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Post-prandial gastrointestinal symptoms such as diarrhea, abdominal distension, flatulence, bloating and a feeling of fullness are common complaints of often unknown etiology and pathogenesis. There is a long history of trials reporting the successful use of products containing a variety of combinations of digestive enzymes including a number of randomized placebo-controlled trials. We provide a narrative review of studies describing the use of multi-digestive enzymes for symptoms consistent with irritable bowel syndrome. We describe clinical trials reported over the past 60 years including double-blinded randomized, placebo-controlled studies and recent trials that focused on post-prandial diarrhea consistent with diarrhea-predominant irritable bowel syndrome. Disaccharidase deficiencies or deficiencies of other carbohydrate digesting enzymes were excluded. Worldwide studies have generally reported success with multi-enzyme preparations although none used a factorial design to identify subgroups or attempted to link specific symptom responses to specific components of therapy. Although there is a long history of the successful use of multi-enzyme preparations for post-prandial symptoms consistent with irritable bowel syndrome, long-term studies using validated scoring systems and factorial designs are needed to confirm the results for specific symptoms and the components of the combination drugs received., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)