Segment-specific amelioration of gut homeostasis by vitamin B3 in high-fat diet-fed mice: Roles in barrier integrity, inflammatory response, and microbiota composition.

A growing body of evidence suggests that disruption of gut homeostasis significantly contributes to the onset and progression of obesity. Owing to their specialized structural and physiological features, gastrointestinal segments may differ in susceptibility to high-fat diet (HFD)-induced disruptions and responses to therapeutic interventions, highlighting the importance of segment-specific investigation. Given that vitamin B₃ (VB₃) is a micronutrient often deficient in obese individuals, this study investigated the ameliorative effects of VB₃ supplementation on HFD-induced gut homeostasis disruption and its spatial variation across different intestinal segments using a mouse model. The results demonstrated that HFD feeding led to significant body weight gain and induced segment-specific disturbances of intestinal homeostasis. In the colon, HFD feeding caused pronounced impairment of tight junction proteins and the mucin barrier, accompanied by elevated oxidative stress and inflammation, reduced microbial diversity, an altered Firmicutes-to-Bacteroidetes (F/B) ratio, and depletion of beneficial genera. The ileum exhibited similar barrier disruption, inflammatory activation and depletion of beneficial genera, while microbial diversity remained unchanged. In contrast, the jejunum and duodenum exhibited mucin barrier deterioration, elevated inflammation, and a reduction in beneficial bacteria, while changes in tight junctions, oxidative stress, and microbial diversity were relatively modest. VB₃ supplementation mitigated HFD-induced weight gain and intestinal permeability. Comparative analysis across the duodenum, jejunum, ileum, and colon revealed that VB₃ exerted its most pronounced effects in the colon, where it alleviated oxidative stress, inflammation, and barrier dysfunction, upregulated tight junction proteins and mucin. In the ileum, VB₃ primarily promoted anti-inflammatory cytokine expression, and upregulated tight junction proteins. In the duodenum and jejunum, effects were largely restricted to reducing selected pro-inflammatory cytokines. Microbiota profiling showed that VB₃ selectively restored diversity, the F/B ratio, and short-chain fatty acid producers within colonic luminal and mucosa-associated communities, whereas such beneficial alterations were not observed in other intestinal segments. Overall, VB₃ modulates gut homeostasis in a segment-specific manner, supporting its potential as a dietary strategy to counter HFD-induced intestinal dysfunction.