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Irritable bowel syndrome (IBS) is a common, heterogeneous disorder characterized by abdominal pain associated with changes in bowel habits. The pathogenesis of IBS is multifactorial and may relate to alterations in the gut microbiota, changes in visceral sensation and motility, and genetic and environmental factors. Administration of systemic antibiotics may increase the risk of IBS by altering gastrointestinal homeostasis. Therapeutic interventions for IBS with diarrhea that are thought to target alterations in the gut microbiota include the nonsystemic antibiotic rifaximin, the medical food serum-derived bovine immunoglobulin, prebiotics, probiotics, and dietary modification. SYN-010 is a modified-release statin formulation that reduces methane production byMethanobrevibacter smithiiand is currently in development for the treatment of patients with constipation-predominant IBS. Use of these interventions in the management of patients with IBS may function to restore a healthy gut microbiota and ameliorate symptoms of IBS.