Serum Short-Chain Fatty Acids in Colorectal Cancer: Diagnostic Performance and Decoupling from Gut Producer Abundance

Gut microbiota-derived short-chain fatty acids (SCFAs) shape epithelial and immune homeostasis, yet systemic SCFA profiles may diverge from gut microbial composition due to absorption and host metabolism. We quantified fasting serum SCFAs in 36 surgically resected colorectal cancer (CRC) patients and 20 cancer-free controls using targeted high-performance liquid chromatography-triple quadrupole mass spectrometry, and integrated these data with fecal and serum bacterial DNA profiles generated by 16S ribosomal RNA sequencing and functional inference. CRC was associated with a distinct circulating SCFA pattern: total SCFAs and acetate were increased, branched SCFAs were higher, and butyrate and valerate were lower relative to controls. Despite this clear systemic signature, associations between serum SCFAs and the relative abundance (RA) of putative SCFA-producing genera were sparse and inconsistent across CRC and control groups, both when considering fecal producers and serum-detected taxa. Interestingly, the total RA of SCFA-producing genera was higher in controls in feces but higher in CRC in serum, further supporting compartment-specific decoupling. Finally, several circulating SCFAs showed inverse associations with indicators of tumor progression within CRC. These results motivate integrative microbiota-metabolite studies and validation in larger cohorts to clarify how circulating SCFAs relate to gastrointestinal disease biology and immune regulation.