Helicobacter pylori promotes gastric intestinal metaplasia through activation of IRF3-mediated kynurenine pathway.

BACKGROUND: Metabolic reprogramming is a critical event for cell fate and function, making it an attractive target for clinical therapy. The function of metabolic reprogramming in Helicobacter pylori (H. pylori)-infected gastric intestinal metaplasia remained to be identified. METHODS: Xanthurenic acid (XA) was measured in gastric cancer cells treated with H. pylori or H. pylori virulence factor, respectively, and qPCR and WB were performed to detect CDX2 and key metabolic enzymes expression. A subcellular fractionation approach, luciferase and ChIP combined with immunofluorescence were applied to reveal the mechanism underlying H. pylori mediated kynurenine pathway in intestinal metaplasia in vivo and in vitro. RESULTS: Herein, we, for the first time, demonstrated that H. pylori contributed to gastric intestinal metaplasia characterized by enhanced Caudal-related homeobox transcription factor-2 (CDX2) and mucin2 (MUC2) expression, which was attributed to activation of kynurenine pathway. H. pylori promoted kynurenine aminotransferase II (KAT2)-mediated kynurenine pathway of tryptophan metabolism, leading to XA production, which further induced CDX2 expression in gastric epithelial cells. Mechanically, H. pylori activated cyclic guanylate adenylate synthase (cGAS)-interferon regulatory factor 3 (IRF3) pathway in gastric epithelial cells, leading to enhance IRF3 nuclear translocation and the binding of IRF3 to KAT2 promoter. Inhibition of KAT2 could significantly reverse the effect of H. pylori on CDX2 expression. Also, the rescue phenomenon was observed in gastric epithelial cells treated with H. pylori after IRF3 inhibition in vitro and in vivo. Most importantly, phospho-IRF3 was confirmed to be a clinical positive relationship with CDX2. CONCLUSION: These finding suggested H. pylori contributed to gastric intestinal metaplasia through KAT2-mediated kynurenine pathway of tryptophan metabolism via cGAS-IRF3 signaling, targeting the kynurenine pathway could be a promising strategy to prevent gastric intestinal metaplasia caused by H. pylori infection. Video Abstract.

Polymorphisms of inflammation-related genes and susceptibility to childhood leukemia: evidence from a meta-analysis of 16 published studies.

OBJECTIVE: This study was to comprehensively clarify the associations between single nucleotide polymorphisms (SNPs) in inflammatory genes and the susceptibility to childhood leukemia. METHODS: Eligible articles were collected from the databases of PubMed, EMBASE, Cochrane Library, CNKI and Wan Fang. The pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to estimate the association strength by using the STATA 15.0 software. RESULTS: Sixteen studies were enrolled. These studies mainly evaluated SNPs in 13 genes, including C-X-C motif chemokine ligand 12 (CXCL12), toll-like receptor (TLR)-4, TLR6, TLR9, CD14, interleukin (IL)-1ß, NLR family pyrin domain containing 3, IL-4, interleukin 4 receptor, IL-10, IL-13, macrophage migration inhibitory factor (MIF) and tumor necrosis factor-α. The meta-analysis indicated that CXCL12 rs1801157 (AG vs GG: OR = 1.99; 95%CI = 1.20-3.30; p = 0.008; AA + AG vs GG: OR = 1.92; 95%CI = 1.18-3.12; p = 0.009), TLR6 rs5743810 (TC vs TT: OR = 0.58; 95%CI = 0.39-0.85; p = 0.005), IL-10 rs1800871 (TC vs CC: OR = 1.19; 95%CI = 1.01-1.41; p = 0.044), rs1800872 (AC vs AA: OR = 1.53; 95%CI = 1.22-1.92; p < 0.001) and MIF rs755622 (CG versus GG: OR = 1.33; 95%CI = 1.07-1.67; p = 0.012) polymorphisms were associated with the risk of childhood leukemia. No significant correlations were found between SNPs in other genes and the childhood leukemia risk. Subgroup analyses of rs1800871 and rs1800872 confirmed the conclusions obtained in their overall meta-analytical processes. CONCLUSION: CXCL12 rs1801157, TLR6 rs5743810, IL-10 rs1800871, rs1800872 and MIF rs755622 polymorphisms may represent candidate biomarkers for the risk prediction of childhood leukemia.

Successful treatment of an infant with congenital bile acid synthesis disorder type 3 by ursodeoxycholic acid: a case report.

BACKGROUND: Congenital bile acid synthesis disorder type 3 caused by oxysterol 7α-hydroxylase deficiency is an extremely rare genetic liver disease. As it may cause rapid progression to end-stage liver disease, a high cautiousness in diagnosis and early treatment are required. Here we describe the first case of congenital bile acid synthesis disorder type 3 in China that was confirmed by genetic analysis. CASE PRESENTATION: A 5-month-old Chinese male infant suffered skin yellowing since birth. The patient showed significantly increased alanine transaminase, aspartate transaminase, and total and direct bilirubin levels, and enlarged liver at admission. Whole-exome sequencing confirmed homozygous mutation in the CYB7B1 gene that encodes oxysterol 7α-hydroxylase. Ursodeoxycholic acid treatment significantly mitigated the condition of the patient and lowered biochemical indicators. Unfortunately, the patient developed septicemia and gave up treatment. CONCLUSIONS: The patient was successfully treated with ursodeoxycholic acid, which has not been reported previously. Ursodeoxycholic acid replacement therapy is an effective and affordable treatment for congenital bile acid synthesis disorder type 3 caused by oxysterol 7α-hydroxylase deficiency.