Gut Microbiota–Metabolism Axis Shapes the Individual Metabolic Phenotype of Different Microbiota‐Accessible Carbohydrates

ABSTRACT Increasing the intake of microbiota‐accessible carbohydrates (MACs) has emerged as a promising nutritional strategy for preventing metabolic diseases. However, the consistency of their beneficial effects remains unclear, hindering their optimized application. This study aimed to compare the efficacy and mechanisms of four widely used purified MACs—konjac glucomannan (KGM), inulin, corn‐resistant starch (CR), and barley β‐glucan (BG) —under standardized experimental conditions. Using metabolic phenotyping, 16S rRNA gene‐based microbial profiling, and metabolomics, we evaluated the effects of these MACs on metabolic disturbances induced by a high‐fat/high‐sucrose (HFHS) diet in mice. We found that inulin, CR, and BG—but not KGM—significantly reduced hepatic triglycerides (TG). Inulin showed a pronounced effect on suppressing white adipose tissue weight, while only BG intake significantly reduced total cholesterol. The modest impact of KGM on hepatic lipid accumulation was associated with an increase in Anaerovorax and its associated metabolite, indolelactic acid. The strong ameliorative effect of CR on liver TG was linked to the enrichment of Oscillibacter and reduction in indolelactic acid. Inulin's suppression of adipose weight correlated with changes in LachnospiraceaeUCG‐006, LysoPC (22: 6 (4Z, 7Z, 10Z, 13Z, 16Z, 19Z) ), and propionate levels. Meanwhile, BG‐mediated cholesterol reduction was potentially driven by an increase in Muribaculum, along with elevated production of butyrate and LysoPC (22: 5 (4Z, 7Z, 10Z, 13Z, 16Z) ). In conclusion, this study demonstrates that a uniform fiber supplementation strategy is unlikely to yield consistent metabolic benefits. Our findings provide a foundation for developing targeted, MAC‐specific nutritional interventions to maintain metabolic homeostasis.