rifampin and Inflammatory-Bowel-Diseases

Rifaximin is a rifamycin analogue with a broad spectrum of activity similar to that of rifampin; however, because it is poorly absorbed in the gastrointestinal tract, the focus of its development has been on intestinal infections and diseases. This agent has proven to be as effective as ciprofloxacin in treating travelers' diarrhea due to Escherichia coli, although it is ineffective in treating infections due to Campylobacter jejuni. Other potential uses for rifaximin in gastroenterologic disorders include treatment of hepatic encephalopathy, intestinal gas and gas-related symptoms, diverticular disease, intestinal bacterial overgrowth, pouchitis, ulcerative colitis, and active Crohn's disease. This article highlights several studies demonstrating the efficacy of rifaximin in treating travelers' diarrhea as well as other gastrointestinal diseases and discusses the drug's pharmacokinetics, indications, contraindications, warnings, precautions, adverse reactions, and dosing.

Topics: Anti-Infective Agents; Diarrhea; Escherichia coli Infections; Gases; Hepatic Encephalopathy; Humans; Inflammatory Bowel Diseases; Intestinal Absorption; Intestines; Lactulose; Microbial Sensitivity Tests; Rifampin; Rifamycins; Rifaximin

The Pregnane X Receptor (PXR) is a principal signal transducer in mucosal responses to xenobiotic stress. It is well-recognized that inflammatory bowel disease is accompanied by xenobiotic stress, but the importance of the PXR in limiting inflammatory responses in inflammatory bowel disease remains obscure at best.. We stimulate a total of 106 colonic biopsies from 19 Crohn's disease patients with active disease, 36 colonic biopsies from 8 control patients, colonic organoids and various cell culture models (either proficient or genetically deficient with respect to PXR) in vitro with the PXR ligand rifampicin or vehicle. Effects on NF-κB activity are assessed by measuring interleukin-8 (IL-8) and interleukin-1ß (IL-1ß) mRNA levels by qPCR and in cell culture models by NF-κB reporter-driven luciferase activity and Western blot for signal transduction elements.. We observe a strict inverse correlation between colonic epithelial PXR levels and NF-κB target gene expression in colonic biopsies from Crohn's disease patients. PXR, activated by rifampicin, is rate-limiting for mucosal NF-κB activation in IBD. The correlation between colonic epithelial PXR levels and NF-κB target gene expression was also observed in intestinal organoids system. Furthermore, in preclinical in vitro models of intestinal inflammation, including intestinal organoids, genetic inactivation of PXR unleashes NF-κB-dependent signal transduction whereas conversely NF-κB signaling reduces levels of PXR expression.. Our data indicate that the PXR is a major and clinically relevant antagonist of NF-κB activity in the intestinal epithelial compartment during inflammatory bowel disease.

Topics: Biopsy; Cell Line, Tumor; Cytokines; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; NF-kappa B; Pregnane X Receptor; Rifampin; Signal Transduction

The prevalence of Clostridium difficile infection (CDI) in pediatric patients with inflammatory bowel disease (IBD) is still not sufficiently recognized. We assessed the prevalence of CDI and recurrences in outpatients with IBD. In addition, the influence of IBD therapy on CDI and antimicrobial susceptibility of the potentially causative C. difficile strains was assessed. This was a prospective, single-center, observational study. All specimens were obtained between January 2005 and January 2007 from the IBD outpatient service and screened for C. difficile and its toxins. C. difficile isolates were genotyped by PCR ribotyping. Diagnosis of Crohn's disease (CD) and ulcerative colitis (UC) was based on Porto criteria. Severity of disease was assessed using the Hyams scale (for Crohn's disease) and the Truelove-Witts scale (for ulcerative colitis). One hundred and forty-three fecal samples from 58 pediatric IBD patients (21 with Crohn's disease and 37 with ulcerative colitis) were screened. The risk of C. difficile infection was 60% and was independent of disease type (CD or UC) (χ2 = 2.5821, df = 3, p = 0.4606). About 17% of pediatric IBD patients experienced a recurrence of CDI. All C. difficile strains were susceptible to metronidazole, vancomycin and rifampin. A high prevalence of C. difficile infection and recurrences in pediatric outpatients with IBD was observed, independent of disease type. There was no significant correlation between C. difficile infection and IBD therapy. PCR ribotyping revealed C. difficile re-infection and relapses during episodes of IBD in pediatric outpatients.

Topics: Adolescent; Ambulatory Care; Anti-Bacterial Agents; Child; Child, Preschool; Clostridioides difficile; Clostridium Infections; DNA, Bacterial; Feces; Female; Humans; Inflammatory Bowel Diseases; Male; Metronidazole; Microbial Sensitivity Tests; Prevalence; Recurrence; Ribotyping; Rifampin; Severity of Illness Index; Vancomycin

Human pregnane X receptor (PXR) has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Rifaximin, a human PXR activator, is in clinical trials for treatment of IBD and has demonstrated efficacy in Crohn's disease and active ulcerative colitis. In the current study, the protective and therapeutic role of rifaximin in IBD and its respective mechanism were investigated. PXR-humanized (hPXR), wild-type, and Pxr-null mice were treated with rifaximin in the dextran sulfate sodium (DSS)-induced and trinitrobenzene sulfonic acid (TNBS)-induced IBD models to determine the protective function of human PXR activation in IBD. The therapeutic role of rifaximin was further evaluated in DSS-treated hPXR and Pxr-null mice. Results demonstrated that preadministration of rifaximin ameliorated the clinical hallmarks of colitis in DSS- and TNBS-treated hPXR mice as determined by body weight loss and assessment of diarrhea, rectal bleeding, colon length, and histology. In addition, higher survival rates and recovery from colitis symptoms were observed in hPXR mice, but not in Pxr-null mice, when rifaximin was administered after the onset of symptoms. Nuclear factor κB (NF-κB) target genes were markedly down-regulated in hPXR mice by rifaximin treatment. In vitro NF-κB reporter assays demonstrated inhibition of NF-κB activity after rifaximin treatment in colon-derived cell lines expressing hPXR. These findings demonstrated the preventive and therapeutic role of rifaximin on IBD through human PXR-mediated inhibition of the NF-κB signaling cascade, thus suggesting that human PXR may be an effective target for the treatment of IBD.

Topics: Animals; Cell Line; Colon; Dextran Sulfate; Gastrointestinal Agents; Humans; Inflammatory Bowel Diseases; Leprostatic Agents; Liver; Luciferases; Male; Metabolomics; Mice; Mice, Inbred C57BL; Mice, Knockout; Microsomes; NF-kappa B; Pregnane X Receptor; Receptors, Steroid; Rifampin; Rifamycins; Rifaximin; RNA, Messenger; Stearoyl-CoA Desaturase