Longitudinal multi-omics profiling reveals dynamic remodeling of the gut microbiota-metabolite-immune axis in locally advanced rectal cancer

Background Patients diagnosed with locally advanced rectal cancer (LARC) exhibit substantial heterogeneity in their response to neoadjuvant chemoradiotherapy (nCRT). The gut microbiota (GM) - bile acid (BA) & short-chain fatty acids (SCFA) axis may play an important role in regulating LARC microscopic inflammation and may represent a potential target for delaying or reversing LARC. To explore whether the therapeutic outcomes of well-responsive LARC patients before and after nCRT are driven by remodeling of the intestinal immune microenvironment involving BAs and SCFAs. Methods A total of 63 LARC patients were included in this study, and their baseline clinical characteristics were assessed according to predefined inclusion and exclusion criteria. In addition, we integrated microbiomic, metabolomic, and transcriptomic analyses to characterize the GM-BA&SCFA-immune axis in pathological complete response LARC (pCR-LARC) patients before treatment (pre-nCRT, n = 25) and after treatment (post-nCRT, n = 25). Results Serum levels of CEA, LCR, PLR, and SII were significantly lower in pCR-LARC patients. Subsequently, the GM composition and diversity differed significantly between the pre-nCRT and post-nCRT in pCR-LARC. Beneficial intestinal bacterial taxa and microbial functional genes involved in distinct metabolic pathways were differentially enriched from pre-nCRT to post-nCRT. Deoxycholic acid (DCA) and lithocholic acid (LCA) were significantly decreased in post-nCRT compared with pre-nCRT. Notably, targeted SCFA metabolomic demonstrated a significant elevation of butyrate levels. Meanwhile, fecal metabolomic showed that 511 differentially abundant metabolites (DAMs) tended to be associated with enriched primary bile acid biosynthesis and biosynthesis of unsaturated fatty acids. Serum transcriptomic identified 2,289 differentially expressed genes (DEGs) associated with immune-related processes and lipid metabolism, among which the inflammation-associated proteins S100A9, S100A8, CXCL8, MMP9, LY96, and CXCL1 were markedly downregulated following nCRT. Notably, a potential Phocaeicola vulgatus associated KEGG orthologs (KOs) bsh and buk gene, secondary bile acids (e.g., DCA and LCA) and short-chain fatty acids (e.g., butyrate), immune regulatory axis that may contribute to the modulation of nCRT response in pCR-LARC patients.. Conclusions Together, these findings support a potential role of the gut microbiota-BA/SCFA- host immune axis in modulating therapeutic responses in pCR-LARC patients. Although further functional validation is required, targeted modulation of the microbiota-metabolite balance and the subsequent remodeling of the immune microenvironment may represent a promising strategy to improve nCRT efficacy.