The bright future of next generation microbiome-based therapies
Eugene B. Chang from the University of Chicago (USA) kicked off the GMFH World Summit 2023 summarizing the current developments in microbiome-based medicines and providing insight into the next steps required for therapeutic development.
From a regulatory perspective, the FAO/WHO definition of probiotics covers both a ‘food’ or ‘food supplement’ and a ‘drug’ depending on the intended use and the target population. When products containing live microorganisms are used as drugs with the intention to prevent or treat disease, both the Food and Drug Administration (FDA) and the European Directorate for the Quality of Medicines and healthcare (EDQM) proposed the term “live biotherapeutic product” (LBP). As for all drugs, LBPs need to demonstrate quality, efficacy and safety. However, LBPs pose extra challenges because they contain live organisms, raising issues of the role of engraftment in shaping their efficacy and stability of the final product over time. In addition, a healthy microbiome has not been defined yet and patients’ baseline microbiomes and diets can influence the effect of LBP administration.
On the whole, despite the potential of microbiome-based interventions for the clinical practice, there is still a need to document and bring in ecological principles. Chang highlighted the need to find functional metrics of relevance (i.e., defining accessory and core genes for a complete picture to assess how do microbes work together) when defining a healthy gut microbiome.
The gut microbiota has been associated with clinical responses to immune checkpoint inhibitor (ICI) treatment. Michael Scharl from University Hospital Zurich (Zurich, Switzerland) presented preliminary data on the role of specific gut bacteria in modulating immune system and mediating effective anti-cancer immune response against solid tumors. Intestinal bacteria can have intrinsic anti-cancer effects. Four Clostridiales species (CC4 mix composed of Roseburia intestinalis, Eubacterium hallii, Faecalibacterium prausnitzii and Anaerostipes caccae) blocked tumor growth via CD8+ T cells as efficient as chemotherapy or immunotherapy in colorectal cancer and melanoma, which suggests the strategy of boosting the function of the gut microbiota as means to improve the efficacy of T cell checkpoint inhibitors. While extensive metabolomics analyses have shown that specific bacterial metabolites such as 3OH dodecanoic acid could play a central role in inducing antitumor response, further studies are needed to better elucidate which microbiome components are involved in the human setting.
Harry Sokol from Saint Antoine Hospital (Paris, France) presented preliminary findings showing high levels of Faecalibacterium prausnitzii at baseline are associated with better response in multiple types of cancer. This observation has led to the development of EXL01 as a novel drug candidate containing F. prausnitzii that was shown to boost effects of ICI in vivo. It seems that cell wall molecules are more important than soluble bacterial metabolites, but it is too early to recommend it in the clinical practice for immune-oncology indications. Sokol acknowledged that next step includes evaluating the effects of EXL01 in a clinical trial.
Marie-Claire Arrieta from the University of Calgary (Canada) covered recent findings on the role of specific probiotics in accelerating gut microbiome maturation in extremely preterm infants. Preterm infants have immature systems and show a delayed Bifidobacterium colonization while an overabundance of Staphylococcus, Enterobacteriaceae and Enterococcaceae that increase the risk of necrotizing enterocolitis. Beyond bacteria, the gut mycobiome can also shape early childhood growth with a link between the maturation of the mycobiome in the first year of life and body mass index up to 5 years of age. Preterm infants with low weight show a delayed maturation in their gut microbiome with a decreased community stability and an increased proinflammatory milieu in their gut. By contrast, the administration of a probiotic containing four strains of Bifidobacterium and one Lacticaseibacillus strain accelerated the transition of the gut microbiome in extremely preterm births into a mature, term-like and more stable microbiome accompanied with more favourable microbiome metabolic and immune responses.
Drivers of the efficacy of fecal microbiota transplantation
The second session at GMFH World Summit 2023 focused on challenges and improvement opportunities for clinical practice of fecal microbiota transplantation (FMT). Gianluca Ianiro from Università Cattolica del Sacro Cuore (Italy) focused on determinants that shape the clinical success of FMT including donor gut microbiome composition, FMT working protocols and the engraftment capacity of the donor microbiome into the recipient gut. The efficacy of FMT is also affected by recipient factors such as genetics, immunity, microbiota and lifestyle. Ianiro introduced the figure of “microbiome clinicians” as the translational figure of a practitioner up-to-date on microbiome research and an expert in microbiome-targeted interventions (i.e., probiotics, prebiotics and FMT) and that translates discoveries into evidence-based medicine and practical insights to the final patient.
Beyond the established role of FMT for recurrent Clostridioides difficile infection, this treatment approach has also been investigated in non-communicable disorders including inflammatory bowel diseases. Rupert W. Leong from the University of Sidney (Australia) discussed FMT in ulcerative colitis. Leong presented clinical data on donor gut microbiota stability, species evenness and the abundance of individual microbial species as important determinants associated with therapeutic efficacy in ulcerative colitis (UC). The baseline gut microbiota diversity of recipient patients could also affect FMT efficacy, as supported by recent findings showing treatment with antibiotics followed by orally administered FMT was associated with the induction of remission in patients with active UC.
Instead of current drugs for patients with UC that are based on immune suppression, the modulation of the microbiome by FMT or diet can be successful in generating clinical remission. This is the case for an ulcerative colitis elimination diet that is rich in fruits and vegetables and includes prescribed amounts of chicken, eggs and yoghurt, and that is able to achieve higher clinical remission and mucosal healing than single donor FMT with or without diet. Interestingly, FMT combined with an anti-inflammatory diet (avoiding gluten-based grains, dairy products, margarines, processed and red meat, food additives and refined sugars and increasing intake of fresh fruits and vegetables, fermented foods, cruciferous and polyphenols) is more effective than optimized standard medical therapy in inducing remission in mild to moderate UC. What is more interesting is the fact that anti-inflammatory diet could sustain the remission until 1 year and was more effective than standard medical therapy alone.
FMT is also being studied in the context of metabolic health. Karen L. Madsen from the University of Alberta (Canada) explored the role of combining fibers with FMT in metabolic syndrome. A recent proof-of-principle study conducted by Madsen and colleagues found that low fermentable fiber supplementation and oral FMT for 6 weeks may improve insulin sensitivity and microbial engraftment in individuals with severe obesity. In line with findings presented by Leong, this research strengthens the importance of considering recipient diet when companies try to standardize FMT preparation, formulation and mode of delivery.
A quick glimpse at the topics covered at workshops sessions
The first day of GMFH World Summit four different workshops ran in parallel. They focused on: 1) bioengineered probiotics to trigger immune control in tumours and to deliver therapeutic proteins; 2) the potential of prebiotics and probiotics in liver disease; 3) detrimental effects of western diet (in particular food emulsifiers and low fiber diet) on gut microbiota-mucus interaction and 4) the role of maternal gut microbiome in influencing neurodevelopment during critical prenatal periods and probiotics for depression and anxiety in patients with IBS and to improve psychiatric symptoms and central functioning.
Diet and colon-targeted antibiotics to modulate host immune status and preserve responsiveness to immune checkpoint inhibitors
Mahesh S. Desai from the Luxembourg Institute of Health focused on discerning how fiber-deprived gut microbiome impacts our health and contributes to inflammatory disorders. Previous findings showed that during chronic or intermittent dietary fiber deficiency, the gut microbiota uses host-secreted mucus glycoproteins as a nutrient source, which leads to a weakness of the colonic gut barrier. Desai introduced new findings on how low dietary fiber increases colonic mucus penetrability leading to colitis in interleukin-10-deficient mice. Desai’s research team is nowadays focused in designing dietary therapeutics to strengthen the mucosal barrier and to improve health.
Matthew M. Carter, a member of Justin Sonnenburg’s lab at Stanford University, discussed the RAMP study (Rejuvenation of the Aging Microbiota with Prebiotics) where adults are given a prebiotic human milk oligosaccharide (HMO). This study will determine the degree to which HMOs regulate immune status and function and metabolic markers through impacting gut microbiota composition and function.
Meriem Messaoudene from the CHUM Research Centre (Montreal, Canada), a member of Bertrand Routy’s lab, presented unpublished data linking the gut microbiome to cancer immunotherapy response. The first evidence of the role of the gut microbiota in immune checkpoint inhibitors modulation was observed during antibiotics treatment, where antibiotic-induced dysbiosis inhibited ICI response. Messaoudene presented preclinical findings on the prevention of antibiotic-induced dysbiosis in human volunteers by DAV132, an orally administered colon-targeted antibiotic adsorbent co-administered with antibiotics. These results further document the relevance to prevent antibiotic-induced dysbiosis to preserve responsiveness to anti-PD-1 therapy.
The last talk of the session was given by Yael Haberman from Tel Aviv University (Israel), which focused on high-throughput omics techniques to shed light on the intricate links between diet, the microbiome and metabolic and immune health. While effective integration of meta-omic techniques is limited in microbiome studies, their application provide a new avenue to improving cardiometabolic health.
Tiny contributors to host metabolism and immunity
Pierre-Marie Lledo from the Pasteur Institute (Paris, France) discussed the role of bacterial sensing via neuronal Nod2 in regulating appetite and body temperature. Nod2 receptors are expressed in the brain and open the potential to target them with possible implication on food choices. Byproducts of bacterial cell wall degradation such as peptidoglycans are another mechanism by which microbiota might control the host’s appetite and body temperature. These findings may open new approaches for the treatment of metabolic and psychiatric disorders.
Karine Clément from Sorbonne Université and Assistance Publique – Hopitaux de Paris (Paris, France) presented host biotin status as a novel player in regulating host metabolic state in severe obesity. Clément presented results from the MetaCardis cohorts and murine experiments showing severe obesity is associated with an absolute deficiency in bacterial biotin producers, which abundances are related to host metabolism and inflammation status. In contrast, bariatric surgery associates with increased bacterial biotin producers and improves biotin systemic levels. In mice, the supplementation of biotin and fructo-oligosaccharides improved dysbiosis and the potential of bacterial production of biotin and B vitamins, while preventing the deterioration of cardiometabolic health. Based on these findings, Clement and colleagues hypothesized that increased numbers of adipocytes in individuals with obesity could need a higher demand of vitamin B requirements, which absorption might be reduced in obesity secondary to low-grade inflammation promoted by endotoxemia (LPS).
Specific gut microbiota metabolites, such as butyrate, can influence systemic immune responses. Marie-Laure Michel from Université Paris-Saclay (Paris, France) discussed the role of gut microbiota-derived short-chain fatty acids in regulating IL-17 production by mouse and human intestinal gamma delta T cells. gd T cells are a type of T cells that are enriched in many peripheral tissues including intestines. This is an immune cell population that is a double-edged sword in intestinal inflammation and protection and data presented by Michel unraveled novel mechanisms of regulation of intestinal IL-17-producing gd T cells in mice and humans. These subtype of T cells are repressed by propionate in the colon and antibiotic treatment eliminates this inhibition. Considering their high abundance in the intestinal mucosa of patients with IBD and colorectal cancer, these findings open a new pathway of regulating these immune cells to prevent chronic inflammatory processes.
Cordaillat-Simmons M, Rouanet A, Pot B. Live biotherapeutic products: the importance of a defined regulatory framework. Exp Mol Med. 2020; 52(9):1397-1406. doi: 10.1038/s12276-020-0437-6.
Gutierrez MW, Mercer EM, Moossavi S, et al. Maturational patterns of the infant gut mycobiome are associated with early-life body mass index. Cell Rep Med. 2023; 4(2):100928. doi: 10.1016/j.xcrm.2023.100928.
Samara J, Moossavi S, Alshaikh B, et al. Supplementation with a probiotic mixture accelerates gut microbiome maturation and reduces intestinal inflammation in extremely preterm infants. Cell Host Microbe. 2022; 30(5):696-711.e5. doi: 10.1016/j.chom.2022.04.005.
Ianiro G, Puncochar M, Karcher N, et al. Variability of strain engraftment and predictability of microbiome composition after fecal microbiota transplantation across different diseases. Nat Med. 2022; 28(9):1913-1923. doi: 10.1038/s41591-022-01964-3.
Danne C, Rolhion N, Sokol H. Recipient factors in faecal microbiota transplantation: one stool does not fit all. Nat Rev Gastroenterol Hepatol. 2021; 18(7):503-513. doi: 10.1038/s41575-021-00441-5.
Haifer C, Don Wai Luu L, Paramsothy S, et al. Microbial determinants of effective donors in faecal microbiota transplantation for UC. Gut. 2022. doi: 10.1136/gutjnl-2022-327742.
Haifer C, Paramsothy S, Kaakoush NO, et al. Lyophilised oral faecal microbiota transplantation for ulcerative colitis (LOTUS): a randomised, double-blind, placebo-controlled trial. Lancet Gastroenterol Hepatol. 2022; 7(2):141-151. doi: 10.1016/S2468-1253(21)00400-3.
Shabat CS, Scaldaferri F, Zittan E, et al. Use of faecal transplantation with a novel diet for mild to moderate active ulcerative colitis: the CRAFT UC randomised controlled trial. J Crohns Colitis. 2022; 16(3):369-378. doi: 10.1093/ecco-jcc/jjab165.
Kedia S, Virmani S, Vuyyuru SK, et al. Faecal microbiota transplantation with anti-inflammatory diet (FMT-AID) followed by anti-inflammatory diet alone is effective in inducing and maintaining remission over 1 year in mild to moderate ulcerative colitis: a randomised controlled trial. Gut. 2022; 71(12):2401-2413. doi: 10.1136/gutjnl-2022-327811.
Savage TM, Vincent RL, Rae SS, et al. Chemokines expressed by engineered bacteria recruit and orchestrate antitumor immunity. Sci Adv. 2023; 9(10):eadc9436. doi: 10.1126/sciadv.adc9436.
Chassaing B, Van de Wiele T, De Bodt J, et al. Dietary emulsifiers directly alter human microbiota composition and gene expression ex vivo potentiating intestinal inflammation. Gut. 2017; 66(8):1414-1427. doi: 10.1136/gutjnl-2016-313099.
Vuong HE, Pronovost GN, Williams DW, et al. The maternal microbiome modulates fetal neurodevelopment in mice. Nature. 2020; 586(7828):281-286. doi: 10.1038/s41586-020-2745-3.
Pinto-Sanchez MI, Hall GB, Ghajar K, et al. Probiotic Bifidobacterium longum NCC3001 reduces depression scores and alters brain activity: a pilot study in patients with irritable bowel syndrome. Gastroenterology. 2017; 153(2):448-459.e8. doi: 10.1053/j.gastro.2017.05.003.
Le Morvan de Sequeira C, Hengstberger C, Enck P, et al. Effect of probiotics on psychiatric symptoms and central nervous system functions in human health and disease: a systematic review and meta-analysis. Nutrients. 2022; 14(3):621. doi: 10.3390/nu14030621.
Belda E, Voland L, Tremaroli V, et al. Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism. Gut. 2022; 71(12):2463-2480. doi: 10.1136/gutjnl-2021-325753.
Dupraz L, Magniez A, Rolhion N, et al. Gut microbiota-derived short-chain fatty acids regulate IL-17 production by mouse and human intestinal gdT cells. Cell Rep. 2021; 36(1):109332. doi: 10.1016/j.celrep.2021.109332.
Ribot JC, Lopes N, Silva-Santos B. gd T cells in tissue physiology and surveillance. Nat Rev Immunol. 2021; 21(4):221-232. doi: 10.1038/s41577-020-00452-4.