Project description:Altered tryptophan catabolism has been identified in inflammatory diseases like rheumatoid arthritis (RA) and spondyloarthritis (SpA), but the causal mechanisms linking tryptophan metabolites to disease are unknown. Using the collagen-induced arthritis (CIA) model we identify alterations in tryptophan metabolism, and specifically indole, that correlate with disease. We demonstrate that both bacteria and dietary tryptophan are required for disease, and indole supplementation is sufficient to induce disease in their absence. When mice with CIA on a low-tryptophan diet were supplemented with indole, we observed significant increases in serum IL-6, TNF, and IL-1β; splenic RORγt+CD4+ T cells and ex vivo collagen-stimulated IL-17 production; and a pattern of anti-collagen antibody isotype switching and glycosylation that corresponded with increased complement fixation. IL-23 neutralization reduced disease severity in indole-induced CIA. Finally, exposure of human colon lymphocytes to indole increased expression of genes involved in IL-17 signaling and plasma cell activation. Altogether, we propose a mechanism by which intestinal dysbiosis during inflammatory arthritis results in altered tryptophan catabolism, leading to indole stimulation of arthritis development. Blockade of indole generation may present a novel therapeutic pathway for RA and SpA.
Project description:Sensing of microbial tryptophan catabolites by the aryl hydrocarbon receptor (AhR) plays a pivotal role in host-microbiome homeostasis by modulating the host immune response. Thereby the involved cellular processes triggered by the metabolites are largely unknown. We analyzed proteomic changes in macrophages trough 24h after treatment with the tryptophan metabolites indole-3-acetic acid (I3AA) or indole-3-aldehyde (IAld), as well as the prototypic AhR-ligand Benzo(a)pyrene (BaP) in the absence and presence of LPS to identify affected processes and pathways.
Project description:Recently, gut metabolites have been recognized to play significant roles in liver diseases via the gut-liver axis. In this study, we investigate the regulatory effects of the tryptophan metabolite, indole-3-propionic acid (IPA), on immune cells during liver fibrogenesis using single-cell RNA sequencing (scRNA-seq).
Project description:Aims: Atorvastatin is a commonly used cholesterol-lowering drug that possesses non-canonical anti-inflammatory properties. However, the precise mechanism underlying its anti-inflammatory effects remains unclear. Materials and methods: The acute phase of ulcerative colitis (UC) was induced using a 5 % dextran sulfate sodium (DSS) solution for 7 consecutive days and administrated with atorvastatin (10 mg/kg) from day 3 to day 7. mRNA-seq, histological pathology, and inflammatory response were determined. Intestinal microbiota alteration, tryptophan, and its metabolites were analyzed through 16S rRNA sequencing and untargeted metabolomics. Key findings: Atorvastatin relieved the DSS-induced UC in mice, as evidenced by colon length, body weight, disease activity index score and pathological staining. Atorvastatin treatment reduced the level of pro_x0002_inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). Atorvastatin also relieved the intestinal microbiota disorder caused by UC and decreased the proliferation of pernicious microbiota such as Akkermansia and Bacteroides. Atorvastatin dramatically altered tryptophan metabolism and increased the fecal contents of tryptophan, indolelactic acid (ILA), and indole-3-acetic acid (IAA). Furthermore, atorvastatin enhanced the expression level of aryl hydrocarbon receptor (AhR) and interleukin-22 (IL-22) and further promoted the expression level of intestinal tight junction proteins, such as ZO-1 and occludin, in colitis mice. Significance: These findings indicated that atorvastatin could alleviate UC by regulating intestinal flora disorders, promoting microbial tryptophan metabolism, and repairing the intestinal barrier.
Project description:Colorectal cancer (CRC) is a common malignant neoplasm influenced by both genetic and environmental factors, and its incidence correlates with the composition of the gut microbiota. Relevant studies have demonstrated that gut microbiota dysbiosis is associated with CRC progression. However, the relationship between CRC tumor proliferation and dysregulation of tryptophan metabolism remains unclear. Our investigation addresses the role and mechanisms of amino acid metabolites in tumor progression based on the dysregulation of tryptophan metabolism in clinical CRC patients. Using metagenomic sequencing and targeted tryptophan metabolomics, our research delineates the aberrant levels of indole-3-lactic acid (ILA) in CRC patients. ILA inhibits glycolysis via the STAT3-HK2 axis and exerts a suppressive effect on CRC independent of the aryl hydrocarbon receptor (AHR). By elucidating the inhibitory role of ILA in CRC and uncovering its underlying mechanisms, our study provides a prospective therapeutic avenue for CRC treatment.
Project description:Inflammatory bowel disease (IBD) is one of the intractable diseases. Nutritional components associated with IBD have been identified, and it is known that excessive methionine intake exacerbates inflammation and that tryptophan metabolism is involved in inflammation. In this study, we examined how temporary methionine, tryptophan, and niacin deficiencies alter gene expression in the intestinal cells of a dextran sulfate sodium (DSS)-fed IBD mouse model. The results showed that feeding amino acid deficient diets increased the expression of serine proteases and fat metabolizing enzymes. Amino acid deficiency also activated one-carbon metabolism and the PPAR pathway. These results suggest that temporary amino acid deficiency may be useful to enhance the antioxidant activity of the host.
2024-03-18 | GSE239475 | GEO
Project description:Sex difference in tryptophan-indole pathway
Project description:Fusarium graminearum is a plant pathogen that can cause the devastating cereal grain disease fusarium head blight (FHB) in temperate regions of the world. Previous studies have shown that F. graminearum can synthetize indole-3-acetic acid (auxin) using L-tryptophan (L-TRP)-dependent pathways. In the present study, Gene expression profiles were obtained using microarray analysis of RNAs from F. graminearum cultures in auxin producing conditions, treated with L-TRP, tryptamine (TAM) and indole-3 acetaldehyde (IAAld). A comparative expression profiling of all treatments identified candidate genes for auxin production in F. graminearum. Additional analysis of the expression profiling between L-TRP-treated and control cultures showed that L-TRP treatment induce the up-regulation of a series of genes with predicted function in the metabolism of L-TRP via anthranilic acid and catechol towards the tricarboxylic acid cycle.