Gut最新文献

Background: Chronic stress is a known risk factor for cancer metastasis. However, the underlying mechanisms, particularly those involving the gut microbiota and their metabolites, remain unclear.

Objective: To investigate whether gut microbiota dysbiosis and metabolic alterations mediate the sustained pro-metastatic effects of chronic stress, even after normalisation of stress hormone levels.

Design: Multiple metastatic models were performed after stress cessation. Shotgun metagenomics and metabolomics were performed to assess changes in microbiota and metabolites. The effects of Bifidobacterium animalis and oleic acid (OA) on metastasis were evaluated in vivo and in vitro. Moreover, we explored how B. animalis degraded OA. Mechanistically, we discovered the interaction between corticosteroids and gut bacteria through guanine metabolism assays. Human samples were collected from patients with colorectal cancer (CRC) with varying perceived stress scores and metastatic status for validation.

Results: Mice that underwent chronic stress exhibited increased metastasis even after hormone levels recovered. The gut microenvironment was altered, with a significant reduction in B. animalis and an increase in OA. B. animalis administration reduced OA levels and suppressed metastasis, while OA supplementation had the opposite effect. B. animalis expresses oleate hydratase, an enzyme that degrades OA. Stress hormones inhibited B. animalis by altering guanine metabolism in the intestinal epithelium. In patients, high stress was associated with more OA, lower B. animalis levels and increased metastasis.

Conclusions: Chronic stress promotes metastasis by altering microbiota and increasing OA. Targeting B. animalis and OA may help prevent stress-related tumour progression.

Background: Gut microbiota dysbiosis is linked to autism spectrum disorder (ASD) in children. However, the role of bacterial genomic structural variations (SVs) in ASD remains largely unexplored.

Objective: We aimed to identify bacterial SVs associated with ASD and explore their mechanistic role and clinical application.

Design: We collected faecal metagenomes from 452 children (261 ASD, 191 neurotypical) across an in-house and seven public datasets. Using linear mixed-effects modelling, we identified ASD-associated SVs and compositional shifts and validated candidate SVs in humanised gut microbiome mice.

Results: We identified 100 bacterial SVs significantly associated with ASD (p<0.05). These SVs were enriched in genes involved in critical biological processes, including ion and amino acid metabolism and bacterial growth regulation in ASD. In particular, we found important SVs in Bacteroides uniformis related to thiamine and iron metabolism. Moreover, SVs in Ruminococcus torques were associated with the MazF (endoribonuclease toxin) and MazE (antitoxin) system, a key regulator of pathobiont proliferation. Validation in humanised mouse models confirmed significant correlations between these SV signatures and ASD-like behaviours, such as reduced social interaction and increased repetitive behaviours. Both phylogeographically conserved and regionally restricted SVs showed strong associations with ASD. A diagnostic model combining nine SVs and three bacterial species achieved an area under the receiver operating characteristic curve of 81.1%, outperforming models based solely on variable SVs (79.1%), deletion SVs (75.2%) or bacterial species abundance alone (72.3%).

Conclusion: Our findings suggest the significant role of bacterial genomic SVs in ASD and highlight their potential as diagnostic biomarkers.

Background: Chronic inflammation and elevated reactive oxygen species are key contributors to hepatocellular carcinoma (HCC) progression.

Objective: This study aims to investigate the role of the oxidative stress sensor protein Pirin (PIR) as a critical mediator of inflammation in HCC progression.

Design: We investigated PIR's role in HCC tumourigenesis through RNA interference, genetic knockout and pharmaceutical inhibition in HCC cell lines and various mouse models. Furthermore, we used transcriptomics, quantitative reverse transcription PCR, western blot, immunofluorescence staining and immunohistochemistry analysis to elucidate the molecular details.

Results: This study reveals a novel redox-dependent mechanism governing PIR's nuclear shuttling, contributing to liver inflammation and HCC progression. We identified a positive feedback axis where nuclear PIR amplifies inflammatory responses, leading to hepatitis and HCC advancement. Cytokines in this loop are regulated by PIR-enhanced v-rel reticuloendotheliosis viral oncogene homolog A (RELA) transcription, promoting PIR's nuclear translocation, increasing proinflammatory cytokine levels, and disrupting redox balance. We confirmed that liver parenchymal cells produce autocrine cytokines supporting their growth and malignancy. Notably, PIR's redox-mediated nuclear shift can be inhibited by N-acetyl cysteine or PIR inhibitors, reducing HCC promotion in mice.

Conclusion: We elucidate a novel redox-dependent regulatory mechanism governing the nuclear localisation of PIR and its role in promoting liver inflammation and HCC progression. Our findings underscore the significance of cellular redox status in regulating PIR's activity and highlight the potential of targeting this pathway with antioxidants to mitigate HCC progression.

IBD is rising worldwide and is now a global disease. With the expanding armamentarium of medical therapies, including biologics and small molecules, there is a decline in hospitalisation rates and IBD-related surgeries. However, high costs, injectable therapy, risk of opportunistic infections and the lifelong nature of the disease pose significant challenges in the management of IBD. Developing countries are also constrained by a lack of trained manpower, as well as economic and infrastructural limitations. Strategies aimed at the prevention of IBD may alleviate the suffering and cost of this disease. Suggested approaches include implementation of prevention and interception trials using dietary, pharmacological and precision medicine approaches. However, these would necessitate massive funding and equitable infrastructural support for identifying the population at risk (for prevention trials) and those with preclinical disease (for interception trials). Hence, these strategies are unlikely to be globally practicable or economically viable, particularly in the Global South. It is believed that IBD, like certain non-communicable diseases (NCDs) such as metabolic syndrome and cardiovascular disorders, may be preventable by modifying the risk factors. Therefore, in this review, we advocate for an alternative approach of combining evidence-based IBD prevention strategies with the time-tested strategies of NCD prevention approaches already being implemented. We suggest a sieving strategy for selecting preventive measures through a series of sieves-interventions that have evidence to support prevention, align with NCD prevention and are economically viable.

Background: The hepatocellular carcinoma (HCC) immune microenvironment is heavily influenced by immunosuppressive neutrophils, yet the mechanisms driving their senescence-associated reprogramming remain elusive.

Objectives: To elucidate the role of Selenoprotein P (Sepp1)-mediated selenium metabolism in driving the accumulation and immunosuppressive function of senescent-like neutrophils in HCC, and its impact on tumour immune evasion.

Design: We performed integrative single-cell RNA sequencing analyses in HCC mouse models, coupled with functional, metabolic and epigenetic assays to characterise neutrophil subpopulations and dissect the regulatory pathways linking Sepp1 and selenium metabolism to neutrophil senescence-associated reprogramming and tumour progression.

Results: We identified a distinct subpopulation of senescent-like tumour-infiltrating neutrophils marked by hepatic depletion of Sepp1, elevated Cdkn1a, S100a8/9 and Vegfa. Loss of tumour-derived Sepp1 impaired selenium uptake via Lrp8-mediated transport, suppressing intracellular selenium metabolism and hydrogen selenide production. This led to S-adenosylmethionine accumulation and increased histone H3 protein of trimethylation of lysine 4 histone modification, driving a prosenescence chromatin landscape. Selenium supplementation reversed these effects, restoring Sepp1 expression, reducing neutrophil senescence-associated reprogramming and reinvigorating anti-tumour immunity. Moreover, selenium synergised with anti-programmed cell death 1 therapy to suppress tumour growth.

Conclusions: Sepp1 is a key regulator of neutrophil senescence-associated reprogramming and immune suppression in HCC through selenium-dependent epigenetic remodelling. Targeting senescent-like neutrophils via selenium supplementation holds therapeutic promise to enhance immunotherapy efficacy in liver cancer.