Decoding the SCFA-CpxAR-OMP axis as a dietary checkpoint against antimicrobial resistance transmission across gut-environment interfaces.

The transmission of environmental-originated antibiotic resistance genes (ARGs) into the human gut via the food chain or water has transformed the intestinal tract into a critical reservoir and dissemination hub for ARGs. Moreover, human to human oral-fecal transmission is likely to intensify this dissemination cycle. Gut microbiota harboring ARGs not only drive clinical infections but also exacerbate diverse pathologies, including inflammatory bowel disease and metabolic disorders. Furthermore, amplified ARGs can re-enter environmental compartments through fecal discharge, establishing a persistent bidirectional "gut-environment" resistance transmission cycle. In this study, we demonstrate that short-chain fatty acids (SCFAs), key metabolites derived from gut microbiota, potently suppress the horizontal transfer of ARGs. A high-fiber diet reshaped gut microbial composition, elevating SCFA production by 1.6-fold and reducing ARGs dissemination rates by up to 5.8-fold in vivo. The anti-conjugation activity of SCFAs was further validated through in vitro observations and in vivo models. Mechanistically, we propose the CpxAR-OMP pathway as a previously uncharacterized regulatory axis, wherein SCFAs inhibit ARGs transfer by downregulating conjugation-associated promoters (trfAp and trbBp) and disrupting membrane function via CpxAR-mediated suppression of OMPs expression. To our knowledge, this work provides comprehensive evidence of SCFAs in curbing exogenous ARGs dissemination within the gut ecosystem, deciphers the CpxAR-OMP-driven molecular mechanism, and proposes dietary fiber intervention as a feasible strategy to mitigate antimicrobial resistance across the "One-Health" continuum.