estimate was. The researchers actually used much lower concentrations of each drug than would actually be found in the human gut for their screening assays and were extremely stringent in what they considered a positive result. Some of their statistical outputs suggested that if they had sampled more species, they would have seen a much greater effect.
Dr. Typas went on to share some of their research on the collateral damage caused by antibiotics, and how this could potentially be ameliorated. He first highlighted that different classes of antibiotics have differential effects on the microbiota: sulfonamides and aminoglycosides seem to target very few strains, whereas macrolides and tetracyclines seem to target virtually all microbes. By screening thousands of different drugs, they were able to identify specific antidotes for certain commensal bacteria that allowed them to survive, even in the presence of macrolides or tetracyclines. This targeted approach is certainly unique, though I couldn’t help but wonder how well it would translate to a clinical setting, where we ideally want to preserve all of our native species. I’ll plan to have a future post dedicated to antibiotics and how to mitigate their damaging effects.
9) Integrative treatments for host-microbes symbiosis may target the vicious cycle of dysbiosis
Last but not least, Dr. Joël Doré of France talked about profiling host-microbe interactions in clinical practice. The human body is a complex system, and despite considerable progress in medicine, chronic disease has been rising in incidence, uncontrolled for over 60 years. Clinical trials thus far have been designed based on a model of one causative agent >> one risk >> one disease. We desperately need tools that deal with innovation and translation in a totally different configuration, one that recognizes the system and understands that in reality, the model looks more like: host-microbe interactions >> risk >> disease. I discussed a similar framework – the germ-organ theory of chronic disease – in a recent article.
Dr. Dore explained that gut dysbiosis, or an altered gut microbiota, is a common thread among various chronic conditions – but does not occur in isolation. When we have an altered gut microbiota, we also have a vicious cycle of intestinal permeability, inflammation, and oxidative stress. Dysbiosis can, therefore, be thought of as a disruption of host-microbes symbiosis. He further suggests that we start to use standardized diagnostics that assess all four components, and rationally combine treatments that can target all aspects of this vicious cycle. I couldn’t agree more, and hope that increasingly more researchers are approaching things from this perspective!!
That’s all for now! I hope you enjoyed this summary. Be sure to subscribe and share what you thought of this research in the comments below!
P.S. I’m hosting a summit in May with some of the top microbiome researchers! Be sure to check it out – it’s completely free to register.