Pomenti, Sydney

ABSTRACT Background Obesity affects over 40% of the US population and contributes to worse outcomes in a variety of diseases and disorders. Glucagon‐like peptide‐1 receptor agonists have drawn attention for their impact on obesity. With a dense population of receptors throughout the gastrointestinal tract, it is critical to understand the way that glucagon‐like peptide‐1 receptor agonists impact gastrointestinal diseases and disorders. Aims To evaluate the expanding role of glucagon‐like peptide‐1 receptor agonists in the management of obesity and gastrointestinal disease, with a focus on therapeutic applications, impact on gastrointestinal cancers, safety profile, and implications for gastroenterology practice. Methods We conducted a narrative review of recent clinical trials, cohort studies, and guideline updates through 2025. Evidence was synthesised on efficacy, safety, and clinical implications across gastrointestinal disorders including steatotic liver disease, gastroesophageal reflux, inflammatory bowel disease, short bowel syndrome, and obesity‐associated cancers. Results Glucagon‐like peptide‐1 receptor agonists induce substantial and durable weight loss and improve obesity‐related gastrointestinal outcomes. They are approved for steatotic liver disease, with demonstrated histologic and biochemical benefits. Evidence suggests a reduced incidence of several gastrointestinal cancers. The most common adverse events include nausea, vomiting, diarrhoea, constipation, and delayed gastric emptying, which may affect peri‐endoscopic management. Discontinuation rates remain substantial but can be mitigated by careful titration and specialist oversight. Conclusions Glucagon‐like peptide‐1 receptor agonists are a critical therapy for obesity and several related gastrointestinal conditions. Gastroenterologists are uniquely positioned to optimize their use, manage adverse events, coordinate multidisciplinary care, and ensure safe and effective integration into practice.

Background Eosinophilic oesophagitis (EoE) is a food allergen-induced inflammatory disorder characterised by interleukin (IL)-13-mediated oesophageal inflammation and epithelial basal cell hyperplasia (BCH). The role of mitochondria in EoE pathogenesis remains elusive. Design Prompted by single cell transcriptomics data, we interrogated the role of mitochondria in EoE pathobiology using patient biopsies, EoE-mouse models and oesophageal epithelial cells grown in monolayer and three-dimensional (3D) organoid cultures treated with EoE-relevant cytokines. 3D organoids and EoE-bearing mice were treated with omeprazole—a proton-pump inhibitor used as first-line EoE therapy. We performed CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) interference in mouse organoids to identify the key mitochondrial regulatory genes whose depletion may lead to BCH. We analysed mitochondrial membrane potential, mass and superoxide production by flow cytometry, cellular oxygen consumption by respirometry, mitochondrial structures and perturbation of cellular energy homeostasis by immunoblotting. Results Mitochondrial dysfunction appeared to be a hallmark of EoE-related BCH where mitochondrial structural damage was associated with impaired oxidative respiratory capacity, elevation of mitochondrial superoxide and decreased adenosine triphosphate (ATP) production, as corroborated by activation of the adenosine monophosphate (AMP) -activated protein kinase and suppression of mammalian target-of-rapamycin signalling. Depletion of PGC1A, the master regulator of mitochondria biogenesis, recapitulated EoE-related BCH, suggesting that mitochondrial dysfunction drives BCH. Further, omeprazole alleviated mitochondrial damage and dysfunction in EoE-related BCH modelled in mice and patient-derived organoids. Conclusion Mitochondrial dysfunction is tightly linked to perturbation of redox homeostasis in EoE-related BCH, which is promoted by IL-13 and reversible with omeprazole treatment.