Objective: Gut microbiota have been linked to inflammatory bowel disease (IBD) and colorectal cancer (CRC). Akkermansia muciniphila ( A. muciniphila ) is a gram-negative anaerobic bacterium that is selectively decreased in the faecal microbiota of patients with IBD, but its causative role and molecular mechanism in blunting colitis-associated colorectal cancer (CAC) remain inconclusive. This study investigates how A. muciniphila engages the immune response in CAC. Design: Mice were given dextran sulfate sodium to induce colitis, followed by azoxymethane to establish CAC with or without pasteurised A. muciniphila or a specific outer membrane protein (Amuc_1100) treatment. Faeces from mice and patients with IBD or CRC were collected for 16S rRNA sequencing. The effects of A. muciniphila or Amuc_1100 on the immune response in acute colitis and CAC were investigated. Results: A. muciniphila was significantly reduced in patients with IBD and mice with colitis or CAC. A. muciniphila or Amuc_1100 could improve colitis, with a reduction in infiltrating macrophages and CD8 ⁺ cytotoxic T lymphocytes (CTLs) in the colon. Their treatment also decreased CD16/32 ⁺ macrophages in the spleen and mesenteric lymph nodes (MLN) of colitis mice. Amuc_1100 elevated PD-1 ⁺ CTLs in the spleen. Moreover, A. muciniphila and Amuc_1100 blunted tumourigenesis by expanding CTLs in the colon and MLN. Remarkably, they activated CTLs in the MLN, as indicated by TNF-α induction and PD-1downregulation. Amuc_1100 could stimulate and activate CTLs from splenocytes in CT26 cell conditioned medium. Conclusions: These data indicate that pasteurised A. muciniphila or Amuc_1100 can blunt colitis and CAC through the modulation of CTLs.

A. muciniphila and its outer membrane protein Amuc_1100 restored the aberrant tryptophan metabolism in colitis.

Chlorogenic acid (ChA)—one of the most abundant polyphenol compounds in the human diet—exerts anti-inflammatory activities. The aim of this study was to investigate the effect of ChA on gut microbiota in ulcerative colitis (UC). Colitis was induced by 2.5% dextran sulfate sodium (DSS) in C57BL/6 mice, which were on a control diet or diet with ChA (1 mM). The histopathological changes and inflammation were evaluated. Fecal samples were analyzed by 16S rRNA gene sequencing. ChA attenuated several effects of DSS-induced colitis, including weight loss, increased disease activity index, and improved mucosal damage. Moreover, ChA could significantly suppress the secretion of IFNγ, TNFα, and IL-6 and the colonic infiltration of F4/80⁺ macrophages, CD3⁺ T cells, and CD177⁺ neutrophils via inhibition of the active NF-κB signaling pathway. In addition, ChA decreased the proportion of Firmicutes and Bacteroidetes. ChA also enhanced a reduction in fecal microbiota diversity in DSS treated mice. Interestingly, ChA treatment markedly increased the proportion of the mucin-degrading bacterium Akkermansia in colitis mice. ChA acted as the intestine-modifying gut microbial community structure, resulting in a lower intestinal and systemic inflammation and also improving the course of the DSS-induced colitis, which is associated with a proportional increase in Akkermansia.

Adult stem cells reside in hypoxic niches, and embryonic stem cells (ESCs) are derived from a low oxygen environment. However, it is not clear whether hypoxia is critical for stem cell fate since for example human ESCs (hESCs) are able to self-renew in atmospheric oxygen concentrations as well. We now show that hypoxia can govern cell fate decisions since hypoxia alone can revert hESC- or iPSC-derived differentiated cells back to a stem cell-like state, as evidenced by re-activation of an Oct4-promoter reporter. Hypoxia-induced “de-differentiated” cells also mimic hESCs in their morphology, long-term self-renewal capacity, genome-wide mRNA and miRNA profiles, Oct4 promoter methylation state, cell surface markers TRA1–60 and SSEA4 expression, and capacity to form teratomas. These data demonstrate that hypoxia can influence cell fate decisions and could elucidate hypoxic niche function. Stem Cells 2013;31:1737-1748

Objective: To investigate the acute effect of air pollutants on ischaemic stroke (IS) and IS-related death. Setting: Five urban districts in Changzhou, China, between 9 January 2015 and 31 December 2016. Participants: A total of 32 840 IS cases and 4028 IS deaths were enrolled. Main outcome measures: A time-series design, generalised additive model and multivariable regression model were used to examine the percentage change (95% CI) in daily IS counts and deaths with an IQR increase in air pollutant levels for different single or multiple lag days in single-pollutant and two-pollutant models. Results: Daily IS counts increased 0.208% (95% CI 0.036% to 0.381%) with an IQR increment in the levels of nitrogen dioxide (NO ₂ ). The estimated risk of NO ₂ was more robust in males and in the cold season. For daily IS counts, the estimated effects of NO ₂ and sulfur dioxide (SO ₂ ) were more significant when adjusted for particulate matter with aerodynamic diameters <2.5 µm (PM _2.5 ) and PM ₁₀ . An IQR increment in the concentration of PM ₁₀ , SO ₂ and NO ₂ significantly increased IS deaths with 6 days of cumulative effects (0.268%, 95% CI 0.007% to 1.528%; 0.34%, 0.088% to 0.592%; and 0.263%, 0.004% to 0.522%, respectively). Young individuals (<65 years old) had a higher IS mortality risk for PM _2.5 , PM ₁₀ , NO ₂ and CO. For IS death, the effect estimates of SO ₂ in the elderly, females and the cold season were more pronounced; statistical significance was also identified for SO ₂ when adjusted for carbon monoxide (CO). Conclusions: This study suggested that short-term exposure to ambient NO ₂ was associated with increased IS risk. In addition, SO ₂ was associated with increased IS onset and death.

Recently, both trivalent chromium Cr (III) and hexavalent chromium Cr (VI) have been reported to produce neurotoxicity. However, the underlying mechanisms of the neurotoxicity caused by different chemical valence of chromium remain unclear. The purpose of this study was to investigate the mechanism of neurotoxicity induced by exposure to chromium with different valence states based on metabolic disturbance in zebrafish larvae. Zebrafish embryos were exposed to 1 mg/L Cr (III) and 1 mg/L Cr (VI) for 120 hpf respectively. The related indexes of neural development were observed by stereoscope and behavior analysis system. 8OH-dG were detected using enzyme-linked immunosorbent assay. The generation of reactive oxygen species was detected using an oxidant-sensing probe 2',7'-dichlorodihydrofluorescein diacetate. AChE activity was determined by a colorimetric assay based on hydrolysis of acetylcholine. The expression levels of neurodevelopmental genes and methyltransferase genes in juvenile zebrafish was analyzed by real-time PCR. The methylation status of neurogenin1 and neurod1 genes was detected by bisulfite sequencing PCR. The binding of H3K27me3 was detected by chromatin immunoprecipitation-qPCR. Metabolic profiles and one carbon metabolic analysis were performed by UPLC-MS. There were no significant differences in survival rate, hatching rate and spontaneous movement of zebrafish in both Cr-exposed groups compared to the control. The malformation rate in Cr (VI) -exposed group was obviously increased compared to the control and Cr (III) -exposed group. At 48hpf and 72hpf of exposure, the embryonic heart rate in Cr (III)-exposed group was significantly higher than that of Cr (VI)-exposed group and the control. At 120hpf, zebrafish in both Cr-exposed groups exhibited decreasing changes in swimming distance and disturbance of sensitivity to light and dark. 8OH-dG in Cr (VI)-exposed group were significantly higher than that in the control. The generation of ROS in both Cr -exposed groups was significantly higher than that in the control. The activity of AchE was significantly decreased in both Cr-exposed groups compared to the control. Most of early neurogenesis related genes, such as α-tubulin, elavl3, gap43, sox19b, neurogenin1 and neurod1 in Cr-exposed groups were significantly up-regulated compared to those in the control. The expression of dnmt1 and dnmt3 genes was significantly down-regulated in both Cr-exposed groups. BSP-PCR results showed that genic sequences in the neurogenin1 and neurod1 genes have lower levels of DNA methylation in both Cr-exposed groups, especial in Cr (VI)-exposed group. ChIP analysis showed that there was a decrease in H3K27me3 binding within the corresponding region of neurogenin1 in both Cr-exposed groups and that of neurod1 in Cr (III)-exposed group. Untargeted metabolomic analysis showed that significant changes in metabolites induced by Cr exposure were associated with differences in primary bile acid biosynthesis, phospholipid biosynthesis (phosphatidylcholine biosynthesis and phosphatidylethanolamine biosynthesis), linoleic acid metabolism, arachidonic acid metabolism, amino acid metabolism, purine metabolism, betaine metabolism, spermidine and spermine biosynthesis, and folate metabolism, the last four of which are related to one carbon metabolism. Targeted analysis of one carbon metabolites (5-MT, Gly, Met, SAH and Hcy) related with folate cycle and methionine metabolism were significantly decreased upon Cr exposure. The elevated SAM to SAH ratio in both Cr- exposed group indicated the decreasing capacity for methylation reaction. Cr (III) and Cr (VI) can induce neurotoxicity by interfering with one carbon metabolism and affecting DNA methylation and histone methylation to regulate the expression of neuro-related genes. Cr exposure also influenced primary bile acid biosynthesis and phospholipid biosynthesis, which are associated with neuroprotective effects and need to be further validated.