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Antibiotic Susceptibility Influenced by Carbon Source in Bacteroides thetaiotaomicron

ABSTRACT: Antibiotic therapy causes changes in bacterial abundance and metabolism within the gut microbiome. These changes can lead to complications in the host such as microbiome dysbiosis and opportunistic infections. Additionally, increasing multidrug resistance causes significant morbidity and mortality in patients with bacterial infections. Bacteroides thetaiotaomicron (Bth) is both a normal commensal in the gut and an opportunistic pathogen in other body sites. Our lab has shown that -lactam treatment in mice decimates nearly all gut bacterial species except Bth, which experiences a bloom. We propose that in the gut, Bth enters a protected state linked to metabolic changes such as an increase in stress response and polysaccharide fermentation, and a decrease in hexose utilization. Bth is also protected from -lactams in vitro when grown on fiber as opposed to glucose. The goal of this project is to understand what mechanism is responsible for this polysaccharide-mediated tolerance (PM-tolerance). Studies of other bacteria show that an increase in respiratory metabolism independent of growth rate promotes susceptibility to bactericidal antibiotics. Bth has a diverse array of metabolic machinery including an electron transport chain (ETC) that works under anaerobic or microaerobic conditions. Transcriptional analysis of Bth treated with the -lactam amoxicillin revealed a decrease in ETC enzyme expression when given fiber vs glucose. We found that knocking out different ETC enzymes alters the PM-tolerance phenotype in vitro. Thus, it appears that respiratory capacity is linked to -lactam susceptibility in Bth. This work improves upon our understanding of bacterial tolerance strategies and could help identify future therapeutic targets to combat multidrug resistance.

ORGANISM(S): Bacteroides thetaiotaomicron VPI-5482

PROVIDER: GSE251676 | GEO | 2024/07/20

REPOSITORIES: GEO

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Project description:The adult human gut microbial community is typically dominated by two bacterial phyla (divisions), the Firmicutes and the Bacteroidetes. Little is known about the factors that govern the interactions between their members. Here we examine the niches of representatives of both phyla in vivo. Finished genome sequences were generated from E. rectale and E. eligens, which belong to Clostridium Cluster XIVa, one of the most common gut Firmicute clades. Comparison of these and 25 other gut Firmicutes and Bacteroidetes indicated that the former possess smaller genomes and a disproportionately smaller number of glycan-degrading enzymes. Germ-free mice were then colonized with E. rectale and/or a prominent human gut Bacteroidetes, Bacteroides thetaiotaomicron, followed by whole genome transcriptional profiling of both organisms in their distal gut (cecal) habitat as well as host responses, high resolution proteomic analysis of cecal contents, and biochemical assays of carbohydrate metabolism. B. thetaiotaomicron adapts to E. rectale by upregulating expression of a variety of polysaccharide utilization loci (PULs) encoding numerous glycoside hydrolase gene families, and by signaling the host to produce mucosal glycans that it, but not E. rectale, can access. E. rectale adapts to B. thetaiotaomicron by decreasing production of its glycan-degrading enzymes, increasing expression of selected amino acid and sugar transporters, and facilitating glycolysis by reducing levels of NADH, in part via generation of butyrate from acetate, which in turn is utilized by the gut epithelium. This simplified model of the human gut microbiota illustrates niche specialization and functional redundancy within members of major gut bacterial phyla, and the importance of host glycans as a nutrient foundation that ensures ecosystem stability. We assessed how E. rectale and B. thetaiotaomicron were affected by changes in host diet. Groups of age- and gender-matched co-colonized mice were fed one of three diets that varied primarily in their carbohydrate and fat content: (i) the standard low-fat, plant polysaccharide-rich diet used for the experiments described above (abbreviated âLF/PPâ for low-fat/plant polysaccharide), (ii) a high-fat, âhigh-sugarâ Western-type diet (abbreviated HF/HS) that contained sucrose, maltodextrin, corn starch as well as complex polysaccharides (primarily cellulose) that were not digestible by B. thetaiotaomicron or E. rectale, and (iii) a control diet that was similar to (ii) except that the fat content was 4-fold lower (âLF/HSâ for low-fat, high-sugar; n=5 mice per group).

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Antibiotic Susceptibility Influenced by Carbon Source in Bacteroides thetaiotaomicron

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