High-fat diet-disturbed gut microbiota-colonocyte interactions contribute to dysregulating peripheral tryptophan-kynurenine metabolism

Abstract

Background Aberrant tryptophan (Trp)-kynurenine (Kyn) metabolism has been implicated in the pathogenesis of human disease. In particular, populations with long-term western-style diets are characterized by an excess of Kyn in the plasma. Host-gut microbiota interactions are dominated by diet and are essential for maintaining host metabolic homeostasis. However, the role of western diet-disturbed gut microbiota-colonocyte interactions in Trp metabolism remains to be elucidated. Results Here, 4-week-old mice were fed with a high-fat diet (HFD), representing a typical western diet, for 4 weeks, and multi-omics approaches were adopted to determine the mechanism by which HFD disrupted gut microbiota-colonocyte interplay causing serum Trp-Kyn metabolism dysfunction. Our results showed that colonocyte-microbiota interactions dominated the peripheral Kyn pathway in HFD mice. Mechanistically, persistent HFD-impaired mitochondrial bioenergetics increased colonic epithelial oxygenation and caused metabolic reprogramming in colonites to support the expansion of Proteobacteria in the colon lumen. Phylum Proteobacteria-derived lipopolysaccharide (LPS) stimulated colonic immune responses to upregulate the indoleamine 2,3-dioxygenase 1 (IDO1)-mediated Kyn pathway, leading to Trp depletion and Kyn accumulation in the circulation, which was further confirmed by transplantation of Escherichia coli (E.coli) indicator strains and colonic IDO1 depletion. Butyrate supplementation promoted mitochondrial functions in colonocytes to remodel the gut microbiota in HFD mice, consequently ameliorating serum Kyn accumulation. Conclusions Our results highlighted that HFD disrupted the peripheral Kyn pathway in a gut microbiota-dependent manner and that the continuous homeostasis of gut bacteria-colonocytes interplay played a central role in the regulation of host peripheral Trp metabolism. Meanwhile, this study provided new insights into therapies against western diet-related metabolic disorders.

Enhanced mucosal mitochondrial function corrects dysbiosis and OXPHOS metabolism in IBD

“…Several studies show that KYN/TRP ratio is associated with important biomarkers of disease activity, C-reactive protein, sedimentation rate 73 , and endoscopic score 74 . Interestingly, phylum Proteobacteria -derived lipopolysaccharide (LPS) stimulated colonic immune responses upregulates the indoleamine 2,3-dioxygenase 1 (IDO1)-mediated Kyn pathway, leading to TRP depletion and KYN accumulation in the circulation 75 . AuPhos treatment reduced the level of KYN (L-Kynurenine) and its hydroxy-derivatives (3-Hydroxykynurenine) in Hu- Il10-/- mice compared to vehicle treated group ( Fig 6C ).…”

Kynurenines, Neuronal Excitotoxicity, and Mitochondrial Oxidative Stress: Role of the Intestinal Flora

“…In a recent study, Sun and his colleagues found that long-term high-fat diets disrupted the metabolism of Trp in the bloodstream in mice [51]. This disruption was characterized by a reduction in Trp levels and an increase in the activity of the KP.…”

“…This disruption was characterized by a reduction in Trp levels and an increase in the activity of the KP. Notably, this aberrant Trp metabolism strongly correlated with the proliferation of the Proteobacteria phylum in the colon, so deviations in Trp metabolism can induce changes in the KP metabolism [51] as well. In this interesting research, the authors could abrogate the long-term high-fat diet shift with antibiotic treatment, but changes induced by the long-term high-fat diet could be transferred to mice with a standard diet through fecal transplantation, thus revealing the role of gut microbiota in this process.…”

Role of microbiota-gut-brain axis in natural aging-related alterations in behavior

“…Also, changes in microbial composition are thought to play a key role in regulating the MGBA and influencing the brain and gut function ( Borre et al, 2014 ; Sun et al, 2023 ). The MGBA is a bi-directional communication network between gut microbes and central neural system.…”