Ecology and function of synthetic bacterial communities to understand and modulate IBD-associated microbiomes

Introduction

Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are linked to gut microbiome disruptions. While fecal microbiota transplant (FMT) has been effective for recurrent Clostridium difficile infections, its broad and non-specific nature poses risks, including the transfer of multidrug-resistant bacteria. To address these issues, defined bacterial synthetic communities (SynComs) offer a more targeted, safer alternative. SynComs are bacterial consortia designed to restore microbiome healthy phenotypes, such as enhanced diversity and stability, and production of beneficial metabolites. Though SynComs have also shown potential in treating C. difficile infections, their application in IBD remains underexplored, likely due to the complexity of IBD’s multifactorial nature involving host-microbiota interactions. Advances in technology now enable scaling SynCom research for IBD. This progress involves new culturomics techniques for building diverse bacterial libraries, sophisticated in vitro bioreactors for studying microbiome dynamics under controlled conditions, and improved genome-scale metabolic models for predicting microbial interactions and metabolic production. As such, we can now start testing causal scenarios, like dysbiosis related to oxidative stress, and optimizing SynCom formulations to improve therapeutic outcomes.

Aims

We hypothesize that custom SynComs can be used to restore healthy gut microbiomes of IBD patients, and that computational approaches can predict community assembly, metabolic functions, and engraftment capacity of SynComs into recipient microbiomes. Our overall objective is to design, assemble and investigate the ecology and function of various gut bacterial SynComs. Investigations with individual bacteria or SynComs will be run in batch and continuous-flow bioreactors that mimic physicochemical conditions of the (healthy or IBD) colonic environment. We will particularly investigate the effect of exposure to oxygenic stress that is characteristic of intestinal inflammation on bacterial monocultures and SynComs. We will then use selected candidate SynComs to intervene on cultured complete microbiomes derived from healthy and IBD patients, to modulate community compositions and metabolomes.

Here, we aim:

• to generate collections of diverse gut bacterial strains from UC patients using both stool and biopsy samples. Bacterial strains will be whole genome sequenced and phenotyped for tolerance to oxygen and reactive-oxygen species (ROS),

• to reconstruct various representative SynComs, and experimentally measure all pairwise interactions between SynCom constituents (WP2). SynCom community structure, metabolic production and engraftment into UC microbiomes will be predicted,

• to experimentally characterize the community assembly and function of these SynComs, validate predictions made in previous aims, and test for the effect of inflammatory oxidants on these features, and

• to predict and experimentally validate SynCom engraftment into recipient microbiomes, and investigate the impact of SynComs on UC-derived microbiome compositions and functions.
  

Outlook

Our work will reveal mechanisms of physiological responses of anaerobic commensal bacteria to inflammatory oxidants that are relevant to IBD contexts. It will further expand our ecological and functional understanding of the consequences of microbiome transfers in the context of IBD, and identify SynComs that restore healthy composition and metabolome signatures in dysbiotic IBD microbiomes. As a long-term perspective, we envision for this work to establish a pipeline for the building of alternative, rationally designed microbiota-based intervention strategies to be used in lieu of FMT that aim at restoring dysbiotic microbiomes.