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Distinct N and C cross-feeding networks in a synthetic mouse gut consortium

ABSTRACT: The complex interactions between gut microbiome and host or pathogen colonization resistance cannot solely be understood from community composition. Missing are causal relationships such as metabolic interactions among species to better understand what shapes the microbiome. Here, we focused on metabolic niches generated and occupied by the Oligo-Mouse-Microbiota, a synthetic community composed of 12 members that is increasingly used as a model for the mouse gut microbiome. Combining mono-cultures and spent medium experiments with untargeted metabolomics uncovered broad metabolic diversity in the consortium, constituting a dense cross-feeding network with more than 100 pairwise interactions. Quantitative analysis of the cross-feeding network revealed distinct C and N food webs that highlight the two Bacteroidetes consortium members B. caecimuris and M. intestinale as primary suppliers of carbon, and a more diverse group as nitrogen providers. Cross-fed metabolites were mainly carboxylic acids, amino acids, and the so far not reported nucleobases. In particular the dicarboxylic acids malate and fumarate provided a strong physiological benefit to consumers, presumably as anaerobic electron acceptors. Isotopic tracing validated the fate of a subset of cross-fed metabolites, in particular validating conversion of the most abundant cross-fed compound succinate to butyrate. Thus, we show that the OMM community is tailored to produce the anti-inflammatory metabolite butyrate. Overall, we provide evidence for metabolic niches generated and occupied by OMM members that lays a metabolic foundation to facilitate understanding of the more complex in vivo behavior of the OMM consortium in the mouse gut.

ORGANISM(S): Mus musculus (mouse)

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PROVIDER: S-BSST686 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:We investigated the requirement of 15 human butyrate-producing gut bacterial strains for eight B vitamins and the proteinogenic amino acids by a combination of genome sequence analysis and in vitro growth experiments. The Ruminococcaceae species Faecalibacterium prausnitzii and Subdoligranulum variabile were auxotrophic for most of the vitamins and the amino acid tryptophan. Within the Lachnospiraceae, most species were prototrophic for all amino acids and several vitamins, but biotin auxotrophy was widespread. In addition, most of the strains belonging to Eubacterium rectale and Roseburia spp., but few of the other Lachnospiraceae strains, were auxotrophic for thiamine and folate. Synthetic coculture experiments of five thiamine or folate auxotrophic strains with different prototrophic bacteria in the absence and presence of different vitamin concentrations were carried out. This demonstrated that cross-feeding between bacteria does take place and revealed differences in cross-feeding efficiency between prototrophic strains. Vitamin-independent growth stimulation in coculture compared to monococulture was also observed, in particular for F. prausnitzii A2-165, suggesting that it benefits from the provision of other growth factors from community members. The presence of multiple vitamin auxotrophies in the most abundant butyrate-producing Firmicutes species found in the healthy human colon indicates that these bacteria depend upon vitamins supplied from the diet or via cross-feeding from other members of the microbial community.IMPORTANCE Microbes in the intestinal tract have a strong influence on human health. Their fermentation of dietary nondigestible carbohydrates leads to the formation of health-promoting short-chain fatty acids, including butyrate, which is the main fuel for the colonic wall and has anticarcinogenic and anti-inflammatory properties. A good understanding of the growth requirements of butyrate-producing bacteria is important for the development of efficient strategies to promote these microbes in the gut, especially in cases where their abundance is altered. The demonstration of the inability of several dominant butyrate producers to grow in the absence of certain vitamins confirms the results of previous in silico analyses. Furthermore, establishing that strains prototrophic for thiamine or folate (butyrate producers and non-butyrate producers) were able to stimulate growth and affect the composition of auxotrophic synthetic communities suggests that the provision of prototrophic bacteria that are efficient cross feeders may stimulate butyrate-producing bacteria under certain in vivo conditions.

Project description:BACKGROUND:Substrate cross-feeding occurs when one organism partially consumes a primary substrate into one or more metabolites while other organisms then consume the metabolites. While pervasive within microbial communities, our knowledge about the effects of substrate cross-feeding on microbial evolution remains limited. To address this knowledge gap, we experimentally evolved isogenic nitrite (NO2-) cross-feeding microbial strains together for 700 generations, identified genetic changes that were acquired over the evolution experiment, and compared the results with an isogenic completely denitrifying strain that was evolved alone for 700 generations. We further investigated how the magnitude of interdependence between the nitrite cross-feeding strains affects the main outcomes. Our main objective was to quantify how substrate cross-feeding and the magnitude of interdependence affect the speed and trajectory of molecular evolution. RESULTS:We found that each nitrite (NO2-) cross-feeding strain acquired fewer genetic changes than did the completely denitrifying strain. In contrast, pairs of nitrite cross-feeding strains together acquired more genetic changes than did the completely denitrifying strain. Moreover, nitrite cross-feeding promoted population diversification, as pairs of nitrite cross-feeding strains acquired a more varied set of genetic changes than did the completely denitrifying strain. These outcomes likely occurred because nitrite cross-feeding enabled the co-existence of two distinct microbial strains, thus increasing the amount of genetic variation for selection to act upon. Finally, the nitrite cross-feeding strains acquired different types of genetic changes than did the completely denitrifying strain, indicating that nitrite cross-feeding modulates the trajectory of molecular evolution. CONCLUSIONS:Our results demonstrate that substrate cross-feeding can affect both the speed and trajectory of molecular evolution within microbial populations. Substrate cross-feeding can therefore have potentially important effects on the life histories of microorganisms.

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Distinct N and C cross-feeding networks in a synthetic mouse gut consortium

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