Background Beneficial effects of carbohydrate fermentation on gastrointestinal health are well established. Conversely, protein fermentation generates harmful metabolites but their relevance to gastrointestinal health is poorly understood. Aim To review the effects of increased protein fermentation on biomarkers of colonic health, factors influencing fermentative activity and potential for dietary modulation to minimise detrimental effects. Methods A literature search was performed in PubMed, Medline, EMBASE and Google scholar for clinical and pre-clinical studies using search terms - 'dietary protein', 'fermentation', 'putrefaction', 'phenols', 'sulphide', 'branched-chain fatty acid', 'carbohydrate fermentation', 'gastrointestinal'. Results High protein, reduced carbohydrate diets alter the colonic microbiome, favouring a potentially pathogenic and pro-inflammatory microbiota profile, decreased short-chain fatty acid production and increased ammonia, phenols and hydrogen sulphide concentrations. These metabolites largely compromise the colonic epithelium structure, causing mucosal inflammation but may also directly modulate the enteric nervous system and intestinal motility. Increased protein fermentation as a result of a high-protein intake can be attenuated by addition of oligosaccharides, resistant starch and nonstarch polysaccharides and a reduction in total protein or specifically, aromatic and sulphur-containing amino acids. These factors may have clinical importance as novel therapeutic approaches to problems, in which protein fermentation may be implicated, such as malodorous flatus, irritable bowel syndrome, ulcerative colitis and prevention of colorectal cancer. Conclusions The direct clinical relevance of excessive protein fermentation in the pathogenesis of irritable bowel syndrome, malodorous flatus and ulcerative colitis are underexplored. Manipulating dietary carbohydrate and protein intake have potential therapeutic applications in such settings and warrant further clinical studies.