Gut最新文献

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.

Metabolic dysfunction-associated steatohepatitis (MASH) is a multifactorial metabolic liver disease that occurs in the context of obesity, insulin resistance and cardiometabolic comorbidities. Monotherapy targeting single pathways often provides only partial improvements in histological liver fibrosis and systemic metabolic parameters, prompting growing interest in multitargeted combination therapies. Multitargeted and combination strategies for MASH can modulate multiple and complementary pathogenic processes, potentially improving efficacy, promoting liver fibrosis regression, optimising systemic metabolic outcomes and reducing treatment-related adverse effects. Liver-directed combination therapies, such as thyroid hormone receptor-beta (THR-β) agonists along with acetyl-CoA carboxylase (ACC) inhibitors or peroxisome proliferator-activated receptor agonists, aim to improve histological features of MASH. Regimens combining systemic metabolic and liver-specific agents, such as glucagon-like peptide-1 (GLP-1) receptor agonists with fibroblast growth factor-21 analogues or THR-β agonists, aim to optimise metabolic outcomes, including body weight, insulin resistance and plasma lipids. Thoughtfully designed drug pairings, such as diacylglycerol O-acyltransferase 2 inhibitors combined with ACC inhibitors or GLP-1 and glucagon receptor dual agonists, could improve safety and tolerability by leveraging complementary mechanisms that may mitigate adverse effects. These therapeutic strategies aim to achieve more comprehensive and durable improvements in both liver pathology and systemic health than single-agent therapy alone. This review integrates current knowledge on multitargeted and combination therapies for MASH, examines mechanistic rationales and emerging clinical evidence and addresses practical considerations for patient-centred implementation. Therefore, we aim to provide clinicians and researchers with a comprehensive framework to optimise individualised management and improve both hepatic and systemic outcomes in individuals living with MASH.

Background: Gut microbiota has been widely recognised as playing a critical role in maintaining immune imbalance and the development of rheumatoid arthritis (RA). As key roles mediating interkingdom crosstalk among plants, microbiomes and mammals, plant-derived exosome-like nanoparticles (ELNs) could use lipids and microRNA components to precisely modulate gene expression of gut microbiota, showing potential as a dietary intervention for RA treatment.

Objective: We aimed to investigate gut microbiota-immune interactions inducing immune dysregulation in RA and explore potential applications of edible plant-derived ELNs for RA treatment through gut microbiota manipulation.

Design: Combinations of microbial analysis of clinical cohort, metabolomics, in vivo and in vitro examination were performed to establish potential gut-immune mechanisms for interventions. Several representative edible plants ELNs were chosen to compare the modulation effects based on the above mechanism. Small RNA sequencing and lipidomic analysis were performed to identify key components and reveal the related mechanisms mediating therapeutic effects.

Results: Ruminococcus gnavus was significantly enriched in RA and aggravated arthritis through secreting phenylethylamine (PEA) to induce excessive neutrophil extracellular traps (NETs) formation. Among several plants ELNs, Pueraria lobata-derived ELNs (Pu-ELNs) were preferentially taken up by R. gnavus and decreased PEA production. Mechanistically, the lipid components of Pu-ELNs induced intestinal accumulation of ELN-derived gma-miR4412, which reduces phenylalanine decarboxylase (PDC) expression, relieving the arthritis aggravation caused by R. gnavus through acting on the PEA-Bruton's tyrosine kinase (BTK)-NETs axis.

Conclusions: Our findings suggest the crucial role of R. gnavus in aggravating RA and underscore the application of plant-derived ELNs for microbiota manipulation.

Background: High ultra-processed food (UPF) intake has been linked to colorectal cancer (CRC), but underlying mechanisms remain unclear.

Objective: To evaluate a metabolomic pattern of UPF intake and its association with CRC risk.

Design: Integrating food frequency questionnaire data and high-throughput metabolomic profiling in 1740 participants (mean age at blood draw: 59.9 years; >95% non-Hispanic white participants) from nested case-control studies within the Nurses' Health Study and Health Professionals Follow-up Study, we derived and validated a UPF-related metabolomic pattern as a weighted sum of metabolites selected via elastic net regression with 10-fold cross-validation. We evaluated prospective associations of this pattern and individual metabolites with CRC risk using multivariable conditional logistic regression in 686 pairs of incident CRC cases and matched controls.

Results: Among 222 metabolites, we constructed a UPF metabolomic pattern comprising 50 metabolites, primarily lipids and amino acids, with 22 positively and 28 inversely associated with total UPF intake (pattern vs intake: Spearman rho=0.35). The pattern was associated with higher CRC risk (highest vs lowest quintile: OR (95% CI) 1.71 (1.15 to 2.53), p value trend=0.002). Correlations of individual metabolites with UPF intake were moderately aligned with their associations with CRC risk (rho=0.50). N2, N2-dimethylguanosine, a marker of meat/poultry intake, was positively associated with CRC risk (1.96 (1.27 to 3.03)), while 21-deoxycortisol, related to cortisol biosynthesis, was inversely associated (0.59 (0.41 to 0.86)).

Conclusion: We developed a UPF metabolomic pattern. The pattern and several metabolites were associated with CRC risk, providing biological insights into potential pathways underlying the UPF-CRC relationship.