Post-infectious ibs following Clostridioides difficile infection; role of microbiota and implications for treatment.

Up to 25% of patients recovering from antibiotic-treated Clostridioides difficile infection (CDI) develop functional symptoms reminiscent of Post-Infectious Irritable Bowel Syndrome (PI-IBS). For patients with persistent symptoms following infection, a clinical dilemma arises as to whether to provide additional antibiotic treatment or to adopt a conservative symptom-based approach. Here, we review the literature on CDI-related PI-IBS and compare the findings with PI-IBS. We review proposed mechanisms, including the role of C. difficile toxins and the microbiota, and discuss implications for therapy. We suggest that gut dysfunction post-CDI may be initiated by toxin-induced damage to enteroglial cells and that a dysbiotic gut microbitota maintains the clinical phenotype over time, prompting consideration of microbiota-directed therapies. While Fecal Microbial Transplant (FMT) is currently reserved for recurrent CDI (rCDI), we propose that microbiota-directed therapies may have a role in primary CDI in order to avoid or mitigate futher antibiotic treatment that further disrupts the microbiota and thus prevent PI-IBS. We discuss novel microbial transfer therapies and as they emerge, we recommend clinical trials to determine whether microbial transfer therapy of the primary infection prevents both rCDI and CDI-related PI- IBS.

Vasoactive Intestinal Polypeptide Plays a Key Role in the Microbial-Neuroimmune Control of Intestinal Motility.

BACKGROUND & AIMS: Although chronic diarrhea and constipation are common, the treatment is symptomatic because their pathophysiology is poorly understood. Accumulating evidence suggests that the microbiota modulates gut function, but the underlying mechanisms are unknown. We therefore investigated the pathways by which microbiota modulates gastrointestinal motility in different sections of the alimentary tract. METHODS: Gastric emptying, intestinal transit, muscle contractility, acetylcholine release, gene expression, and vasoactive intestinal polypeptide (VIP) immunoreactivity were assessed in wild-type and Myd88-/-Trif-/- mice in germ-free, gnotobiotic, and specific pathogen-free conditions. Effects of transient colonization and antimicrobials as well as immune cell blockade were investigated. VIP levels were assessed in human full-thickness biopsies by Western blot. RESULTS: Germ-free mice had similar gastric emptying but slower intestinal transit compared with specific pathogen-free mice or mice monocolonized with Lactobacillus rhamnosus or Escherichia coli, the latter having stronger effects. Although muscle contractility was unaffected, its neural control was modulated by microbiota by up-regulating jejunal VIP, which co-localized with and controlled cholinergic nerve function. This process was responsive to changes in the microbial composition and load and mediated through toll-like receptor signaling, with enteric glia cells playing a key role. Jejunal VIP was lower in patients with chronic intestinal pseudo-obstruction compared with control subjects. CONCLUSIONS: Microbial control of gastrointestinal motility is both region- and bacteria-specific; it reacts to environmental changes and is mediated by innate immunity-neural system interactions. By regulating cholinergic nerves, small intestinal VIP plays a key role in this process, thus providing a new therapeutic target for patients with motility disorders.

Alterations in fecal ß-defensin-3 secretion as a marker of instability of the gut microbiota.

Compositional changes in the microbiota (dysbiosis) may be a basis for Irritable Bowel Syndrome (IBS), but biomarkers are currently unavailable to direct microbiota-directed therapy. We therefore examined whether changes in fecal ß-defensin could be a marker of dysbiosis in a murine model. Experimental dysbiosis was induced using four interventions relevant to IBS: a mix of antimicrobials, westernized diets (high-fat/high-sugar and high salt diets), or mild restraint stress. Fecal mouse ß-defensin-3 and 16S rRNA-based microbiome profiles were assessed at baseline and during and following these interventions. Each intervention, except for mild restraint stress, altered compositional and diversity profiles of the microbiota. Exposure to antimicrobials or a high-fat/high-sugar diet, but not mild restraint stress, resulted in decreased fecal ß-defensin-3 compared to baseline. In contrast, exposure to the high salt diet increased ß-defensin-3 compared to baseline. Mice exposed to the mix of antimicrobials showed the largest compositional changes and the most significant correlations between ß-defensin-3 levels and bacterial diversity. The high salt diet was also associated with significant correlations between changes in ß-defensin-3 and bacterial diversity, and this was not accompanied by discernible inflammatory changes in the host. Thus, dietary change or antimicrobial exposure, both recognized factors in IBS exacerbations, induced marked dysbiosis that was accompanied by changes in fecal ß-defensin-3 levels. We propose that serial monitoring of fecal ß-defensins may serve as a marker of dysbiosis and help identify those IBS patients who may benefit from microbiota-directed therapeutic interventions.