Sex-Dependent Microbiome-Metabolome Remodeling Associated with Bacteroides acidifaciens Modulation of Acute Respiratory Distress Syndrome

Abstract

Acute respiratory distress syndrome (ARDS) is a severe lung disorder influenced by the interplay between the intestinal microbiome, host metabolism, and immune function. We previously found that Bacteroides acidifaciens (BA) has opposing effects on staphylococcal enterotoxin B (SEB)-induced ARDS, worsening the condition in female mice while alleviating it in males. This study aimed to examine whether these outcomes are linked to sex-dependent changes in the intestinal microbiome and gut-lung metabolome. C3H/HeJ mice of both sexes were orally colonized with Bacteroides acidifaciens before SEB exposure. Stool and bronchoalveolar lavage fluid (BALF) were collected for analysis using 16S rRNA sequencing and untargeted liquid chromatography mass spectrometry metabolomics. Our findings revealed distinct sex-dependent metabolic and microbial responses. In females, disease exacerbation correlated with elevated lipid mediators (leukotriene B4, 13-oxoODE, and 13S-HODE) alongside shifts in bile acid and redox metabolism. The intestinal microbiome showed changes in Bacteroides, Akkermansia, and Lachnospiraceae. Conversely, males showed a protective phenotype characterized by increased butyrate and alterations in sphingolipid, amino acid, redox, and nucleotide pathways. Integrated analyses identified sex-associated microbial communities and metabolomic profiles, highlighting distinct patterns of lipid and redox associations in females versus sphingolipid and short-chain fatty acid patterns in males. These results suggest that host sex influences how a commensal bacterium affects inflammatory lung injury and point to pathways for future research. Importance ARDS is a fatal inflammatory response with high mortality and limited targeted therapies. Emerging evidence has pointed to the gut-lung axis as a source of inflammation that shapes pulmonary immune responses. Yet, how individual commensal bacteria influence this axis, and how biological sex alters both the microbiome and immune response remains poorly understood. Bacteroides acidifaciens, drives fundamentally different intestinal microbial and metabolic states in female and male mice during ARDS, and provides some evidence of how both can impact ARDS outcomes. Females develop an environment enriched in inflammatory lipid mediators, while males exhibit a metabolic profile associated with barrier support and reduced inflammation. These findings have implications for understanding sex-based differences in ARDS outcomes and for identifying microbiome-targeted therapeutic strategies.