Microbiome-based therapeutics and precision medicine for better health

Eran Elinav from the Weizmann Institute of Science (Israel) and German Cancer Research Center (Germany) kicked off the conference by highlighting that the current ‘one size fits all’ microbiome treatment approach is outdated and that we should create a new microbiome and clinical data-driven therapeutic ‘toolbox’.

The targeted suppression of human gut commensals contributing to non-communicable diseases remains an unmet challenge. Elinav shared first-of-its-kind findings on using an orally administered cocktail of phages to effectively suppress IBD-contributing pathobionts belonging to Klebsiella pneumoniae clade 2 strains. These pathobionts are expanded in Crohn’s disease and ulcerative colitis flares across patients from Israel, EUA, France, and Germany and contribute to inflammation and tissue damage. To solve phage immunogenicity and phage resistance, Elinav and colleagues administered orally, for the first time, the phages that attacked pathobionts of interest through different receptors. The cocktail of phages showed evidence in mice in eradicating human K. pneumoniae without inducing an off-target dysbiosis. Also, a first-in-human phase 1 clinical trial showed phages are viable and safe in the lower human gut. This pioneering work awaits IBD results1.

Pipeline for the utilization of phage therapy as a means of sustained suppression of gastrointestinal pathobionts associated with IBD and other non-communicable diseases.
Source: Eran Elinav’s presentation at the GMFH World Summit 2024.

The first plenary session addressed the mechanisms by which gut microbiome shapes health and disease. Meng Wu from Washington University in St. Louis focused on how the gut microbiome modulates the gut complement, which acts as the first line of defense in the blood. Wu presented new findings showing that luminal C3 is detectable in fecal samples from healthy humans and mice and modulated by microbiota composition, with stromal cells located in intestinal lymphoid follicles acting as a major source of luminal C3. Interestingly, luminal C3 levels correlate with mice susceptibility against Citrobacter rodentium, highlighting that the gut complement is central in complementing innate immune responses against pathogens2.

How the gut complement interacts with commensal and pathogenic microorganisms. Source: Meng Wu’s presentation at the GMFH World Summit 2024.

Longitudinal multi-omics data, clinical tests, and biomarker analyses open a window into wellness. Nathan Price from Thorne HealthTech presented findings from the pilot study “Pioneer 100 Wellness Project” using systems biology computational methods to produce data clouds for each person based on measuring various samples, including feces, at three-time points for 9 months in a cohort of 108 individuals. Scientific wellness studies like this have taught us that defining a reference ‘healthy’ microbiome is challenging3. In addition, almost half of the variance in gut microbiome diversity and weight loss outcomes in people with obesity is explained by gut microbiome functions, particularly a subset of 40 plasma metabolites (13 of the 40 of microbial origin), rather than baseline diet4,5. Price and colleagues also developed ‘biological body mass index’ scores calculated from multi-omics data and clinical laboratory tests (“biological BMI”). They show that biological BMI predicts health risks more accurately and responds to lifestyle shifts better than a classically measured BMI (“traditional BMI”)6.

It also turns out that as people get older, their gut microbiome tends to change and the greater the change, the better. These findings suggest the gut microbiome is important for healthy aging and is highly personalized, while the resulting metabolic features are consistent, said Price. In contrast, the microbiome’s composition remains static in people who are less healthy and die earlier7.

A gut microbiome that continually transforms as you get older is a sign of healthy aging. Source: Nathan Price’s presentation at the GMFH World Summit 2024.

In the context of disease, Ken Croitoru from Mount Sinai Hospital and University of Toronto highlighted that environmental triggers play an important role in IBD supported by the increasing incidence in newly industrialized countries. Through developing a microbiome risk score using a machine-learning model including bacterial composition and clinical variables from 3500 healthy first-degree relatives of patients with CD, Raygoza Garay and colleagues showed for the first time that changes in the composition of the gut microbiome precede CD onset by up to five years8. These results come from the Genetic, Environmental, Microbial (GEM) project and open the way to predict a person’s risk of developing CD and suggest that early interventions targeting the gut microbiome may be an appropriate preventive strategy.

Pre-disease states (initiation and pre-clinical disease) are key to understanding IBD. Source: Ken Croitoru’s presentation at the GMFH World Summit 2024.

 

Regulatory challenges for microbiome therapeutics in the USA and European markets

The second plenary session focused on how regulators worldwide think about microbiome-based products. Paul E. Carlson Jr. from the Food and Drug Administration gave an overview of the  regulations for investigational new drug applications (INDs). An IND that is in effect is required prior to initiating a clinical trial for companies with a product intended for the clinic.  A pre-IND meeting is highly recommended to get feedback from the FDA prior to the submission of the IND application.  The IND/preIND submissions include product description, the rationale for using the product, the purpose and objectives of the planned investigations, the proposed indication, protocol, and other relevant information from the IND sponsor.

Chemistry, Manufacturing, and Controls (CMC) information is also important for INDs. “Fecal microbiota for transplantation” (FMT) product information should include information regarding screening of stool donors and manufacturing to ensure the safety and effectiveness of FMT for any proposed indication. An FDA guidance document describes an enforcement discretion policy regarding the submission of an IND for the use of certain investigational FMT products for prevention of Clostridioides difficile infections not responsive to standard therapies.  The updated FMT enforcement discretion guidance clearly states, that this enforcement discretion policydoes not apply to FMT obtained from stool banks or to other uses of FMT9,10.

Carlson also shared that an IND is required prior to initiating a clinical trial using an investigational product, including live biotherapeutic products,  if the intent is to treat, prevent, or cure a human disease or condition. Important CMC safety considerations include bioburden testing and assessment of antimicrobial sensitivities of the product organism(s). Note that probiotics, regulated by the Center for Food Safety and Applied Nutrition (CFSAN) as foods and dietary supplements are not subject to the IND requirements unless the intended use of the product is to treat, prevent, or cure a human disease or condition.11

Chemistry, Manufacturing, and Controls items for live biotherapeutic products registered as investigational new drugs. Source: Paul E. Carlson’s presentation at the GMFH World Summit 2024.

 

Céline Druart from Pharmabiotic Research Institute updated the regulatory and scientific requirements for the development of microbiome products for the European market. Druart stated that the European Commission is working with a new proposal for regulation of substances of human origin (SoHOs) that will apply to human microbiomes for human application, therefore increasing harmonization of FMT that is lacking nowadays. Substances of human origin include any substance collected from the human body, whether it contains cells or not and whether those cells are living or not, including preparations resulting from the processing of that substance. The resulting SoHO preparation has a specific clinical indication, is intended for either application to a recipient or to manufacture other regulated products, and needs approval by a competent authority.

Regulatory statuses for products and services that target the microbiome vary depending on the procedure of administration and the type of finished product (e.g., medicinal product, food, food supplement, food for special medical purpose, or cosmetic). Microbiome-based medicinal products intended to treat or prevent disease-FMT, rationally-designed ecosystems, non-living biotherapeutic products, LBPs and bacteriophage therapy- are among the most complex microbiome-based innovative treatments and in Europe are regulated by the pharmaceutical legislation (mainly by Directive 2001/83/EC). These products fall under the category of biological medicinal products and the European Commission is working with a revised legislation that will consider microbiome-derived medicinal products as SoHO-derived medicinal products.

Regulatory landscape of medicinal products and food/food supplements. Source: Céline Druart’s presentation at the GMFH World Summit 2024.

Moving from human-derived to synthetic communities

Amandine Everard from UCLouvain summarized the recent findings and main mechanisms of action by which Akkermansia muciniphila improves metabolic health. First isolated in 2004, the first proof-of-concept study published in 2019 showed that pasteurized A. muciniphila is more efficient than the live bacterium for helping alleviate features of metabolic syndrome in subjects with overweight and obesity12.

A. muciniphila as a potential candidate for improving dopamine responses to nutrients that are severely impaired during obesity. Source: Amandine Everard’s presentation at the GMFH World Summit 2024.

Emerging findings show beneficial effects of A. muciniphila in improving not only glucose and lipid metabolism, but also the motivational component of food reward altered by diet-induced obesity13,14. Other next-generation live biotherapeutics selected for potential application in humans include Faecalibacterium prausnitzii A2-65 for Crohn’s disease, Christensenella minuta DSM 33407, Anaerobutyricum soehngenii L2-7 for metabolic syndrome, and Oxalobacter formigenes OxB for primary hyperoxaluria12.

Alice Cheng from Stanford University updated us on where we are on the administration of FMT and fully synthetic microbial communities in the clinic. While FMT is approved for recurrent Clostridioides difficile infection, its efficacy remains variable (i.e., depending on the mode of delivery and donor, among others) and is associated with the transfer of pathogens. To overcome these caveats, new undefined complex consortia screened against pathogens and selected for the presence of therapeutic microbes have been developed (e.g., MaaT013 for graft-versus-host disease).

Ongoing research based on advanced cultured techniques revealed defined simple or small consortia (8-12 strains) show caveats, although they show potential therapeutic value for managing C. difficle recurrence15, show engraftment heterogenously16, and may harbor fewer metabolic pathways and occupy fewer niches, which is partly explained by the lack of surrounding ‘friends strains’ in the ecosystem that stabilize engraftment and persistence of therapeutic strains. Complex defined consortia of bacteria (more than 100 strains) that are under development harbor highly diverse metabolic pathways that can engraft reliably and consistently and are highly engineerable.

Lights and shadows of current microbiome-based therapeutics. Source: Alice Cheng’s presentation at the GMFH World Summit 2024.

Scott Jackson from the National Institute of Standards and Technology addressed solutions to overcome the bias that microbiome-based products face, from collecting samples to analyzing the DNA data. For instance, many methodological variables can impact the results of next-generation sequencing methodologies, so it is time to refer to metagenomic sequencing not as “unbiased” but as an “untargeted” approach for microbiome measurement.

Some considerations from Jackson for making microbiome-based products stable and reproducible include ensuring the homogeneity and stability of manufactured material for years, working with reference materials, and choosing preservation methods that leave cells intact, and ensure the integrity of cells will not change over time. While different preservation methods (i.e., lyophilization, commercial buffer or water at 4 ºC or -80 ºC) of fecal samples produce a sufficiently homogenous material, each preservation method produced its unique metabolic and taxonomic profile. The Human Fecal Reference Material for Multi’Omic Measurements project, available in late 2024, is expected to understand better the impact on the microbiome of methods for homogenizing fecal samples. Storing fecal samples at -80 ºC appears to be the most appropriate method. Find out more about the International Microbiome and Multi’Omics Standards Alliance here.

 

Gut microbiome, diet, and big data to promote precision medicine for health

Georg Gerber, from the Brigham and Women’s Hospital in Boston, introduced some examples of applications of AI to the microbiome including the prediction of host phenotype through microbiome-related data, microbial phenotypes from their genome, and efficacy of microbial consortia as live therapeutics and characterizing networks of interactions between host and immune status and spatial structure of the microbiome. However, there are varying levels of difficulty in exploiting the potential of AI in microbiome-based therapeutics, including the availability of relatively limited data, the high level of noise (e.g., high subject-to-subject variability), the complexity of data, special experimental designs and the need for interpretability of the applied methods.

Chemist Matthew Redinbo of the University of North Carolina at Chapel Hill delved into recent research using big data to understand how the gut microbiome shapes our response to drugs. Gut microbial b-glucuronidase (GUS) enzymes are universal in the gut microbiome and diverse and could be targeted to avoid dose-dependent diarrhea seen with Irinotecan. Irinotecan used for fighting advanced colon and pancreatic cancers is inactivated in the liver through the addition of a simple sugar, a process that is blocked by members from Enterobacteriaceae thus reactivating the toxic drug on its way out of the body17. Furthermore, specific GUS enzymes that bind the flavin mononucleotide may be involved in reactivation of immunosuppressant Mycophenolate and emerge as a potential target to mitigate Mycophenolate-induced gastrointestinal toxicity18.

Giving patients a b-glucuronidase inhibitor alongside drug could enhance drug’s effectiveness by reducing its gastrointestinal toxicity. Interestingly, gut microbial GUS can also process glucuronides of endogenous bile acids, hormones and neurotransmitters and affect their gut and systemic levels and clearance time. It is also true that certain drugs such as Ceritinib alter serotonin homeostasis, which is an overlooked mechanism of action explaining the inter-individual variability in chemotherapy.

Gut microbial enzymes can process drugs in ways that both help and harm us explaining why not all people respond the same to a particular medication. Source: Matthew Redinbo’s presentation at the GMFH World Summit 2024.

Joël Doré, gut microbial ecologist and scientific director at INRAE, updated where we are on applying microbiome testing in clinical practice. A disruption of host-microbes symbiosis is behind the current rise of non-communicable diseases, with some relevant triggers involving low-richness microbiota, increased intestinal permeability, inflammation and oxidative stress. This context explains that one of the most common applications of microbiome testing should be as a tool for clinicians for better clinical management of patients. While a definition of a healthy gut microbiome is lacking, Doré acknowledged that gene richness is a health stratifier and that a high abundance of specific taxa such as Faecalibacterium species may be associated with longer progression-free survival in patients treated for melanoma and longer remission after infliximab withdrawal in Crohn’s disease, whereas its depletion would be typical of IBD, colo-rectal cancer and IBS19-21. This information could be used by healthcare professionals to develop better diagnostics and treatments for microbiome-related diseases.

The EU-funded Human Microbiome Action project has currently an ongoing survey that addresses the potential applications of microbiome testing results. The most reported potential applications in current clinical practice include biological research and clinical studies followed by precision dietary management, while applications in future practice also involve diagnosis of diseases, prognosis and risk assessment. Heterogeneity in results is one of the main caveats of microbiome testing, with results being more influenced by the laboratory and its workflow rather than by subject22. While awaiting more regulation of companies selling direct-to-consumer microbiome testing services23, Doré acknowledged that coupling microbiome testing data with host data would improve their relevance for the clinician. While as healthcare professionals we must be critical, making progress towards evidence-based demonstration of clinical benefits of microbiome testing will require a fully integrated microbiome testing pipeline including standards end-to-end, from fecal sample processing to metagenomic data science24. Join the European Microbiome Centers Consortium and World Microbiome Partnership for advancing towards an evidence-based prescription of microbiome testing to assess the state of host-microbes symbiosis in clinical practice.

Microbiome testing from bench to bedside. Source: Joël Doré’s presentation at the GMFH World Summit 2024.

James Walter closed the GMFH World Summit by providing insights into rethinking healthy eating in light of the gut microbiome. Microbiome research has changed what is healthy eating and Walter focused on contemporary nutritional recommendations from a microbiome science perspective. After reviewing national food-based dietary guidelines from 17 countries, consistent recommendations of how we should eat in the light of the gut microbiome include vegetables and fruits and whole grains as more than half of diet and smaller proportions of plant- and animal-based proteins, and a limited amount of foods high in added sugar, salt, and saturated fat25. Controversies exist regarding the role of dairy products as food staples of a healthy diet and microbiome studies may clarify their role in health. For instance, the FDA has recently approved a health claim supporting that the regular consumption of yogurt (at least 2 cups per week) may reduce the risk of type 2 diabetes.

When improving dietary recommendations in the light of diet-microbiome interactions, Walter also highlighted that evolutionary considerations are of utmost importance. One step that we can take to prevent microbiota changes associated with industrialization that establish inflammation as a common hallmark of chronic diseases is microbiome restoration with microbiota-accessible carbohydrates and health-promoting lost microbial taxa26. Limosilactobacillus reuteri has beneficial effects in modulating the immune system and dampening inflammation and has been negatively impacted by industrialization.

Walter and colleagues have also performed a controlled crossover feeding trial on the impact of foods based on dietary patterns of rural Papua New Guineans and L. reuteri (i.e., “Restore diet” rich in vegetables, legumes, whole grains, one serving of animal protein per day and no dairy or wheat) on fecal microbiota composition and metabolism and host metabolism. The preliminary results suggest that the redundancy of some microbial taxa that are enriched by the Restore diet may partly reverse the negative impact of the industrialized lifestyle on the microbiome. The second step will be identifying microbiome features that predict clinical outcomes through machine learning.

Microbiome testing from bench to bedside. Source: James Walter’s presentation at the GMFH World Summit 2024.

Addressing microbial function deficits, developing microbiome-based biomarkers, and leveraging diet for precise engineering of the microbiome

Beyond plenary sessions, two workshop sessions occurred during the first day of the GMFH World Summit and covered preclinical and translational advances in the gut microbiome. From correcting dysbiotic microbial functional deficit through multidonor faecal microbiota transplants to the potential of leveraging diet to engineer the gut microbiome, worldwide scientists covered microbial drivers behind the altered gut microbiome and barrier dysfunction seed in non-communicable diseases.

While individual variation in host factors makes a uniform treatment unlikely, one big idea that arose from the workshops is that addressing the microbiome and host together is essential for the maintenance of health and well-being, and the development of microbiome-targeted interventions will become an essential tool of the future personalized preventive nutrition and medicine.

Attendees can access on-demand content for GMFH World Summit 2024 keynote, plenary and workshops recordings. The 13rd GMFH World Summit is due to take place 15-16 March 2025 in Washington, D.C.

 

Further Reading:

  1. Federici S, Kredo-Russo S, Valdés-Mas R, et al. Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation. Cell. 2022; 185(16):2898.e24. doi: 10.1016/j.cell.2022.07.003.
  2. Wu M, Zheng W, Song X, et al. Gut complement induced by the microbiota combats pathogens and spares commensals. Cell. 2024; 187(4):897-913.e18. doi: 10.1016/j.cell.2023.12.036.
  3. Price ND, Magis AT, Earls JC, et al. A wellness study of 108 individuals using personal, dense, dynamic data clouds. Nat Biotechnol. 2017; 35(8):747-756. doi: 10.1038/nbt.3870.
  4. Wilmanski T, Rappaport N, Earls JC, et al. Blood metabolome predicts gut microbiome a-diversity in humans. Nat Biotechnol. 2019; 37(10):1217-1228. doi: 10.1038/s41587-019-0233-9.
  5. Diener C, Qin S, Zhou Y, et al. Baseline gut metagenomic functional gene signature associated with variable weight loss responses following a healthy lifestyle intervention in humans. mSystems. 2021; 6(5):e0096421. doi: 10.1128/mSystems.00964-21.
  6. Watanabe K, Wilmanski T, Diener C, et al. Multiomic signatures of body mass index identify heterogeneous health phenotypes and responses to a lifestyle intervention. Nat Med. 2023; 29(4):996-1008. doi: 10.1038/s41591-023-02248-0.
  7. Wilmanski T, Diener C, Rappaport N, et al. Gut microbiome pattern reflects healthy ageing and predicts survival in humans. Nat Metab. 2021; 3(2):274-286. doi: 10.1038/s42255-021-00348-0.
  8. Raygoza Garay JA, Turpin W, Lee SH, et al. Gut microbiome composition is associated with future onset of Crohn’s disease in healthy first-degree relatives. Gastroenterology. 2023; 165(3):670-681. doi: 10.1053/j.gastro.2023.05.032.
  9. Carlson Jr PE. Regulatory considerations for fecal microbiota transplantation products. Cell Host Microbe. 2020; 27(2):173-175. doi: 10.1016/j.chom.2020.01.018.
  10. Food and Drug Administration. Enforcement policy regarding investigational new drug requirements for use of fecal microbiota for transplantation to treat Clostridium difficile infection not responsive to standard therapies. November 2022. Available on: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/enforcement-policy-regarding-investigational-new-drug-requirements-use-fecal-microbiota
  11. Food and Drug Administration. Early clinical trials with live biotherapeutic products: chemistry, manufacturing, and control information. June 2016. Available on: https://www.fda.gov/media/82945/download
  12. Cani PD, Depommier C, Derrien M, et al. Akkermansia muciniphila: paradigm for next-generation beneficial microorganisms. Nat Rev Gastroenterol Hepatol. 2022; 19(10):625-637. doi: 10.1038/s41575-022-00631-9.
  13. de Wouters d’Oplinter A, Rastelli M, Van Hul M, et al. Gut microbes participate in food preference alterations during obesity. Gut Microbes. 2021; 13(1):1959242. doi: 10.1080/19490976.2021.1959242.
  14. Huwart SJP, de Wouters d’Oplinter A, Rastelli M, et al. Food reward alterations during obesity are associated with inflammation in the striatum in mice: beneficial effects of Akkermansia muciniphila. Cells. 2022; 11(16):2534. doi: 10.3390/cells11162534.
  15. Louie T, Golan Y, Khanna S, et al. VE303, a defined bacterial consortium, for prevention of recurrent Clostridioides difficile infection: a randomized clinical trial. JAMA. 2023; 329(16):1356-1366. doi: 10.1001/jama.2023.4314.
  16. Dsouza M, Menon R, Crossette E, et al. Colonization of the live biotherapeutic product VE303 and modulation of the microbiota and metabolites in healthy volunteers. Cell Host Microbe. 2022; 30(4):583-598.e8. doi: 10.1016/j.chom.2022.03.016.
  17. Bhatt AP, Pellock SJ, Biernat KA, et al. Targeted inhibition of gut bacterial b-glucuronidase activity enhances anticancer drug efficacy. PNAS. 2020; 117813):7374-7381. doi: 10.1073/pnas.1918095117.
  18. Simpson JB, Sekela JJ, Graboski AL, et al. Metagenomics combined with activity-based proteomics point to gut bacterial enzymes that reactive mycophenolate. Gut Microbes. 2022; 14(1):2107289. doi: 10.1080/19490976.2022.2107289.
  19. Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018; 359(6371):97-103. doi: 10.1126/science.aan4236.
  20. Rajca S, Grondin V, Louis E, et al. Alterations in the intestinal microbiome (dysbiosis) as a predictor of relapse after infliximab withdrawal in Crohn’s disease. Inflamm Bowel Dis. 2014; 20(6):978-986. doi: 10.1097/MIB.0000000000000036.
  21. Rajilic-Stojanovic M, Biagi E, Heilig HGHJ, et al. Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome. Gastroenterology. 2011; 141(5):1792-1801. doi: 10.1053/j.gastro.2011.07.043.
  22. Roume H, Mondot S, Saliou A, et al. Multicenter evaluation of gut microbiome profiling by next-generation sequencing reveals major biases in partial-length metabarcoding approach. Sci Rep. 2023; 13(1):22593. doi: 10.1038/s41598-023-46062-7.
  23. Hoffmann DE, von Rosenvinge EC, Roghmann MC, et al. The DTC microbiome testing industry needs more regulation. Science. 2024; 383(6688):1176-1179. doi: 10.1126/science.adk4271.
  24. Sergaki C, Anwar S, Fritzsche M, et al. Developing whole cell standards for the microbiome field. Microbiome. 2022; 10(1):123. doi: 10.1186/s40168-022-01313-z.
  25. Armet AM, Deehan EC, O’Sullivan AF, et al. Rethinking healthy eating in light of the gut microbiome. Cell Host Microbe. 2022; 30(6):764-785. doi: 10.1016/j.chom.2022.04.016.
  26. Sonnenburg ED, Sonnenburg JL. Starving our microbial self: the deleterious consequences of a diet deficient in microbiota-accessible carbohydrates. Cell Metab. 2014; 20(5):779-786. doi: 10.1016/j.cmet.2014.07.003.