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Background: Streptococcus anginosus has been linked with an increasing risk of gastric cancer (GC) and recognised as a signature for GC screening.

Objective: To investigate the promotional effect of S. anginosus in terms of its metabolic interactions with the host.

Design: We used the functional profiles of shotgun metagenomic sequencing from stools to detect bioactive molecules relevant to S. anginosus. In vivo and in vitro experiments were used to validate the facilitation of S. anginosus to GC progression. S. anginosus clinical strains were isolated and cultivated from cancerous tissues to verify its promotion of GC via methionine production. S. anginosus ΔmetE mutant strains were constructed to confirm the critical role of metE in methionine biosynthesis.

Results: We verified S. anginosus facilitated GC progression in vivo and in vitro. Our functional analysis of metagenomes revealed a significant enrichment of bacterial methionine biosynthesis pathways in GC patients with high S. anginosus abundance. Methionine, identified here as one of the primary microbial metabolites derived from S. anginosus, contributed to GC progression in humans and mice. S. anginosus strains from cancerous tissues were found to promote GC via methionine production. We further observed a higher abundance and prevalence of metE gene in cancer stool metagenomes. By constructing an S. anginosus ΔmetE mutant strain, we confirmed the critical role of metE in methionine biosynthesis.

Conclusion: Our results elucidate the role of S. anginosus-derived methionine in GC progression, shedding light on intricate metabolic interplay between S. anginosus and host.

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality with limited therapeutic options. Despite promising immunotherapy, response rates remain suboptimal. Tumour-associated macrophages (TAMs) constitute a pivotal component of the immunosuppressive HCC microenvironment, yet TAM heterogeneity and contributions to tumour progression and immunotherapy resistance remain poorly defined.

Objective: To identify and characterise critical TAM subsets in HCC and evaluate their potential as therapeutic targets.

Design: Integrated multiomics analysis of hepatocellular carcinoma (HCC) clinical specimens was performed and validated across independent cohorts. Single-cell RNA sequencing identified tumour-associated macrophage (TAM) subpopulations. Functional characterisation employed whole-body and macrophage-specific CD48 knockout mice, adoptive transfer experiments and co-culture systems. Mechanistic studies used immunoprecipitation-mass spectrometry, immunofluorescence colocalisation and pathway analysis. Therapeutic efficacy was evaluated using anti-CD48 monotherapy and combination with anti-programmed cell death protein 1 (PD1) in orthotopic HCC models.

Results: CD48⁺ TAMs were identified associating with accelerated tumour progression, immunotherapy resistance and poor clinical outcomes. These TAMs exhibited protumorous phenotypes, driving immunosuppression and promoting extracellular matrix remodelling. Genetic CD48 ablation attenuated HCC progression while promoting CD8⁺ T-cell function. Adoptive transfer of CD48-deficient macrophages validated tumour-suppressive effects. Mechanistically, matrix metalloproteinase-14 (MMP14) was identified as a novel cis-interacting partner for CD48, functioning independently of the canonical CD48-CD244 axis. This interaction activated RAP1 GTPase, triggering Yes-associated protein (YAP) nuclear translocation and YAP-signal transducer and activator of transcription 3 (STAT3) complex formation to upregulate immunosuppressive genes. Anti-CD48 antibodies effectively inhibited tumour progression and demonstrated synergistic effects with anti-PD1 therapy.

Conclusion: CD48 represents a novel immune checkpoint on TAMs critical for HCC progression and immunotherapy resistance. Targeting CD48 may overcome immunosuppression and increase therapeutic efficacy in HCC.

Background: Recurrent acute pancreatitis (RAP) or acute-on-chronic flares in chronic pancreatitis (CP) have limited preventive options beyond addressing the underlying aetiology. Statins, due to their anti-inflammatory properties, have been proposed as a potential prophylactic treatment.

Objective: We aimed to evaluate whether simvastatin could reduce the recurrence of pancreatitis.

Design: At 23 centres, we conducted a triple-blind, randomised, controlled, superiority trial enrolling patients with at least two episodes of RAP or CP flares in the previous 12 months. Participants were randomly assigned to receive simvastatin or placebo for 1 year. The primary endpoint was the recurrence of pancreatitis. The target sample size was 144 patients; however, an interim analysis was planned in the event of slow recruitment.

Results: A total of 85 patients (42.1% women) were included in the interim analysis. In the intention-to-treat analysis, no significant differences were observed regarding recurrence: 46.2% simvastatin versus 44.4% placebo; OR 1.07, 95% CI 0.43 to 2.66; p=0.88, or time to recurrence. No statistically significant differences were observed in recurrence in per-protocol analysis (35.5% simvastatin vs 41.9% placebo; OR 0.76, 95% CI 0.27 to 2.12; p=0.60). Development of diabetes mellitus was more frequent in the simvastatin group (4 vs 0 patients; OR not calculable, p=0.04).

Conclusion: This trial, evaluating simvastatin versus placebo for the prevention of pancreatitis, did not demonstrate a reduction in recurrence rate, although results might be underpowered due to early termination. The relationship between statins in these patients and new-onset diabetes requires further investigation.

Trial registration number: NCT04021498.

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.