Enhanced Intestinal Protein Fermentation Correlates With Severe Psychiatric Symptoms of Schizophrenia

Abstract Emerging findings highlighted the associations of mental illness to nutrition and dysbiosis in the intestinal microbiota, but the underlying mechanisms, especially in schizophrenia (SZ), remain unclarified. Here we conducted a case-control study of SZ by performing gut metagenome, fecal and plasma non-targeted metabolome, short-, medium-, and long-chain fatty acids, and targeted metabolite analysis. The results uncovered an apparent contradiction in SZ patients between inadequate protein intake and protein-fermentation-dominated intestinal microbial metabolism, which shifted from carbohydrate fermentation and protein synthesis in healthy conditions. Moreover, the extent of protein fermentation represented as the abundance of related enzymes and fecal levels of related products, usually nitrogenous and neurologically active, correlated with the severity of psychiatric symptoms. These findings provide a previously uncharacterized pathophysiological process in SZ related to the dysbiosis of gut microbiota and dysregulation in macronutrient metabolism, highlighting the importance of nutrition care and the potentials for developing microbiota-targeted therapeutics in SZ.