Gut最新文献

Background: Metabolic dysfunction associated steatotic liver disease (MASLD), the most common chronic liver disease globally, may originate early in life. While maternal obesity is linked to offspring MASLD, the roles of paternal obesity and mediation by childhood adiposity remain unclear.

Objectives: This study evaluates prospective associations between pre-pregnancy biparental adiposity and offspring MASLD in adulthood.

Design: We included 1933 offspring from the UK Avon Longitudinal Study of Parents and Children (ALSPAC) to assess the associations between parental pre-pregnancy body mass index (BMI) and odds of offspring MASLD at age 24 years. MASLD was defined as hepatic steatosis on transient elastography and ≥1 cardiometabolic risk factors. We evaluated causal mediation by childhood adiposity measures.

Results: At age 24 years, 10.4% of offspring had MASLD. Pre-pregnancy maternal and paternal obesity were independently associated with an increased odds of offspring MASLD. Each 1 kg/m² increase in maternal BMI increased the odds of MASLD by 10% (Odds Ratio [OR] 1.10, 95% CI 1.06 to 1.14), while each 1 kg/m² increase in paternal BMI raised the odds by 9% (OR 1.09, 95% CI 1.04 to 1.13). Biparental overweight or obesity was associated with 3.73 times the odds of offspring MASLD (OR 3.73, 95% CI 2.43 to 5.73) compared with parents with a normal BMI, with 67% of this association mediated by cumulative excess childhood BMI, a defined area under the curve for BMI Z score >1 for ages 7-17 years.

Conclusions: Excess parental adiposity pre-pregnancy was associated with a higher odds of offspring MASLD, mediated by cumulative excess childhood BMI, highlighting the potential of life course interventions to reduce the risk of MASLD in future generations.

Background: Liver metastasis is a common and fatal event for patients with pancreatic ductal adenocarcinoma (PDAC). Dysregulated mitochondrial dynamics reshape biological processes, including metabolism reprogramming, which disrupts immune cell function and promotes metastatic progression.

Objective: To identify key drivers that reprogramme PDAC mitochondrial function and its role in remodelling the immunosuppressive tumour microenvironment (TME) during PDAC liver colonisation.

Design: Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) loss-of-function screening, in vivo mouse model screening and in vitro anoikis-resistant cell selection were employed to identify key drivers during PDAC liver colonisation. PDAC organoids, metabolic flux analysis, single-cell RNA sequencing, spatial metabolomics and glutathione S-transferase (GST) pull-down assay were used to explore the regulation of mitochondrial fission process protein 1 (MTFP1) on PDAC liver colonisation and unravel the underlying mechanism.

Results: We revealed MTFP1, a protein that plays an important role in cell viability and mitochondrial dynamics, as a driver of PDAC liver colonisation. Mechanistically, MTFP1 is recognised as a novel ATP synthase modulator through its interaction with numerous ATP synthase subunits, thereby enhancing oxidative phosphorylation (OXPHOS). Increased mitochondrial fission and subsequent redox signalling (ROS production) upregulates solute carrier family A1 member 5 (SLC1A5) expression by activating the PI3K/AKT/c-MYC pathway, competing for glutamine uptake and impaired antitumour responses of CD8⁺ T cells. By performing virtual screening, we identified KPT 9274 (ATG-019) as an effective inhibitor of MTFP1. Limitation of glutamine uptake in PDAC cells or MTFP1 inhibition reverses the immunosuppressive TME and reduces liver colonisation of PDAC.

Conclusion: Our data demonstrate that the enhanced MTFP1 expression leads to an upregulated glutamine-OXPHOS axis in PDAC liver colonisation. This metabolic shift is triggered by the ROS/PI3K/AKT/c-MYC/SLC1A5 pathway. Targeting MTFP1 may be a potential therapeutic strategy for PDAC patients with liver metastasis.

Background: Hypertriglyceridaemia-induced acute pancreatitis (HTG-AP) is frequently complicated by acute lung injury (ALI), which worsens prognosis. Oleic acid (OA), a major circulating free fatty acid, may play a key role, but the underlying mechanism remains unclear.

Objective: To investigate the relationship between plasma OA and HTG-AP-associated ALI and to explore the mechanism by which OA disrupts endothelial barrier through PIEZO1-mediated impairment of fatty acid oxidation (FAO).

Design: This study used clinical sample analysis, an HTG-AP mouse model and OA-stimulated human umbilical vein endothelial cells. The association between OA and ALI was evaluated, and PIEZO1 was identified as a potential OA target through calcium imaging, transcriptomics and the Human Protein Atlas. Genetic/pharmacological interventions, lipidomics, Seahorse assays and barrier function tests were used to characterise FAO impairment and barrier disruption. NR4A1 regulation of CPT1A was investigated through transcriptomic and ChIP assays. Finally, the pathway's function was validated in mice with endothelial-specific Piezo1 knockdown.

Results: Clinical and animal data showed elevated plasma OA in HTG-AP, positively associated with ALI incidence and severity. Multidimensional data identified PIEZO1 as a key target mediating OA-induced endothelial dysfunction. Mechanistically, OA activated and upregulated PIEZO1, which suppressed NR4A1 expression, leading to downregulation of CPT1A and impaired FAO, ultimately disrupting the endothelial barrier. Endothelial-specific Piezo1 knockdown significantly alleviated HTG-AP-associated ALI in mice.

Conclusion: OA promotes endothelial barrier dysfunction and exacerbates HTG-AP-associated ALI via the Piezo1/NR4A1/CPT1A axis by impairing FAO, offering a novel mechanistic insight and identifying potential therapeutic targets for HTG-AP-associated ALI.

Background: CDH1 is commonly mutated in sporadic diffuse gastric cancer (DGC) and germline CDH1 mutations underlie most cases of the cancer syndrome hereditary DGC.

Objective: We aimed to develop mouse models of sporadic and hereditary DGC by inactivation of Cdh1 in the mouse stomach.

Design: We generated tamoxifen-inducible Cre/loxP mouse models of DGC driven by the Cd44 promoter with a tdTomato reporter. Two models were developed, one with Cdh1-knockout alone (Cd44-Cre/tdTom^loxP/loxP/Cdh1^loxP/loxP (Cdh1-KO)) and a second more aggressive model with combined Cdh1 and Trp53 knockout (Cd44-Cre/tdTom^loxP/loxP/Cdh1^loxP/loxP/Trp53^loxP/loxP (Cdh1-KO/Trp53-KO)).

Results: Cdh1 inactivation alone led to multiple foci of in situ (pTis) signet ring cells (SRCs) within 1 week of induction and intramucosal DGC (stage pT1a) within 2 months. By 9 months, 50% of mice had developed advanced (pT3) DGC. The morphology of most gastric carcinomas was comparable to human DGC, exhibiting poorly cohesive SRC and poorly differentiated cells. Additional Trp53 knockout accelerated cancer development, resulting in pT3 DGC within 3 months. From this point, Cdh1-KO/Trp53-KO mice frequently developed thymic lymphomas and soft tissue sarcomas. DNA sequencing did not find evidence of additional genetic events necessary for cancer progression in either model. Organoids derived from Cdh1-KO and Cdh1-KO/Trp53-KO mice showed a disrupted morphology with SRCs displaced out of the epithelial plane. Transcriptional changes associated with processes including cell-to-cell adhesion, interaction with the actin cytoskeleton and NF-κB signalling were observed.

Conclusion: Inactivation of Cdh1 alone in Cd44-expressing cells is sufficient to induce DGC in mice. Tumour growth is significantly accelerated by concurrent Trp53 inactivation.

Barrett's oesophagus (BE) continues to rise in prevalence alongside oesophageal adenocarcinoma; understanding and identifying early neoplastic changes is critical. Crypt dysplasia (CD) in BE is an emerging concept characterised by dysplasia confined to the crypt base without surface involvement. Recent studies suggest that CD shares molecular alterations with low-grade and high-grade dysplasia, such as TP53 mutations and chromosomal instability, and may represent an early phase of neoplasia. Grading of CD remains inconsistent, with limited correlation to clinical outcomes, although classifying CD into low-grade and high-grade categories provides a practical diagnostic framework. High-grade crypt atypia typically warrants a diagnosis of CD, whereas low-grade crypt atypia poses greater diagnostic challenges and requires careful differentiation from reactive changes. This framework also incorporates exclusionary criteria, such as inflammation, ulceration and erosion. This review encompasses key features of CD, the diagnostic pitfalls encountered in clinical practice and the underlying biology driving crypt dysplasia. Future studies focusing on the natural history of CD, its molecular underpinnings and interobserver reproducibility will be pivotal in refining diagnostic criteria and improving patient outcomes in BE.