What is new on fecal microbiota transplants for disorders of gut-brain interaction?

Current indications of fecal microbiota transplantation (FMT) in Europe are recurrent (more than 2 times) C. difficile infection  and refractory C. difficile infection that does not respond to conventional treatments, according to an International Expert Consensus and a consensus report from a multidisciplinary UEG working group presented by Juozas Kupcinskas from the Lithuanian University of Health Sciences. However, based on a European survey there is a large gap between the number of recurrent C. difficile infections and availability of FMT. There is a need to increase clinical awareness and scale the European FMT activity at least by a 10-fold increase to meet the needs.

William Fusco from the Fondazione Policlinico Universitario Agostino Gemelli in Rome acknowledged some caveats of FMT that hinder its translation into clinical practice including short-term and long-term safety issues (e.g., risk of transmitting pathogenic taxa and procarcinogenic microbiota), effectiveness still limited to C. difficile infection, and protocol-related issues (e.g., differences in working protocols among centers and the lack of reproducibility in specific donor microbial signatures).

Jeroen Raes from the Rega Institute for Medical Research acknowledged that FMT allows understanding that an intervention can work from a microbiologic point of view but does not necessarily translate into meaningful clinical benefits for the patient and vice versa. In that regard, Raes highlighted that the right selection of donor matters, but maybe what actually engrafts is even more relevant. It is also important to keep in mind that potentially beneficial microbiota changes do not necessarily mean clinical success (as seen in unpublished FMT studies in IBD presented by Raes) and clinical success of FMT does not always mean beneficial microbiota changes as seen in a case report on FMT in major depressive disorder.

Beyond recurrent C. difficile infection, potential indications of FMT presented at NeuroGASTRO 2023 include ulcerative colitis, hepatic encephalopathy, graft vs. host disease, enhancement of PD-1 therapy in advanced patients with melanoma, and refractory immune checkpoint inhibitor-associated colitis. Fecal transplants also allow to better understand the causal role of the microbiome in neurodevelopmental disorders. For instance, ongoing findings presented by Morgane Eileen Le Dréan from Inserm characterized the impact of fecal microbiota from adults with autism spectrum disorders in brain and digestive functions in recipient mice. When it comes to the communication between gut microbiota and enteric neurons in autism spectrum disorders, Caillaud Martial presented preliminary data on the potential of extracellular vesicles as relevant mediators.

Extracellular vesicles from altered intestinal microbiota could remodel enteric nervous system in autism. Source: Martial’s talk at NeuroGASTRO 2023.

 

When it comes to the efficacy of FMT in DGBI, Peter Holger Johnsen from the University Hospital of North Norway shared seven available randomized controlled trials of FMT in IBS. One caveat when interpreting current evidence of FMT in IBS is heterogeneity in studies in terms of patient selection, protocols for processing treatments, dose of stool, route of delivery, and outcome measures. Johnsen stated that complete remission of IBS symptoms is possible but not all patients respond to FMT. These findings explain that for many patients repeated treatment will most probably be needed for a sustained response and even combined treatments for complete remission.

Suggested next steps to proceed for advancing FMT from bench to bedside in the management of disorders of gut-brain interaction according to Peter Holger Johnsen. Source: Peter Holger Johnsen’s talk at NeuroGASTRO 2023.

 

Could future microbiome therapeutics overcome current FMT issues?

Future microbiome therapeutics consisting of defined microbial consortia, postbiotics, phages, and engineered bacteria that are nowadays at different research stages could help overcome current FMT limitations according to William Fusco:

  • Microbial consortia: consortia RBX2660 and SER-109 were recently approved by the FDA to treat recurrent difficile infection and showed nearly 90% cure. For other diseases, the use of microbial consortia is still under investigation, but several of them are in clinical trials already. Current focus is on IBD (GUT 103, GUT 108, VE202, MH002, and SER-301), allergic diseases (VE416 for peanut allergy and STMC-103H for allergies in infants), and cancer (MET4, SER-401 and VE800 combined with immunotherapies).
  • Postbiotics: the most studied postbiotics are short-chain fatty acids but these did not achieve consistent results in human clinical trials. A promising postbiotic under study is ursodeoxycholic acid for intestinal motility and inflammation. Coal tar is not a postbiotic but it mimics the effects of microbial indoles that cannot be delivered to skin directly. When administered, coal tar favours the release of anti-inlammatory cytokines in  atopic dermatitis.
  • Bacteriophage-based therapies: bacteriophage cocktails are a potential treatment against bacterial infections (e.g., otitis and abdominal abscesses) that allow overcoming the current rise in antibiotic resistance, but may also target bacteria involved in IBD pathogenesis. Bacteriophage therapies however, are still in the earliest phase of advancement.
  • Engineered bacteria: lactis AG019 is currently under a phase II trial for delivery of proinsulin and to attenuate inflammation in type 1 diabetes. A phase III trial is being conducted on engineered L. monocytogenes to enhance immune response against cervical carcinoma. Similar trials are being conducted for other cancers. Microbial membrane vesicles cause less adverse reactions than live bacteria and provide a promising approach. Preliminary findings also suggested the role of engineered bacteria to detect colon cancer.

 

Do probiotics and prebiotics play a therapeutic role in functional dyspepsia and pain reduction?

Current clinical guidelines recognize the role of specific probiotics and prebiotics in achieving intestinal comfort as acknowledged by Lucian Negreanu from the University Emergency Hospital of Bucharest. It is important to remember that the clinical efficacy of probiotics depends on the type of strain, the dose, and the duration, considering the different mechanism of action. Also, when probiotics are administered as a first-line treatment for global symptoms and abdominal pain in IBS, it should be taken for up to 12 weeks in order to obtain a conclusion on its effectiveness for symptom improvement. Certain prebiotics such as inulin at low doses (5 grams/day) have also shown to contribute to the normal functioning of the intestine by increasing the frequency of stools.

When it comes to addressing functional dyspepsia, the altered duodenal microenvironment opens a potential way of managing it. Recent findings from a pilot randomized, double-blind, placebo-controlled trial by Lucas Wauters concluded that a spore-forming probiotic blend (Bacillus coagulants MY01 and Bacillus subtilis MY02) shows potential for managing functional dyspepsia in adults through shaping gut microbiota composition and the immune function. As a long-term treatment of functional dyspepsia with PPIs can alter the gut microbiome, these findings open the potential of probiotics in this group of patients.

 

Spore-forming probiotic blend showed potential for functional dyspepsia in adults. Source: Wauters’ talk at NeuroGASTRO 2023.

Regarding the potential role of live bacteria for pain reduction, Yehuda Ringel, Chief Scientific Officer at Biomica, presented preliminary data on the development of a rationally designed live bacterial consortium BMC428 based on 4 strains that target intestinal microbial functions that are associated with reduced pain and bloating. Moreover, Frédéric Carvalho from Inserm presented Parabacteroides distasonis as a potential probiotic tested in vitro and in mice with anti-hyperalgesia effect for low-grade intestinal inflammation, post-inflammatory model, and post-infectious-IBS model. While both new probiotics used for the management of visceral pain observed in DGBI are validated in animal models, further research in humans is required before using them in clinical practice.

 

Further reading:

Fecal microbiota transplantation:

Probiotics and prebiotics in chronic post-inflammatory pain, intestinal comfort, and functional dyspepsia: