The gut microbiome and circadian clocks in personalized treatments for disorders of gut-brain interaction and type 2 diabetes

Purna Kashyap from Mayo Clinic (USA) kicked off the GMFH World Summit with a summary of current evidence on using the gut microbiome for precision medicine.

While the one-size-fits-all approach in medicine has ceased to be efficient, precision medicine is a model focused on tailoring treatments to subgroups of patients by using an integrated multidisciplinary approach combining different kinds of genomic and environmental data. Precision medicine requires considering both the microbiome as an integral component of our hologenome and the exposome (i.e., drugs, pathogens and diet).


Microbiome as a potentially modifiable factor at the frontier of personalized medicine.
Source: Purna Kashyap’s presentation at the GMFH World Summit 2022.

One example of the gut microbiome’s relevance in personalized nutrition and medicine is the prediction of postprandial blood glucose responses to diet using an unbiased machine learning approach. It highlights a strong microbiome impact as driver of interindividual variability. While the microbiome is an integral component of precision medicine, Kashyap suggested that the future work needed to incorporate the microbiome as a tool for individualized interventions includes identifying clinically actionable microbiome-driven mechanisms that will enable more effective subtyping of patients and improving the comparability of microbiome data worldwide. In that regard, a checklist has recently been published for guiding scientists and encouraging reproducibility in reporting the results of human microbiome research.

Nicola Segata from the University of Trento presented large-scale studies showing links between some microbes, favorable metabolic traits and dietary patterns, which were especially driven by the presence and diversity of healthy and plant-based foods. While we are far from predicting what a person should eat based on their gut microbiome, Segata highlighted that machine learning algorithms allow us to better predict how each individual may respond to dietary patterns, foods and nutrients.

As it becomes possible to identify the microbes most associated with specific foods, the challenges in unraveling nutrition-microbiome links that need to be solved to move the field forward include: strain-level resolution in microbiome studies; unraveling the unknowns in the human microbiome; using large integrative cohorts; considering the transmission of the microbiome; considering phages; better functional profiling; and using integrative omics. Nicola Segata also presented the Microbiome Virtual International Forum:

Dirk Haller from the Technical University of Munich shared recent data on arrhythmic bacterial signatures that enable classification and prediction of type 2 diabetes across different cohorts, supporting the hypothesis that daily oscillation of microbial profiles is functionally linked to metabolic health. Up to 15% of identified operational taxonomic units were rhythmic, some of them peaking during the day and others peaking at night. The findings also show the importance of considering time of defecation in microbiome research and highlights that collecting a single daily fecal sample when studying the gut microbiome may not be enough to achieve an overall picture.

Gut bacteria oscillate during the day and night, which makes it a challenge
studying the gut microbiome based on a single day sample.
Source: Dirk Haller’s presentation at the GMFH World Summit 2022.

Emeran Mayer from University of California Los Angeles shared epidemiological and clinical studies that support the hypothesis that irritable bowel syndrome (IBS) symptoms and anxiety/depression are indeed two closely linked manifestations of the brain-gut-microbiome system. While a causal role for the gut microbiome in IBS is yet to be confirmed, multiomics analyses have established significant differences in the composition and function of the gut microbiome between IBS and healthy controls and between IBS subgroups based on bowel habits. As such, it seems that multiomic microbiome classifiers for IBS perform better than those only focused on composition, metagenome, metatranscriptome and metabolome.

Furthermore, IBS-diarrhea and IBS-constipation can be differentiated through diverse microbiome functional shifts. When it comes to clinical translation of targeting the gut-brain system, a randomized controlled trial found that cognitive behavioral therapy reduced IBS severity through involving changes in the gut microbiome composition and increased levels of microbiome-derived serotonin levels in fecal samples.


How human migration and diet drive an altered gut microbiome

Dan Knights from the University of Minnesota covered the effects of immigration and diet on microbiome variation. In that regard, moving to an industrialized country increases the risk of metabolic disorders such as obesity within just a few years of residence. That is partly explained by the loss of ancestral gut microbes related to many diseases, as reported by the Immigrant Microbiome Project. The gut microbiome diversity decreased with each generation of residence in the United States. After two generations, the microbiomes of residents that immigrated from Thailand were no longer distinguishable to US residents.

Knights also presented data showing that food intake is highly individualized and diet alone only explains up to 10% of microbiome variation. Indeed, he noted in his presentation that “Our gut microbes care about actual foods and see a lot more than what’s on food labels”. That explains some links between gut microbes and foods but not at the nutrient level, with the current understanding of how diet affects health limited to nutritional components tracked by available databases and not including untracked biochemicals in food.


Why thinking in terms of foods rather than isolated nutrients is more important for gut microbes.
Source: Dan Knights’s presentation at the GMFH World Summit 2022.

Diet composition can also impact the metabolic products that are ultimately present in the gut lumen and plasma, as suggested by data presented by Gary Wu from the University of Pennsylvania. By following individuals with a vegan, omnivore or synthetic enteral nutrition diet lacking in fiber, Wu and colleagues showed the dramatic reduction in gut microbiome recovery seen with a fiber-free diet, which was also accompanied by an alteration of carbohydrate and amino acid-derived bacterial metabolites. Thus, depriving the human gut microbiome of a dietary component such as fiber can affect metabolites related to other dietary substrates involving the induction of specific gut bacterial taxa.

Rachel Carmody from Harvard University focused on how not only diet but also food processing shapes gut microbiome structure and function, highlighting the plasticity of the gut microbiome to adapt to food availability in the environment. Low-digestibility starch (raw sweet potato) and high-digestibility starch (cooked sweet potato) led to profound changes in gut microbiome composition and function within hours, and that was also seen in humans who ate plant-based diets served raw or cooked. The key impact of starch digestibility was confirmed when it was found that the effects of cooking on the gut microbiome were most profound for starch-rich foods (sweet and white potato) compared with nonstarchy foods (beet and carrot).

In addition, cooking foods led to an inactivation of antimicrobial compounds that plants use to defend themselves, while raw plant diets increased xenobiotic metabolism and let to a fall in susceptible gut microbes. Finally, transplanting gut microbes from mice fed raw-versus-cooked plant foods into germ-free mice showed that recipients of the raw plant diet gained more body mass and fat. On a raw diet, less energy was gained directly by the host and more nutrients reached the colon and led to increased microbiota-driven energy gain.


Potential applications of microbiome-based therapies for pathogen infection and modulation of cancer therapy

While fecal microbiota transplantation has been widely used for recurrent Clostridioides difficile infection (CDI), limitations such as heterogeneity and safety issues prompted scientists to supplant the technique with rationally designed microbial therapeutics consisting of a well-characterized mixture of effector bacterial strains.

Sahil Khanna from Mayo Clinic gave an overview of available standardized microbiome-based therapies, including available standardized microbial replacement therapies proven to be a safe and effective in treating recurrent CDI. For use after a first, second or third episode of C. difficile, they potentially reduce the heterogeneity of fecal microbiota transplants while correcting the disrupted microbiome that antibiotics do not address.

Current standardized microbiome-based therapies in the pipeline, tested in phase I, II and III clinical trials.
Source: Sahil Khanna’s presentation at the GMFH World Summit 2022.

Other conditions in which standardized therapies are being investigated in preclinical and phase I clinical trials are ulcerative colitis, urinary tract infections, hepatic encephalopathy, solid tumors, gram negative infections and food allergy.

Kenya Honda from Keio University and RIKEN Center for Integrative Medical Sciences in Tokyo explained a reductionist approach focused on identifying a minimal effector species or consortium that acts on a specific phenotype for therapeutic purposes. The research has identified different effector bacteria consortia with immunomodulatory properties, of interest for IBD and cancer treatment, for managing pathogen infection and improving metabolic health. Honda focused his talk on the role of Klebsiella decolonization and trypsin-degrading bacteria as targets for managing IBD, multidrug-resistant bacterial microorganisms and viral infections. Honda’s research group is now working on translating the findings into the clinical setting for managing multidrug-resistant bacterial microorganisms, viral infections and inflammatory bowel disease.

Jennifer Wargo from MD Anderson Cancer Center updated microbiome-related interventions studied in the context of improving responses to cancer therapy and limiting toxicity in patients with established cancer. Wargo shared recent findings on the impact of intra tumoral microbes and gut microbes in response to cancer immunotherapy. She also discussed how the gut microbiome can be modulated to enhance responses to immunotherapy and abrogate toxicity. For instance, gut microbiome modulation via fecal microbiota transplants has been shown to improve responses to treatment in patients with metastatic melanoma and in treating immunotherapy toxicity.

In addition, diet can affect response to immune checkpoint blockade, with patients who consume at least 20 grams of dietary fiber a day with no probiotic use living longer without their cancer progressing than those who consumed less dietary fiber.

Dietary fiber is linked to cancer immunotherapy response.
Source: Jennifer Wargo’s presentation at the GMFH World Summit 2022.


The future outlook for probiotics

The last plenary session focused on how the field of probiotics can approach rational selection of microbes and genetically engineered and synthetic bacteria. Eric Alm from Massachusetts Institute of Technology focused on designing microbiome-based therapeutics through a rationally designed cocktail of probiotics. Alm presented research showing the potential of specific bacterial clades from the gut, including Faecalibacterium prausnitzii levels within Ruminococcaceae, as a means of predicting risk of antibiotic-associated diarrhea (study in 30 healthy subjects).

In addition, Alm is trying to cultivate and isolate a broad diversity of bacteria from the fecal samples derived from human communities across the planet coupled with genome sequences and multi-omics data with the final goal to develop a library of gut bacteria before they disappear and explore mechanistic microbiome research. One of the challenges is the fact that gut bacteria continuously acquire new functionalities based on host lifestyle secondary to industrialization.

Philippe Langella from INRAE focused on genetically modified lactic acid bacteria to deliver proteins of therapeutic interest for inducing both mucosal and systemic immune responses. For instance, Lactococcus lactis and Lactobacillus casei can deliver proteins such as elafin and secretory leukocyte peptidase inhibitor to counterbalance protease-antiprotease imbalance and restore membrane permeability in patients with IBD. Likewise, lactic acid bacteria can also be used to deliver cDNA plasmid with microbial anti-inflammatory molecules from F. prausnitzii to reduce colitis.


Food-grade lactic acid bacteria are good candidates for mucosal delivery strategies for therapeutic proteins and DNA vaccines.
Source: Philip Langella’s presentation at the GMFH World Summit 2022.

Moreover, Sloan Devlin from Harvard Medical School explored recent data on the potential of microbiota-derived small molecules that may have probiotic effects. Devlin’s research focuses on understanding molecular mechanisms behind the causal involvement of the gut microbiota in human health and disease. In particular, Devlin’s lab focuses on inhibiting bile salt hydrolase that converts primary bile acids into secondary bile acids as a means of affecting host metabolism and immune pathways in the gut and liver. New findings presented suggest that human gut bacteria produce abundant gut metabolites known as isolithocholic acid, which inhibit TH17 cell differenciation in mice. They also contribute to gut immune balance and may be of interest in relation to inflammatory bowel disease.

Dr Devlin illustrated the protective impact of a Bile Salt Hydrolase inhibitor in a rat model with marked modulation of intestinal permeability biomarkers. Finally showed that isoallo lithocholic acid promote Treg cells (anti-inflammatory) while 3oxoLCA and isoLCA inhibit Th17 Tcells differenciation.


Gut microbiota-derived bile acids metabolites exhibit anti-inflammatory properties with therapeutic potential in the context of inflammatory bowel diseases.
Source: Sloan Devlin’s presentation at the GMFH World Summit 2022.


COVID-19, the gastrointestinal tract and the microbiome

COVID-19 is not only a respiratory disease and Siew Ng from The Chinese University of Hong Kong closed the GMFH World Summit with an update on what we have learned so far about the connection between COVID-19 and the microbiome.

The gut may act as a SARS-CoV-2 reservoir and the gut microbiome can shape COVID-19 risk and severity. That is supported by findings that show how several immunomodulatory species, depleted in COVID-19, persist for more than 30 days after clearance of the virus, together with an excessive inflammatory response and an altered gut microbiome composition that persisted for more than 6 months.

Gut microbiome composition emerges as a predictor of COVID-19 vaccines’ immunogenicity and adverse events.
Source: Siew C Ng’s presentation at the GMFH World Summit 2022.

There are 14 interventional trials taking place on gut microbiota modulation in COVID-19. Some recent data exploring microbiota modulation as potential therapeutics in COVID-19 presented by Ng include a recent observational study involving more than 7,300 subjects (with SIM01 Microbiome Immunity Formula), in which well-controlled blood glucose correlated with improved outcomes in COVID-19, suggesting the potential of a low glycemic index diet rich in vegetables and fruits for improving outcomes in hospitalized patients. Proof-of-concept research has also shown the benefits of cocktail formulas with probiotics and prebiotic fibers as adjuvant therapy in immunological responses and changes in the gut microbiome of hospitalized patients with COVID-19. Finally, there was mention of preliminary evidence in mice and humans on the role of gut microbiome composition as a predictor of immune response to COVID-19 vaccines and vaccine-related adverse events.


References and recommended reading:

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4. The future outlook for probiotics

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5. COVID-19, gut microbiome and probiotics

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Online COVID-19 gastroenterology collection published by Gut, Frontline Gastroenterology and BMJ Open Gastroenterology: