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Abstract
Background The effect and mechanism of microbiota involvement in the anti-TNF treatment of UC remains to be revealed.
Methods We collected UC tissues and stool samples. Stool samples were collected to observe the effect of faecal bacteria from NRUC and RUC patients on IFX treatment in mice. Cells incubated with Fn, NAD+ inhibitor or NAMPT-targeting siRNA conducted RNA-seq analysis and metabolomics analysis, then the expression of mRNAs, proteins and the contents of NAM, NMN and NAD+ were verified. Mice were treated with ABX, fecal bacteria, Fn, DSS, Adezmapimod or FK866 to observe intestinal mucosal injury and pathological changes.
Results Mice in NR+DSS+IFX group exhibited rapid weight loss, higher DAI, shorter colon size ratio and disruption of mucosal structures than mice treated with DSS+IFX or NR+DSS+IFX. The abundance of Lactobacillus and Fusobacterium in tissues of NR+DSS+IFX group was significantly increased. Fn was abundant in NRUC tissues ((P < 0.01). Compared with control cells, the expression of NAD+, NMN, NAM, p-ERK, p-P38 was significantly increased, and the expression of ZO-1 and Occludin was downregulated in cells infected with Fn. These effects were attenuated by exposure to FK866, knockdown of NAMPT. Mice treated with Fn+DSS+IFX developed significantly rapid weight loss, higher DAI, shorter colon size ratio and disruption of mucosal structures, higher content of NAD+, NMN, NAM, upregulated expression of NAMPT, p-P38, downregulated expression of ZO-1 and Occludin, higher secretion of IL-6, IL-18 and TNF-α in serum and tissues than mice treated with DSS+IFX,which were attenuated by exposure to Adezmapimod or FK866.
Conclusions Gut microbiota plays an important role in anti-TNF resistance in UC. We identified that Fn was enriched in NRUC tissues from patients. Fn orchestrates a molecular network involving NAMPT and NAD+ slvage pathways to control the responsiveness of anti-TNF therapy in UC. Measuring and targeting Fn and its associated pathways will yield valuable insights into the prevention and treatment for drug resistance of Fn -related UC.