Relangi, T. R. | bioRxiv Science

bioRxiv2026

Chronic stress remodels gut bacterial ecology and polysaccharide metabolism with neuroendocrine consequences despite unchanged behavior

The gut-microbiome-brain axis (GMBA) links the gut and brain through metabolic, immunological, and neuroendocrine pathways, and can become dysregulated during psychological stress (PS). While previous studies primarily infer microbial function and use physical stressors that incompletely model human PS, here, functional multi-omics was applied to a chronic social-isolation mouse model. Although isolation caused no measurable behavioral changes, brain proteomics revealed stress-associated molecular responses. Taxonomic and short-chain fatty acid analyses suggested limited microbiome changes; however, metaproteomics uncovered sex-specific restructuring of bacterial ecology and carbohydrate-active enzymes. In females, isolation increased Petralouisia muris proteins involved in bacterial microcompartment metabolism and {beta}-glucuronidases across Lachnospiraceae taxa. Enriched {beta}-glucuronidase abundance coincided with reduced circulating glucuronides and altered brain estrogen-receptor activity, suggesting a microbial deconjugation-host estrogen-signaling interaction. These findings demonstrate that functional GMBA alterations may precede or occur independently of overt behavioral phenotypes and highlight the value of direct functional profiling in PS.

microbiology↗

bioRxiv2026

Commensal Bacteria in the Gut Microbiome Encode Previously Unrecognized Aromatic Hydrocarbon Catabolic Machinery

Introduction. Polycyclic aromatic hydrocarbon (PAH) toxicology has been primarily defined by host metabolic bioactivation to reactive intermediates. Yet ingested PAHs and biliary-delivered metabolites also enter the intestinal lumen, where they encounter the gut microbiota, an additional but understudied metabolic compartment that may alter toxicant fate. Although PAH interactions are well characterized in environmental microbes, resulting in defined enzymatic pathways for their catabolism, whether gut commensal organisms express related machinery in vivo remains poorly understood. To address this gap, we used an oral murine-exposure model of naphthalene and integrated compartment-resolved 16S rRNA gene profiling, global metaproteomics, and chemoproteomics to resolve the PAH-processing repertoire of the gut microbiota and its spatial distribution. Results. Naphthalene, a common environmental toxicant and representative PAH, elicited a compartment-dependent functional response that was most pronounced in the large intestine. Distally, exposure was associated with 2,386 differential proteins and accounted for 48.4% of metaproteomic variation, compared with 7.9% of 16S rRNA gene compositional variation. The small intestine showed a reduced proteomic response, with 994 differentially abundant proteins. Hydrocarbon catabolic markers showed a 4.8-fold distal expansion (36 to 172 proteins), including the naphthalene-catabolic nahE, proteins associated with phenylacetate, {beta}-ketoadipate, catechol/TOL, and anaerobic CoA-linked redox machinery. The small-intestinal repertoire decreased from 19 to 14 proteins, though aromatic-catabolic markers doubled, indicating a selective expansion. Critically, these homologs concentrated in Lachnospiraceae, a gut family that is prevalent in humans, primarily known for anaerobic fermentation, with no priorly described PAH-processing capacity. An uncultured Acetatifactor showed the largest hydrocarbon hits (14 to 82 protein increase), with additional contributions from Kineothrix, Eisenbergiella, and Petralouisia. Chemoproteomics, using a naphthalene-based probe, revealed enrichment of an orthogonal proteome of proteins interacting with naphthalene, capturing 171 small-intestinal and 67 large-intestinal proteins that were undetected in the global metaproteomes. Conclusions. Gut commensals express homologs of aromatic-hydrocarbon catabolic enzymes characterized in environmental microorganisms, and naphthalene amplifies this repertoire most strongly in the large intestine. The decoupling of taxonomic structure, expressed-protein representation, and probe engagement identifies a functional dimension of PAH exposure that composition-based profiling does not resolve and positions microbiome variation as a candidate modifier of PAH metabolic fate.

microbiology↗