Erythritol Exacerbates DSS-Induced Colitis and Influences Behavioral Responses in Mice Through Gut Microbiota and Metabolic Alterations

Excessive consumption of ultra-processed foods (UPFs) containing non-nutritive sweeteners (NNS) has been implicated in inflammatory bowel disease (IBD), yet the effects of erythritol on intestinal inflammation remain poorly understood. In this study, we assessed NNS-containing UPF exposure in patients with IBD and healthy controls, and then investigated the effects of erythritol in a dextran sulfate sodium (DSS)-induced colitis. Food frequency questionnaire (FFQ) results showed that patients with IBD, particularly those with active disease, had a higher proportion of NNS-containing UPF categories among total UPFs consumed. In mice, erythritol administration exacerbated DSS-induced colitis, as evidenced by sustained body weight loss, increased disease activity index, impaired intestinal barrier integrity, and elevated inflammatory cytokine expression. Transcriptomic analysis revealed significant enrichment of ferroptosis-related pathways in the colonic mucosa of erythritol-treated colitic mice. Furthermore, erythritol markedly altered gut microbial composition, characterized by increased abundance of potentially pathogenic bacteria and enrichment of Alistipes sp. CHKCI003. Untargeted metabolomics demonstrated alteration of tryptophan metabolism. Consistently, erythritol aggravated depression-like behavior in DSS-induced mice. Collectively, these findings suggest that erythritol exacerbates experimental colitis and depression-like behavior, potentially through microbiota dysbiosis, ferroptosis-associated alterations, and disrupted tryptophan metabolism.