Trending Topics in Gastroenterology | GastroAGI

PPARα Emerges as a Target in Lean MASLD : Acta Pharm Sin B | Jun 2026

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) is traditionally linked to obesity, but an increasing number of patients develop significant hepatic steatosis despite having a normal body mass index. This entity, known as lean MASLD, presents a clinical paradox because affected individuals remain at substantial risk for progressive fibrosis, cardiovascular complications, and liver-related mortality. The mechanisms driving disease progression in this population are distinct and incompletely understood. Problem Statement: Unlike obesity-associated MASLD, lean MASLD cannot be fully explained by excess body weight alone. Factors such as visceral adiposity, dietary exposures, genetic susceptibility, and metabolic dysfunction contribute to disease development. Identifying the molecular pathways underlying lean MASLD is essential for developing targeted therapies tailored to this unique patient population. Summary: This review highlights peroxisome proliferator-activated receptor alpha (PPARα) as a central regulator in the pathogenesis of lean MASLD. PPARα plays a critical role in hepatic fatty acid oxidation, ketogenesis, and anti-inflammatory signaling, helping maintain metabolic homeostasis within the liver. The authors describe how multiple mechanisms—including aging-related signaling pathways, fructose-induced epigenetic changes, gut–liver axis disturbances, lipotoxicity, and genetic predisposition—converge to suppress PPARα activity, even in the absence of obesity. This impairment contributes to hepatic lipid accumulation and progressive metabolic dysfunction. The review further explores the limitations of currently available synthetic PPARα agonists in lean MASLD and highlights growing interest in natural product–derived modulators that simultaneously influence interconnected nuclear receptor pathways, including FXR and LXR. Particular attention is given to the PPARα–FGF21–ketogenesis axis as a key metabolic network with therapeutic potential. The authors propose that future treatment strategies should focus on selective hepatic reactivation of PPARα combined with biomarker-driven and genotype-guided patient selection. Overall, this review positions PPARα as a promising therapeutic target in lean MASLD and underscores the need for precision medicine approaches that recognize the distinct biological mechanisms underlying steatotic liver disease in non-obese individuals.

Who Should Receive Resmetirom?: CGH | April 2026

• Resmetirom is the first FDA-approved therapy for patients with MASH/MASLD and stage F2–F3 fibrosis, creating an urgent need for reliable noninvasive methods to identify treatment candidates. • This study evaluated whether currently proposed noninvasive treatment eligibility criteria accurately identify patients with biopsy-proven F2–F3 disease. • The analysis included 1,281 patients from the HEPAmet registry with liver biopsy, elastography, metabolic profiling, and clinical characterization. • Approximately 38% of patients had biopsy-confirmed F2–F3 fibrosis, representing the target population for treatment. • Current expert panel recommendations and existing practice guidance performed poorly in real-world settings. • Depending on the criteria used, only 39%–56% of eligible F2–F3 patients would have been identified for treatment. • False-negative rates were particularly concerning, meaning that many patients who could potentially benefit from therapy would not receive treatment. • Existing approaches also generated substantial false-positive rates, exposing some lower-risk patients to unnecessary therapy. • The authors proposed a simplified two-step strategy. • Step 1: FIB-4 ≥1.3 OR diabetes plus overweight/obesity even if FIB-4 is <1.3 • Step 2: Liver stiffness measurement between 8 and 25 kPa • This strategy improved identification of patients with clinically significant fibrosis and captured approximately 74% of the target F2–F3 population. • The model also showed better diagnostic performance than currently proposed treatment algorithms. • The findings emphasize that reliance on a single noninvasive marker is insufficient for treatment selection in MASLD. • Combining metabolic risk factors with fibrosis assessment provides a more clinically useful approach. • As additional therapies for MASLD become available, accurate noninvasive treatment selection will become increasingly important. • The study supports moving toward pragmatic clinical algorithms that can be easily implemented in routine hepatology practice. Bottom line: Current noninvasive criteria for selecting patients for resmetirom miss a substantial proportion of biopsy-proven F2–F3 MASLD patients. A simple strategy combining FIB-4, metabolic risk factors (diabetes/overweight), and liver stiffness measurement may more accurately identify patients who are likely to benefit from treatment.

GLP-1RAs Linked to Lower Obesity-Related Cancer Risk : Ann Oncol | June 2026

Introduction: Obesity is a major risk factor for several malignancies, including colorectal, pancreatic, liver, endometrial, and other obesity-associated cancers (OACs). With the growing global burden of obesity, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have rapidly emerged as effective weight-loss therapies, even among individuals without diabetes. Beyond their metabolic benefits, increasing attention has focused on whether these agents may also influence cancer risk. Problem Statement: Previous studies have suggested a potential association between GLP-1RA use and reduced cancer incidence; however, most analyses included patients with diabetes, making it difficult to separate the effects of weight reduction from those of improved glycemic control. The impact of GLP-1RAs on cancer risk specifically in obese individuals without diabetes has remained largely unknown. Summary: In this large real-world study involving obese, nondiabetic adults, GLP-1RA therapy was associated with a substantially lower incidence of obesity-associated cancers compared with standard lifestyle interventions alone. The analysis evaluated a broad spectrum of obesity-related malignancies and demonstrated a consistent reduction in cancer occurrence among patients receiving GLP-1RAs during short-term follow-up. Importantly, the findings persisted across multiple sensitivity analyses and were observed in most patient subgroups, including different sexes, body mass index categories, and treatment agents such as semaglutide and tirzepatide. These results suggest that the benefits of GLP-1RAs may extend beyond weight loss and metabolic improvement, potentially influencing biological pathways involved in carcinogenesis. The study is particularly important because it isolates the association between GLP-1RA exposure and cancer risk in patients without diabetes, reducing a major source of confounding present in previous investigations. While the observational design and relatively short follow-up preclude conclusions regarding causality, the findings provide compelling evidence supporting further prospective evaluation. As GLP-1RAs become increasingly integrated into obesity management, their potential role in reducing obesity-related cancer burden may represent an important additional clinical benefit with significant implications for preventive oncology.

AI Fibrosis Mapping Redefines Risk in MetALD and ALD : Gastroenterology | June 2026

Introduction: Metabolic Dysfunction-Associated Steatotic Liver Disease, Alcohol-Associated Liver Disease, and the recently recognized MetALD phenotype represent a rapidly expanding spectrum of chronic liver disease with overlapping metabolic and alcohol-related injury. Although steatotic liver disease (SLD) classifications have evolved, real-world outcome data comparing biopsy-proven subtypes remain limited, particularly regarding fibrosis biology and long-term prognosis. Problem Statement: Current fibrosis staging systems may not adequately capture biologic differences between MASLD, MetALD, and ALD. Whether these subtypes differ in clinical outcomes and fibrosis architecture despite similar conventional fibrosis stages remains uncertain. Improved phenotypic characterization is essential for precision risk stratification and individualized disease management. Summary: This multicenter prospective cohort study evaluated 2551 individuals with biopsy-proven steatotic liver disease or non-SLD controls between 2010 and 2023 to compare clinical outcomes across SLD subtypes. The investigators assessed risks of all-cause mortality, liver-related events, cardiovascular disease, and extrahepatic malignancies using competing-risk models. Additionally, artificial intelligence–based quantitative fibrosis analysis using second harmonic generation imaging was performed on liver biopsies from MASLD, MetALD, and ALD patients to characterize zone-specific collagen distribution patterns. During a median follow-up of nearly 44 months, both MetALD and ALD demonstrated markedly worse outcomes compared with non-SLD controls. MetALD was associated with a threefold increase in all-cause mortality risk and a sixfold increase in liver-related events, while ALD showed even greater risk amplification with substantially higher mortality and hepatic complication rates. Importantly, among patients with advanced fibrosis, ALD carried significantly worse outcomes than MASLD despite similar histologic fibrosis stages, highlighting important biological differences not captured by traditional staging systems. A major strength of the study was the incorporation of AI-driven fibrosis quantification. The imaging analysis demonstrated that MetALD and ALD had significantly greater collagen deposition within periportal and zone 2 regions compared with MASLD, despite comparable conventional fibrosis grades. These findings suggest that alcohol-associated injury may drive distinct fibrotic remodeling pathways with different prognostic implications. The study is highly relevant because it provides prospective biopsy-based evidence supporting the concept that MetALD behaves more aggressively than isolated MASLD and shares fibrosis characteristics closer to ALD. This has major implications for clinical practice because MetALD patients may currently be under-recognized despite carrying substantially elevated hepatic risk. The findings also reinforce the emerging role of AI-assisted pathology in liver disease. Traditional fibrosis staging offers semiquantitative assessment, whereas AI-based collagen mapping may provide more precise characterization of fibrosis architecture, disease biology, and prognostic heterogeneity. Clinically, the data support more intensive surveillance and risk stratification strategies for patients with MetALD and ALD, particularly those with advanced fibrosis. The study additionally highlights the importance of systematically assessing alcohol intake even in patients meeting metabolic dysfunction criteria, as coexistence of alcohol-related injury substantially alters prognosis. From a translational perspective, the identification of subtype-specific fibrosis patterns may facilitate development of targeted antifibrotic therapies and more individualized treatment algorithms. Overall, this study demonstrates that MetALD and ALD confer significantly higher mortality and liver-related complication risks than MASLD, while AI-based fibrosis mapping reveals distinct collagen distribution signatures that may redefine future precision hepatology approaches.

Breathomics Redefines Functional Liver Assessment : Clin Liver Dis | May 2026

Introduction Chronic Liver Disease continues to rise globally, driven predominantly by Metabolic Dysfunction-Associated Steatotic Liver Disease and alcohol-associated liver disease. Accurate evaluation of fibrosis severity and hepatic functional reserve remains fundamental for prognostication, transplant assessment and therapeutic decision-making. Problem Statement Current diagnostic tools, including liver biopsy and serum-based fibrosis scores, primarily provide static structural information and incompletely capture real-time hepatic metabolic function. There remains an unmet need for dynamic, non-invasive methods capable of simultaneously assessing hepatocyte function, fibrosis burden and metabolic reserve. Summary This narrative review highlights the evolving role of breath-based diagnostics as a physiologically grounded approach for functional liver assessment. Unlike conventional fibrosis tools that estimate structural injury indirectly, breath testing evaluates active hepatic metabolic capacity in real time. The review focuses primarily on isotope-based breath tests using 13C-labelled substrates. Following hepatic metabolism, these substrates generate measurable 13CO2 in exhaled breath, providing dynamic information regarding enzymatic activity, mitochondrial function, hepatic perfusion and viable hepatocyte mass. Importantly, breath-test kinetics also reflect the functional consequences of fibrosis progression rather than merely quantifying scar burden. This creates a clinically relevant distinction between structural fibrosis assessment and true hepatic reserve evaluation. The article further discusses volatile organic compound (VOC) analysis, an emerging “breathomics” strategy capable of identifying endogenous metabolic signatures associated with oxidative stress, inflammation and fibrogenesis. VOC profiling may eventually permit non-invasive molecular phenotyping of liver disease. A major focus of the review is the development of the Liver Isoform Breath Assessment platform. LIBRA integrates multiple 13C-labelled substrates simultaneously to interrogate several hepatic metabolic pathways within a single assessment, thereby generating a composite measure of dynamic liver function. Preliminary evidence suggests potential utility of LIBRA in fibrosis risk stratification, prediction of hepatic decompensation and transplant evaluation. By integrating multiple metabolic domains, LIBRA may provide a more comprehensive representation of hepatic reserve than conventional single-marker approaches. The review also positions breath diagnostics within the broader movement toward precision hepatology. Functional metabolic phenotyping may eventually help distinguish biologically heterogeneous patient subgroups within MASLD and cirrhosis populations. Clinically, breath testing offers several practical advantages. The technique is non-invasive, repeatable, radiation-free and potentially suitable for serial monitoring. Dynamic assessment may be particularly valuable in tracking disease progression, treatment response and peri-transplant physiology. The review additionally emphasizes the conceptual shift from static fibrosis staging toward integrated structure-function assessment. Patients with similar fibrosis stages frequently demonstrate markedly different metabolic reserve and clinical trajectories, highlighting limitations of purely structural evaluation. Importantly, the authors acknowledge several current limitations preventing routine clinical implementation. Standardization of testing protocols, validation across etiologies, establishment of diagnostic thresholds and demonstration of cost-effectiveness remain necessary before widespread adoption. Technical variability, substrate selection, analytical platform harmonization and reproducibility across centers also require further refinement. Large prospective studies will be essential to determine whether breathomics meaningfully improves clinical outcomes beyond existing fibrosis algorithms. Nevertheless, the review underscores the growing translational importance of non-invasive functional hepatology diagnostics. As MASLD prevalence increases globally, scalable tools capable of identifying patients at highest risk of decompensation and progression will become increasingly valuable. Overall, this review positions breath-based diagnostics and multi-substrate platforms such as LIBRA as promising next-generation tools that integrate hepatic structure, metabolism and functional reserve, potentially reshaping future non-invasive assessment strategies in chronic liver disease.

Histidine–ImP Axis Links Gut, Liver and Vascular Injury in MASLD : Biomed Pharmacother | May 2026

Introduction Metabolic Dysfunction-Associated Steatotic Liver Disease is increasingly recognized as a systemic disorder extending beyond hepatic steatosis and fibrosis. Cardiovascular disease remains the leading cause of mortality in MASLD, yet cardiovascular risk varies markedly among patients and is often poorly explained by liver disease severity or traditional metabolic risk factors alone. This discrepancy has intensified interest in microbiota-driven metabolic pathways linking the gut, liver and vascular system. Problem Statement Current models of MASLD inadequately explain why some patients develop disproportionate vascular and cardiometabolic complications despite similar hepatic disease burden. Novel mechanistic frameworks integrating microbial metabolism, host signaling and vascular inflammation are needed to better define biologic heterogeneity within MASLD. Summary This hypothesis-generating review proposes a novel gut–liver–vascular axis centered on microbial histidine metabolism and production of Imidazole Propionate (ImP). The authors suggest that altered microbial conversion of dietary L-histidine through the bacterial urdA pathway may represent a key mechanistic driver of both hepatic metabolic dysfunction and vascular inflammation in MASLD. The proposed model centers on a dual pathogenic mechanism. First, enhanced microbial histidine metabolism reduces bioavailable histidine, potentially impairing protective signaling pathways mediated through TAAR1. Histidine depletion may therefore weaken anti-inflammatory, metabolic and vascular homeostatic responses. Simultaneously, excessive production and systemic accumulation of ImP exerts direct deleterious metabolic effects. Experimental evidence reviewed in the article indicates that ImP interferes with insulin signaling within hepatocytes, thereby promoting hepatic steatosis and metabolic dysfunction. Beyond the liver, ImP also appears to activate proinflammatory and proatherogenic signaling cascades within endothelial tissue, suggesting a direct mechanistic bridge between intestinal microbial metabolism and cardiovascular injury. The review additionally highlights the bacterial urdA enzyme pathway as a potential functional biomarker of pathogenic microbiota activity. The authors introduce the concept of an “ImP-positive/urdA-high” microbial biotype, which could represent a clinically important MASLD endophenotype characterized by persistent cardiometabolic and vascular risk despite otherwise similar hepatic disease severity. This framework is especially important because it shifts focus from static taxonomic microbiome analysis toward functional microbial metabolism. Rather than simply identifying bacterial species abundance, the proposed model emphasizes metabolically active microbial pathways capable of directly modulating host cardiometabolic physiology. The implications for precision medicine are substantial. Therapeutic strategies could theoretically target multiple levels of the histidine–ImP axis, including dietary histidine modulation, suppression of microbial urdA activity, inhibition of ImP production or blockade of downstream ImP-mediated inflammatory signaling. Such approaches may help identify and treat MASLD patients with residual cardiovascular risk not captured by conventional metabolic profiling. Importantly, the review positions MASLD as a multidimensional gut-driven systemic disease rather than an isolated hepatic disorder. The proposed histidine–ImP pathway integrates microbiota metabolism, hepatic insulin resistance and vascular inflammation into a unified mechanistic model potentially explaining interpatient heterogeneity in disease expression and cardiovascular outcomes. Overall, this integrative review introduces the histidine–imidazole propionate axis as a compelling new conceptual framework for understanding gut–liver–vascular crosstalk in MASLD. The model provides a strong rationale for future microbiota-guided precision stratification and targeted metabolic interventions aimed at both hepatic and cardiovascular complications of steatotic liver disease.

Diet Quality Shapes MASLD Fibrosis Progression : Hepatol Commun | May 2026

Introduction Metabolic Dysfunction-Associated Steatotic Liver Disease is increasingly recognized as a major driver of progressive liver fibrosis, cirrhosis and liver-related mortality worldwide. Although obesity, insulin resistance and diabetes are well-established contributors, growing evidence suggests that specific dietary patterns independently influence hepatic inflammation and fibrogenesis. However, large-scale human data evaluating how individual foods and nutrient profiles affect MASLD progression have remained limited. Problem Statement While experimental models demonstrate that diet composition modulates hepatic fibrosis and metabolic injury, the specific dietary factors associated with fibrosis progression in real-world MASLD populations are not well defined. Identifying protective versus harmful nutritional patterns may help refine lifestyle interventions beyond simple caloric restriction. Summary This large Veterans Health Administration Million Veteran Program study evaluated more than 84,000 individuals with MASLD who completed detailed dietary and lifestyle assessments, including semiquantitative food frequency questionnaires. Investigators examined associations between dietary intake patterns, fibrosis progression and incident cirrhosis using longitudinal Fibrosis-4 trajectories and validated multivariable modeling approaches. Several dietary components were consistently associated with reduced fibrosis progression. Protective dietary patterns included frequent consumption of coffee, tea, legumes, nuts, vegetables such as broccoli and spinach, dairy products, white meat, rice/pasta and modest alcohol intake. Nutrients linked with favorable outcomes included caffeine, nitrate/vitamin K, betaine, amino acids and beta carotene. These findings support growing evidence that plant-rich, minimally processed diets with anti-inflammatory and antioxidant properties may mitigate hepatic fibrogenesis. In contrast, refined and processed carbohydrate-rich dietary patterns were strongly associated with accelerated fibrosis progression. Higher intake of white bread, cookies, breakfast cereals and non-heme iron–rich processed foods correlated with worsening fibrosis trajectories. Certain nutrient profiles, including excess refined carbohydrates and high-fructose processed foods, were similarly linked to adverse liver outcomes. The findings reinforce mechanistic data implicating hyperinsulinemia, oxidative stress, lipotoxicity and chronic low-grade inflammation in MASLD progression. Importantly, the study moves beyond generalized dietary recommendations by identifying specific food groups and nutrient signatures associated with either protection or progression. Coffee and caffeine again demonstrated strong hepatoprotective associations, consistent with prior studies showing antifibrotic, antioxidant and metabolic benefits. Similarly, nitrate- and vitamin K–rich vegetables may influence hepatic inflammation and endothelial function through modulation of nitric oxide signaling and oxidative pathways. The study also highlights that dietary quality may influence MASLD natural history independently of traditional metabolic risk factors. Even after adjustment for diabetes, obesity, alcohol use and baseline fibrosis severity, several dietary associations remained significant, suggesting direct biologic effects of nutritional composition on hepatic fibrogenesis. Overall, this large longitudinal cohort provides compelling real-world evidence that diet composition substantially influences fibrosis progression in MASLD. The findings support prioritization of plant-forward, minimally processed dietary patterns rich in vegetables, legumes, nuts and caffeine-containing beverages while limiting refined carbohydrates and ultra-processed foods as part of long-term MASLD management strategies.

Updated EASO Framework for Obesity Pharmacotherapy : Nat Med | May 2026

Introduction Obesity is increasingly recognized as a chronic, relapsing, multisystem disease requiring long-term, complication-oriented management rather than a purely weight-centric approach. The rapid expansion of anti-obesity pharmacotherapy, particularly incretin-based therapies and emerging combination agents, has substantially altered the therapeutic landscape. This 2026 update from the European Association for the Study of Obesity refines the European framework for obesity treatment by integrating new evidence regarding weight reduction, cardiometabolic outcomes and obesity-associated liver disease. Problem Statement Traditional obesity management algorithms relied heavily on body mass index thresholds and often underestimated the heterogeneity of obesity-related complications. The emergence of highly effective pharmacologic therapies has created uncertainty regarding optimal patient selection, treatment sequencing, duration of therapy and integration with metabolic, cardiovascular and hepatic risk stratification. In addition, obesity-related complications such as Metabolic Dysfunction-Associated Steatotic Liver Disease and Type 2 Diabetes increasingly require coordinated multidisciplinary treatment approaches. Summary This updated EASO framework emphasizes a complication-centric model of obesity care that prioritizes improvement in obesity-related disease burden rather than weight loss alone. The document highlights obesity as a biologically regulated chronic disease involving neuroendocrine, metabolic, inflammatory and behavioral pathways, thereby supporting earlier and more individualized pharmacologic intervention. The updated algorithm incorporates recent evidence from incretin-based therapies, particularly GLP-1 receptor agonists and dual incretin agonists, which now achieve weight reductions previously attainable mainly through bariatric surgery. The framework strongly advocates comprehensive baseline assessment including adiposity distribution, cardiometabolic risk, liver disease, sleep disorders, musculoskeletal disease and psychological health. Pharmacologic therapy is recommended not only according to BMI but also according to obesity-related complications and disease severity. Patients with established cardiovascular disease, MASLD/MASH, obstructive sleep apnea or diabetes are prioritized for early pharmacotherapy escalation because these populations derive substantial metabolic and organ-specific benefits beyond weight reduction alone. A major update in the 2026 guidance is the integration of emerging liver disease evidence. The framework recognizes the growing role of obesity pharmacotherapy in improving hepatic steatosis, metabolic dysfunction-associated steatohepatitis and fibrosis risk. GLP-1–based therapies are increasingly positioned as important therapeutic options for patients with obesity-associated liver disease, particularly when accompanied by diabetes or cardiometabolic dysfunction. The document also acknowledges the evolving role of combination therapies and future precision-based obesity medicine targeting specific biological phenotypes. Importantly, EASO emphasizes that pharmacotherapy should be integrated with structured lifestyle intervention rather than viewed as a replacement for behavioral treatment. Nutritional optimization, physical activity, sleep regulation and psychological support remain foundational. The framework also highlights the importance of preserving lean muscle mass during substantial pharmacologically induced weight loss through adequate protein intake and resistance exercise. The update further addresses the chronicity of obesity treatment, recognizing that discontinuation of therapy commonly results in weight regain and recurrence of metabolic complications. Long-term maintenance therapy is therefore increasingly viewed analogously to treatment strategies for hypertension or diabetes. Overall, the 2026 EASO framework reflects a major shift toward personalized, complication-driven obesity care integrating metabolic, cardiovascular and hepatic outcomes into therapeutic decision-making.

Global Consensus for MASLD Risk Stratification and Therapy : Clin Gastroenterol Hepatol | May 2026

Introduction Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) have emerged as dominant causes of chronic liver disease worldwide, paralleling the epidemics of obesity and type 2 diabetes. Fibrosis stage remains the strongest determinant of liver-related and overall mortality, shifting modern management toward fibrosis-centered care. With recent approval of resmetirom and semaglutide for noncirrhotic MASH with F2–F3 fibrosis, there is a growing need for standardized, noninvasive, globally applicable treatment algorithms. Problem Statement Clinical practice remains heterogeneous regarding the use of noninvasive tests (NITs), thresholds for treatment initiation and definitions of therapeutic response. Existing guidance varies across regions, while advanced imaging modalities remain inaccessible in many routine practice settings. Furthermore, the expanding therapeutic landscape requires practical strategies integrating fibrosis risk stratification, cardiometabolic profiling and longitudinal treatment monitoring. Summary This updated international Delphi consensus involved 40 multidisciplinary global experts who reviewed emerging evidence from 2025 onward to establish standardized recommendations for MASLD management. The panel strongly endorsed a sequential fibrosis-based approach using Fibrosis-4 Index (FIB-4) as the preferred first-line screening test, followed by vibration-controlled transient elastography (VCTE) or Enhanced Liver Fibrosis (ELF) testing for secondary risk stratification. For ELF testing, values below 9.2 were considered low risk for advanced fibrosis, whereas ELF ≥9.2 warranted hepatology referral and treatment consideration. Most experts favored higher treatment thresholds between 9.8 and 10.5 to improve specificity. ELF values >11.3 were considered suggestive of cirrhosis, making initiation of resmetirom or semaglutide inappropriate. For VCTE, liver stiffness <8 kPa indicated low risk, while values between 10–15 kPa represented the preferred therapeutic window for initiating pharmacologic therapy in noncirrhotic F2–F3 disease. Liver stiffness ≥20 kPa suggested cirrhosis and contraindicated treatment initiation with currently approved agents. The consensus emphasized individualized pharmacologic selection through shared decision-making. Semaglutide was generally preferred in treatment-naïve patients with coexisting obesity or type 2 diabetes because of its cardiometabolic benefits, whereas resmetirom was favored in patients already receiving GLP-1 receptor agonists. Upfront combination therapy with semaglutide and resmetirom was not recommended because of insufficient evidence, although sequential addition of the alternate agent for suboptimal responders was considered reasonable. Importantly, the document established objective response-monitoring criteria using NITs. A therapeutic response after approximately one year was defined as either a ≥30% reduction in liver stiffness on VCTE or a ≥0.5-point reduction in ELF score. Conversely, worsening fibrosis was defined as a >30% increase in liver stiffness or >0.5 increase in ELF, ideally confirmed using a second concordant NIT before treatment modification. The consensus also reinforced that lifestyle optimization remains foundational even in the era of pharmacologic therapy. Mediterranean-style dietary patterns, minimization of ultra-processed foods, structured aerobic and resistance exercise, and sustained weight reduction remain critical components of management. The authors particularly highlighted the risk of lean muscle loss during GLP-1RA-induced weight reduction and emphasized the importance of adequate protein intake and resistance training to prevent sarcopenic obesity. Overall, this consensus provides one of the first globally harmonized, fibrosis-centered, NIT-driven clinical algorithms integrating recently approved therapies into routine MASLD practice. The recommendations aim to standardize care pathways while maintaining flexibility for individualized cardiometabolic and hepatic risk assessment.

Wine, Food and Gut Health Multiomics : Adv Nutr | May 2026

Introduction Wine has historically been investigated for its cardioprotective effects, particularly in the context of the “French paradox,” but emerging evidence suggests that moderate wine consumption may exert broader physiological effects, especially on gut health and the microbiome. Wine contains a highly complex molecular matrix composed of polyphenols, organic acids, oligosaccharides, lipids, peptides and trace elements that interact dynamically with gut microbes and host metabolism. Advances in multiomics technologies are now enabling deeper characterization of these interactions and the biological “dark matter” of wine. Problem Statement Current understanding of wine-related health effects remains limited by reductionist approaches focused primarily on isolated compounds such as resveratrol or ethanol. The broader interactions between wine composition, co-consumed foods, gut microbiota and host physiology remain poorly defined. In particular, the molecular mechanisms underlying wine-food-gut interactions, interindividual metabolic variability and the role of microbial biotransformation require systematic investigation using integrated omics platforms. Summary This review proposes a comprehensive multiomics framework to investigate how wine components interact with food matrices and gut microbial ecosystems to influence local and systemic health. Moderate red wine consumption has been associated with increased gut microbial diversity and enrichment of potentially beneficial taxa including Bifidobacterium, Prevotella, Faecalibacterium prausnitzii and Roseburia, alongside reductions in lipopolysaccharide-producing bacteria. These microbiome shifts correlate with improvements in inflammatory and cardiometabolic markers, although causality remains unproven. Wine polyphenols undergo extensive microbial transformation in the colon, generating xenometabolites with bioactive potential that may contribute to intestinal barrier protection, antioxidant activity and metabolic regulation. The review highlights how metabolomics, glycomics, lipidomics, proteomics and ionomics are expanding understanding of wine’s molecular complexity. Metabolomic studies have identified hundreds of wine-associated metabolites linked to amino acid, lipid, carbohydrate and antioxidant pathways. Glycomic analyses reveal substantial diversity in wine oligosaccharides, which may possess prebiotic properties capable of modulating microbial communities and short-chain fatty acid production. Lipidomic and peptidomic approaches further suggest that wine-derived lipids and peptides could exert anti-inflammatory, antihypertensive and antimicrobial effects, although their physiological relevance remains insufficiently explored. Importantly, the authors emphasize that wine should not be studied in isolation from dietary context. Interactions between wine and Mediterranean dietary patterns, fats, proteins and carbohydrates substantially alter polyphenol bioavailability, microbial fermentation and metabolite generation. The review also underscores marked interindividual variability driven by genetics, microbiota composition and metabolic phenotypes, suggesting that personalized responses to wine consumption are likely substantial. Overall, the article advocates for integrated systems-level approaches that combine advanced multiomics, gut microbial profiling and human physiological phenotyping to better define how moderate wine consumption influences gut and systemic health.