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20230825_PFBBrPanel_Odenwald_Liverdiseasestudy

ABSTRACT: Samples were derivatized and analyzed by GC-MS operating in positive mode. See "PFBBrPanel_Methods" file for full assay protocols. Identification of endogenous compounds was confirmed by comparison to authentic standards. Normalized peak areas were calculated by dividing raw peak areas of targeted analytes by averaged raw peak areas of spiked internal standards. Concentrations were determined by plotting against a 10-point calibration curve generated alongside samples from serial dilutions of a known concentration of SCFAs.

INSTRUMENT(S): Agilent 8890/7890B GC system, Agilent 5977B MSD

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Matthew Odenwald

PROVIDER: MSV000092751 | MassIVE | Fri Aug 25 08:02:00 BST 2023

REPOSITORIES: MassIVE

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Project description:Background and Aims: Many inflammatory diseases are associated with microbial dysbiosis, which may considerably alter the production of short-chain fatty acids (SCFAs). SCFAs are produced in the large bowel through bacterial fermentation of dietary fiber and play an important role in maintaining gut homeostasis. SCFAs, particularly acetate and butyrate, show beneficial immunomodulatory effects contributing to the prevention of inflammatory and allergic reactions. Thus, reduced production of SCFAs may impact on the mucosal immune responses critical to fighting pathogens. This study aims to determine the influence of SCFAs on a murine model of colonic bacterial infection. Methods: In the present study, we used acetate- (HAMSA) or butyrate- (HAMSB) yielding diets to deliver high concentrations of individual SCFAs to the large bowel of mice infected with C. rodentium. We assessed the effects of these SCFAs on clinical burden and gut pathogenicity in correlation with changes in bacteria growth, fecal microbiota composition, function and changes in the immunological profile. Results: Here we show in vitro that acetate and butyrate directly inhibited growth of the attaching and effacing (A/E) pathogen C. rodentium in a bacteriostatic manner. This correlated with reduced expression of Tir, a gene responsible for bacterial adherence and pathogenicity. Interestingly, HAMSA-fed mice presented reduced clinical scores during C. rodentium infection associated with high concentrations of fecal acetate. This was linked with compositional and functional changes in the microbiota when examining 16s sequencing and proteomics analysis. The HAMSA mediated is protection involved increased expression IL-22 and Muc-2 in the colon and increased numbers of CD8αα+ TCRγδ T cells in the colonic epithelium. These effects were dependent on GPR43, a metabolite-sensing GPCR that binds acetate. Conclusions: We established a promising new approach to moderate bacterial gut infections by manipulating the gut microbiota and mucosal immune tolerance through diets that yield the SCFA acetate.

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20230825_PFBBrPanel_Odenwald_Liverdiseasestudy

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