Probing short and long term consequences of Small and Large Bowel Microbiota Transplants on Host Physiology: Implications for the development of future live biotherapeutics

The intestinal tract is comprised of functionally different regions, each having distinct and highly selected microbiota assembled through evolutionary and ecological drivers to achieve a mutualistic relationship important to host health. However, with ever increasing shifts in environment, diet, lifestyles, and prevalent use of antibiotics it is becoming evident that perturbations of host-microbial balance affect states of health and give rise to a multitude of disorders. This recognition has fostered interest in “natural” remedies such as Fecal Microbiota Transplant (FMT) and Live Biotherapeutic Products (LBPs) to maintain or restore gut microbiota health in patients with Clostridioides difficile infection and other disorders (IBD, metabolic disorders). However, one has to question the appropriateness of these preparations, given that most are comprised of colonic anaerobic microbes not indigenous or fit to inhabit the small intestine.

Mismatches between regional host gut ecosystems and their microbiota could have adverse consequences to the host. This possibility leads us to hypothesize that colonic microbiota of FMT will not properly restore the microbiome of the small intestine (and vice versa) and that this will have long-term regional and systemic consequences. Our preliminary data show merit for this hypothesis, i.e., the engraftment of donor microbiota in non-indigenous ecosystems create mismatches that lead to regional and systemic consequences particularly of immune and metabolic networks that persist at least 3 months in a post-antibiotic (Abx) microbial transplant murine model. Planned studies will employ in vivo and in vitro experimental models to assess the long-term impact (one-year post transplant) of regional microbiota on host tissues because studies of this nature are technically challenging if not infeasible in human subjects.

We propose two specific aims: (1) to examine to what extent do post-Abx jejunal (JMT) vs fecal (FMT) microbiota transplants restore regional gut microbiota composition and function, and host immune and metabolic function following antibiotic-induced dysbiosis compared to cecal microbiota transplant (CMT) and saline controls; and (2) to determine the direct impact of JMT vs FMT-specific microbes identified through a novel cross ‘omics bioinformatic integration platform and their metabolites on host metabolism and immune function using in vivo and in vitro approaches. To reflect the cut in the budget, we propose assessing outcomes after one year of transplant vs assessing outcomes at also 3 and 6 months given that we have extensive preliminary data for the earlier time points. Findings of Aim 1 will raise awareness of the potential concerns of improper restitution of regional gut microbiota with microbiota transplants that may require a rethinking of current FMT practices and LBP formulations. Aim 2 will provide insights to how to solve the problem, creating a new path for future and more strategic development of effective and safe omni-microbial transplants (OMTs).

This multi-PI study stems from a long-time collaboration between laboratories of Drs. Eugene Chang and Kristina Martinez-Guryn that have complementary expertise in the study of immunity and metabolism.

Grant Number: 5R01DK138072-03
NIH Institute/Center: NIH
Principal Investigator: EUGENE CHANG