Microbiota-derived D-amino acids in intestinal homeostasis and inflammatory bowel disease

Inflammatory bowel disease (IBD) encompasses chronic, relapsing inflammatory disorders of the gastrointestinal tract, which are driven by intricate interactions between the host immune system and intestinal microbiota. Recent studies have revealed that microbiota-derived D-amino acids (D-AAs), once considered biologically inert, play critical roles in maintaining mucosal homeostasis and modulating immune responses. These metabolites, which are increasingly classified as postbiotics, directly influence epithelial barrier integrity, immune cell activity, and microbial ecology. In this review, we summarize the current insights into the biosynthesis, bacterial functions, and immunological implications of D-AAs in the gut, with a particular focus on their involvement in IBD pathogenesis. Specific D-AAs, such as D-alanine, contribute to bacterial cell wall integrity and quorum sensing and interact with host immune cells, alter microbial communities, and regulate mucosal barrier function. Evidence from both human studies and murine models highlights how disrupted D-AAs’ metabolism through dysbiosis or impaired host sensing via enzymes such as D-amino acid oxidase (DAO) exacerbates inflammation. Finally, we discuss the translational potential of D-AAs as non-invasive biomarkers and therapeutic targets in IBD, emphasizing the need for integrative multi-omics approaches that connect microbial metabolism with host immune regulation and disease outcomes.