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In humans, this is exemplified by the association between high-protein intake and fermentation metabolite concentrations in patients with inflammatory bowel disease. In production animals, dietary protein intake is associated with postweaning diarrhea in piglets and with the occurrence of wet litter in poultry. The underlying mechanisms by which dietary protein contributes to intestinal problems remain largely unknown. Fermentation of undigested protein in the hindgut results in formation of fermentation products including short-chain fatty acids, branched-chain fatty acids, ammonia, phenolic and indolic compounds, biogenic amines, hydrogen sulfide, and nitric oxide. Here, we review the mechanisms by which these metabolites may cause intestinal disease. Studies addressing how different metabolites induce epithelial damage rely mainly on cell culture studies and occasionally on mice or rat models. Often, contrasting results were reported. The direct relevance of such studies for human, pig, and poultry gut health is therefore questionable and does not suffice for the development of interventions to improve gut health. We discuss a roadmap to improve our understanding of gut metabolites and microbial species associated with intestinal health in humans and production animals and to determine whether these metabolite\/bacterial networks cause epithelial damage. 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