The therapeutic management of Crohn’s disease (CD), a chronic relapsing–remitting inflammatory bowel disease (IBD), is highly challenging. Surgical resection is sometimes a necessary procedure even though it is often associated with postoperative recurrences (PORs). Tofacitinib, an orally active small molecule Janus kinase inhibitor, is an anti-inflammatory drug meant to limit PORs in CD. Whereas bidirectional interactions between the gut microbiota and the relevant IBD drug are crucial, little is known about the impact of tofacitinib on the gut microbiota. The HLA-B27 transgenic rat is a good preclinical model used in IBD research, including for PORs after ileocecal resection (ICR). In the present study, we used shotgun metagenomics to first delineate the baseline composition and determinants of the fecal microbiome of HLA-B27 rats and then to evaluate the distinct impact of either tofacitinib treatment, ileocecal resection or the cumulative effect of both interventions on the gut microbiota in these HLA-B27 rats. The results confirmed that the microbiome of the HLA-B27 rats was fairly different from their wild-type littermates. We demonstrated here that oral treatment with tofacitinib does not affect the gut microbial composition of HLA-B27 rats. Of note, we showed that ICR induced an intense loss of bacterial diversity together with dramatic changes in taxa relative abundances. However, the oral treatment with tofacitinib neither modified the alpha-diversity nor exacerbated significant modifications in bacterial taxa induced by ICR. Collectively, these preclinical data are rather favorable for the use of tofacitinib in combination with ICR to address Crohn’s disease management when considering microbiota.

Chitin–glucan (CG) is a new generation of prebiotic. Lactobacillus acidophilus NCFM^® (NCFM) is a probiotic with the ability to decrease abdominal pain. We evaluate the functional and molecular gastrointestinal responses to a synbiotic administration combining CG and NCFM in a rat model of long-lasting colon hypersensitivity. The intracolonic pressure was assessed during the 9-week experiment in animals receiving CG in association or not with NCFM and compared to that in Lacticaseibacillus paracasei Lpc-37^®-treated animals and control rats receiving tap water. The effects of the synbiotic were evaluated using the Wallace score, the quantification of colon myeloperoxidase (MPO) and the master genes driving analgesia and inflammation. CG 1.5 alone and NCFM 10⁹ colony forming units (CFU) alone similarly decreased the visceral pain sensitivity. Lpc-37 had no significant effect. The best profile of pain perception inhibition was obtained with the combination of CG 1.5 g and NCFM 10⁹ CFU, confirming a synbiotic property. This synbiotic treatment significantly reduced macroscopic colonic lesions and MPO concentrations, and induced master genes involved in analgesia (CB1, CB2, MOR, PPARα), with a downregulation of inflammatory cytokines (IL-1β, TNFα) and an induction of IL-10 and PPARγ. In conclusion, CG 1.5 g + NCFM 10⁹ CFU significantly decreased visceral pain perception and intestinal inflammation through the regulation of master genes.

Postoperative recurrence (POR) remains a common complication following ileocecal resection (ICR) in patients with Crohn’s disease (CD), and no therapy is currently approved. This study aimed to study the benefits of JAK/STAT pathway inhibition in preventing POR using an ICR model in HLA-B27 transgenic (Tg) rats. Twenty-nine Tg rats underwent ICR at 12 weeks of age (W12). TOFA (15 mg/Kg/day) or placebo was administered at W10 as a preventive intervention. Disease extent and severity were assessed by monitoring body weight, stool consistency, performing endoscopy (W15) and evaluating macroscopic and histologic scores (W18). Ileal STATs phosphorylation was assessed by Western blotting and immunohistochemistry, while inflammatory cytokine expression was quantified by qRT-PCR and ELISA. In the placebo-treated Tg group, 57% of rats exhibited mucosal ulcerations in at least 20% of the anastomotic area (macroscopic score ≥2), which correlated with an endoscopic score ≥9. In contrast, only 13% of TOFA-treated Tg rats had a macroscopic score ≥2 and all had endoscopic scores ≤9. TOFA reduced mucosal inflammation and decreased ilealSTAT3 phosphorylation and pro-inflammatory cytokine expression. These findings provide a preclinical rationale for further investigating JAK inhibition as a potential preventive strategy against POR in CD.