Disease-specific loss of microbial cross-feeding interactions in the human gut

Abstract

Many gut microorganisms critical to human health rely on nutrients produced by each other for survival; however, these cross-feeding interactions are still challenging to quantify and remain poorly characterized. Here we introduce a Metabolite Exchange Score (MES) to quantify those interactions. Using metagenome-wide metabolic models from over 1600 individuals, the MES allowed us to identify and rank metabolic interactions that were significantly affected by a loss of cross-feeding partners in 10 out of 11 diseases. When applied to a Crohn's disease case-control study, our approach identified a lack of species with the ability to consume hydrogen sulphide as the main distinguishing microbiome feature of disease. We propose that our conceptual framework will help prioritize in-depth analyses, experiments and clinical targets, and that targeting the restoration of microbial cross-feeding interactions is a promising mechanism-informed strategy to reconstruct a healthy gut ecosystem.

A meta-analysis of the gut microbiome in inflammatory bowel disease patients identifies disease-associated small molecules

“…As our ability to de novo assemble metagenomic datasets gets better, and as new biosynthetic classes are characterized, the comprehensiveness of our approach will increase. Second, an enriched small molecule BGC does not necessitate a causative role in disease, but could also indicate a selection process as a consequence of the disease, where the produced molecule provides a survival or competitive advantage to the producer (Marcelino et al, 2023; Watson et al, 2023). For example, it is often suggested that the expansion of facultative anaerobes in the CD microbiome is a consequence of disease-associated inflammation and oxidative stress (Morgan et al, 2012).…”

The value of connections

“…Instead, they might simply be the only ones capable of surviving in a poorly diverse gut. The study also adds key evidence to the growing awareness of the relationships between microbial cross-feeding and microbiome composition, paving the way to test interesting questions in future research ( Wang et al, 2019 ; Marcelino et al, 2023 ; Gralka et al, 2020 ; Watson et al, 2023 ). For example, what are the roles of bacteria with high metabolic independence in re-establishing a healthy gut microbiome after disruption?…”

Demonstrating the Beneficial Effect of Low Protein Diet in Primary Sclerosing Cholangitis through a Randomized Clinical Trial and Multi-omics Data Analysis

“…Conversely, the cysK gene, involved in metabolizing H2S in the biosynthesis of cysteine, increased throughout LPD (Fig. 4k) [39,40]. Similarly, there was an increase in the bsh gene that metabolizes taurine and aids in the deconjugation of tauro-conjugated bile acids excreted to the gut from the biliary tree (Fig.…”

“…Interestingly, LPD led to a reduced amount of cysJ, a critical enzyme for producing hydrogen sulfide (H2S) from sulfite, and a reduced amount of dycD, key for H2S production from cysteine (Fig. 4k) [39,40]. Conversely, the cysK gene, involved in metabolizing H2S in the biosynthesis of cysteine, increased throughout LPD (Fig.…”

“…We focused on genes involved with sulfur metabolism to decipher the relationship between sulfurrelated metabolite changes and microbial functional changes. We referred to a comprehensive list of 74 genes involved in microbial sulfur metabolism in humans [39,40]. Of these, 27 were detected in at least one sample in this study, with 6 (or 5) of these genes significantly decreasing (or increasing) during intervention in LPD responders (Wilcoxon rank-sum test, p-value < 0.05), and 4 genes increasing with marginal significance (0.05 < p-value < 0.06) (Fig.…”