The Gut Microbiota Activates AhR Through the Tryptophan Metabolite Kyn to Mediate Renal Cell Carcinoma Metastasis

Background: The incidence of renal cell carcinoma (RCC) is increasing year by year. It is difficult to have complete treatment so far. Studies have shown that tryptophan metabolite Kynurenine (Kyn) affects cell proliferation, migration, apoptosis, adhesion, and differentiation. Our aim is to explore whether Kyn activates aromatic hydrocarbon receptor (AhR) to mediate RCC metastasis.Methods: We collected RCC tissues and feces from RCC patients. 16S rRNA technology was performed to analyze the gut microbial composition of RCC patients. LC-MS/MS was used to analyze the gut microbial metabolites. The AhR was inhibited and treated with Kyn. Immunofluorescence was used to measure the degree of AhR activation. The migration and invasion ability of 786-O cells was tested by Transwell assay. Flow cytometry and cell cycle assay were utilized to observe the apoptosis and cycle of 786-O cells. CCK-8 assay was used to detect 786-O cells proliferation. qRT-PCR and Western blot were used to detect AhR and EMT-related genes expression level.Results: AhR expression was up-regulated in RCC tissues. RCC gut microbiota was disordered. The proportion of Kyn was increased in RCC. After being treated with Kyn, the migration, invasion, and proliferation ability of 786-O cells were decreased. Furthermore, the expression of EMT-related protein E-cadherin decreased, and the expression of N-cadherin and Vimentin increased. The proportion of 786-O cells in the S phase increased. The apoptosis rate of 786-O cells was inhibited.Conclusion: The tryptophan metabolite Kyn could activate AhR. Kyn could promote 786-O cells migration and invasion. Gut microbiota could activate AhR through its tryptophan metabolite Kyn to mediate RCC metastasis.

Cancer Associated Fibroblasts Promote Renal Cancer Progression Through a TDO/Kyn/AhR Dependent Signaling Pathway

Cancer associated fibroblasts (CAFs) play crucial roles in cancer development, however, the specific mechanisms of CAFs associated renal cancer progression remain poorly understood. Our study observed enriched CAFs in high degree malignant tumor tissues from renal cancer patients. These CAFs isolated from tumor tissues are prone to facilitate drugs resistance and promote tumor progression in vitro and in vivo. Mechanistically, CAFs up-regulated tryptophan 2, 3-dioxygenase (TDO) expression, resulting in enhanced secretion of kynurenine (Kyn). Kyn produced from CAFs could up-regulated the expression of aromatic hydrocarbon receptor (AhR), eventually resulting in the AKT and STAT3 signaling pathways activation. Inhibition of AKT signal prevented cancer cells proliferation, while inhibition of the STAT3 signal reverted drugs resistance and cancer migration induced by kynurenine. Application of AhR inhibitor DMF could efficiently suppress distant metastasis of renal cancer cells, and improve anticancer effects of sorafenib (Sor)/sunitinib (Sun), which described a promising therapeutic strategy for clinical renal cancer.

Gut microbiota-derived 5-hydroxyindole-3-acetic acid mediates the anti-colitis effect of Phellinus gilvus in mice

Background: The gut microbiota plays crucial roles in various diseases and mediates the therapeutic effect of many drugs. Results: In this study, we found that ingestion of Phellinus gilvus extract (SH), a traditional Chinese medical mushroom, effectively ameliorated dextran sodium sulfate (DSS)-induced colits in mice, and the gut microbes were essential for its therapeutic effect. The enrichment of Alistipes spp. especially A. onderdonkii was highly associated with the amelioration of colitis by SH, and oral gavage of live A. onderdonkii potently and strain-specifically mitigated DSS-induced colitis in mice. 5-Hydroxyindole-3-acetic acid (5HIAA), a structural analogue of a known aromatic hydrocarbon receptor (AhR) activator indole-3-acetic acid (IAA), was significantly enriched after SH treatment and exhibited more potent anti-colitis efficiency than IAA in mice.Conclusion: Our results demonstrated the gut microbiota-derived 5HIAA could be an effective candidate in treatment of colitis, and modulation of the gut microbiota-indole derives-AhR pathway may be a novel strategy in development of next-generational anti-colitis drugs.

Protective Action of Ostreococcus Tauri and Phaeodactylum Tricornutum Extracts towards Benzo[a]Pyrene-Induced Cytotoxicity in Endothelial Cells

Marine microalgae are known to be a source of bioactive molecules of interest to human health, such as n-3 polyunsaturated fatty acids (n-3 PUFAs) and carotenoids. The fact that some of these natural compounds are known to exhibit anti-inflammatory, antioxidant, anti-proliferative, and apoptosis-inducing effects, demonstrates their potential use in preventing cancers and cardiovascular diseases (CVDs). Benzo[a]pyrene (B[a]P), a polycyclic aromatic hydrocarbon (PAH), is an ubiquitous environmental pollutant known to contribute to the development or aggravation of human diseases, such as cancer, CVDs, and immune dysfunction. Most of these deleterious effects are related to the activation of the polycyclic aromatic hydrocarbon receptor (AhR). In this context, two ethanolic microalgal extracts with concentrations of 0.1 to 5 µg/mL are tested, Ostreoccoccus tauri (OT) and Phaeodactylum tricornutum (PT), in order to evaluate and compare their potential effects towards B[a]P-induced toxicity in endothelial HMEC-1 cells. Our results indicate that the OT extract can influence the toxicity of B[a]P. Indeed, apoptosis and the production of extracellular vesicles were decreased, likely through the reduction of the expression of CYP1A1, a B[a]P bioactivation enzyme. Furthermore, the B[a]P-induced expression of the inflammatory cytokines IL-8 and IL1-β was reduced. The PT extract only inhibited the expression of the B[a]P-induced cytokine IL-8 expression. The OT extract therefore seems to be a good candidate for counteracting the B[a]P toxicity.

Evolution of hominin detoxification: Neanderthal and modern human AHR respond similarly to TCDD

ABSTRACTIn studies of hominin adaptations to fire use, the role of the aromatic hydrocarbon receptor (AHR) in the evolution of hominin detoxification, especially regarding toxic smoke components, has been highlighted, including statements that the modern human AHR is significantly better at dealing with smoke toxins. We compared the AHR-controlled induction of cytochrome P450 1A1 (CYP1A1) in cultured cells transfected with an Altai-Neanderthal respectively a modern human reference AHR expression construct, and exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We compared the complete AHR mRNA sequences including the untranslated regions (UTRs), maintaining the original codon usage, in HeLa human cervix epithelial adenocarcinoma cells. Our experiments complement a previous study of the AHR coding region optimized for mammalian codon usage and expressed in rat cells. Our results show no significant difference in CYP1A1 induction by TCDD between Neanderthal and modern human AHR (instead of a previously reported 150-1000 times difference range before), demonstrating that expression in a homologous cellular background is of major importance. The two dose-response curves almost coincide, except for a higher extrapolated maximum induction level for the Neanderthal AHR, possibly caused by a 5’-UTR G-variant known from modern humans (rs7796976). Our results are strongly at odds with a major role of the modern human AHR in the evolution of hominin detoxification of smoke components and consistent with our previous study which concluded that efficient detoxification alleles are more dominant in ancient hominins than in modern humans based on 18 relevant genes in addition to AHR.