Aim: This study aimed to evaluate and compare the therapeutic effects of resmetirom, semaglutide, and obeticholic acid (OCA) on non-alcoholic fatty liver disease (NAFLD) activity score (NAS) and fibrosis progression across three distinct metabolic dysfunction-associated steatohepatitis (MASH) models. A secondary objective was to assess model-specific variations in drug efficacy to inform future preclinical model selection for MASH research. Methods: The Gubra-Amylin NASH (GAN) diet-induced obesity (DIO)-MASH model was induced by the GAN diet in C57BL/6 mice for 24 weeks, followed by semaglutide and resmetirom treatment for 4 weeks. The ob/ob-MASH model was induced by the GAN diet in ob/ob mice for 6 weeks, followed by semaglutide and resmetirom treatment for 4 weeks. GAN-carbon tetrachloride (CCL4) MASH model was induced by 10 weeks of GAN diet and followed by 4 weeks of CCL4 in C57BL/6 mice, resmetirom and OCA were given in the last 4 weeks. Body weights, serum biochemical markers [alanine aminotransferase (ALT), aspartate aminotransferase (AST), lipids], histopathological NAS scores, fibrosis staging, and α-smooth muscle actin (α-SMA) expression were analyzed. Results: In the GAN DIO-MASH model, both semaglutide and resmetirom reduced NAS significantly, and resmetirom but not semaglutide reduced α-SMA expression. In the ob/ob MASH model, treatment with semaglutide and resmetirom reduced NAS. Semaglutide significantly reduced α-SMA expression. In the GAN-CCL4 MASH model, both resmetirom and OCA significantly reduced MASH progression, resmetirom reduced liver fibrosis and α-SMA expression while OCA reduced α-SMA expression only. Conclusions: Resmetirom, semaglutide, and OCA exhibited model-dependent efficacy in attenuating MASH progression. Although all agents improved the NAS, their antifibrotic effects diverged significantly: resmetirom demonstrated pan-model efficacy, semaglutide selectively reduced α-SMA expression in leptin-deficient models, and OCA showed minimal impact on fibrosis biomarkers. These observations highlight the critical importance of preclinical model selection for MASH therapeutic development, particularly when assessing fibrosis-targeted interventions.

The glucocorticoid receptor (GR) signaling pathway is essential for supporting the integrity of the intestinal barrier, regulating the gut microbiome, and preserving systemic homeostasis in critically ill patients. GR signaling limits bacterial translocation and systemic inflammation by suppressing pro-inflammatory cytokines, reinforcing tight junction proteins, and promoting epithelial renewal. Additionally, physiological levels of glucocorticoids (GCs) stimulate glutamine and proline metabolism, supporting intestinal maturation, with potential clinical relevance. GR signaling modulates inter-organ communication via the gut-lung and gut-brain axes, improving outcomes. Probiotics enhance GC therapy by restoring microbial balance, increasing short-chain fatty acid (SCFA) production, and modulating immune responses. Vitamins A, C, D, and E contribute to gut resilience by stabilizing tight junctions, mitigating oxidative stress, and strengthening mucosal immunity. Specifically, vitamin D balances T-cell subsets and promotes antimicrobial peptides; vitamin C supports collagen synthesis, antioxidant defenses, and immune function; vitamin A promotes immune tolerance and epithelial regeneration; and vitamin E mitigates oxidative damage and excessive cytokine release. GCs, probiotics, and vitamins counteract key drivers of critical illness, including hyperinflammation and dysbiosis, while maintaining strong safety profiles. This integrative approach leverages these interventions’ distinct yet complementary roles to provide a multi-layered defense against gut dysfunction. GCs reduce excessive inflammation and restore immune balance; probiotics enhance microbial diversity and strengthen gut-associated immunity; and vitamins support epithelial integrity and antioxidant defenses. Targeting multiple pathways simultaneously protects the gut barrier and modulates systemic immunity, potentially reducing complications such as sepsis, multiple organ dysfunction syndrome (MODS), and prolonged intensive care unit (ICU) stays. Incorporating these elements into critical care practice offers a novel strategy to mitigate gut dysfunction, reduce systemic inflammation, and enhance immune resilience. This approach may lower infection rates, decrease the incidence of sepsis and MODS, and accelerate recovery by targeting GR signaling, restoring microbial homeostasis, and reinforcing epithelial integrity.

Aim: Current diabetes guidelines recommend people with gestational diabetes mellitus (PwGDM) use primarily blood glucose meters (BGM) for diabetes management. We evaluated glycemic trends and guideline-recommended glycemic targets achieved in PwGDM using a diabetes app with a family of Bluetooth® connected BGMs. Methods: Anonymized glucose and app analytics data from 26,382 PwGDM were sourced from a server. Data from their first 7-days using the app with connected BGMs was compared to 7-days prior to a 10-week timepoint. Results: Percent fasting readings in range (RIR, < 5.3 mmol/L) improved by +20.3 percentage points in the overall population. Improved glucose RIR (3.5 to 7.8 mmol/L) (+8.3 percentage points), mean blood glucose (BG, –0.59 mmol/L), and fasting RIR (+33.2 percentage points) were observed in those with baseline mean BG ≥ 6.1 mmol/L. Improvements in mean BG of –0.32 to –2.36 mmol/L, and RIR of +3.0 to +38.3 percentage points correlated with higher baseline mean BG ≥ 6.1 to ≥ 7.8 mmol/L. Only 58.5% of PwGDM with baseline mean BG ≥ 6.1 mmol/L had > 80% RIR at baseline, which improved to 79.5% at 10 weeks. PwGDM averaged 17 app sessions and 90 minutes per week on the app. Conclusions: PwGDM engaged with the diabetes app and connected BGM, facilitating attainment of glycemic targets, an especially important outcome for those with higher mean glucose at baseline.