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Ask the author session

The Swiss NASH Foundation is pleased to highlight a transformative conversation in the field of metabolic dysfunction-associated steatotic liver disease (MASLD). In a recent edition of the “Ask the Author” series, host Prof. Jean-François Dufour sits down with Prof. Jérôme Boursier, Head of Hepatology at the University Hospital of Angers, to explore his research publication in Clinical Gastroenterology and Hepatology.

The interview dissects a major clinical challenge: moving beyond static, single-snapshot liver evaluations toward dynamic, personalized risk modeling. By capturing how non-invasive test results evolve over time, Prof. Boursier and an international collaboration of researchers have developed a model capable of calculating a patient’s individual probability of developing severe liver complications.

👉 You can watch the full interview below between Prof. Jérôme Boursier and Prof. Jean-François Dufour — don’t miss it.

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1. The Clinical Need: Beyond Static Diagnostic Snapshots

For clinicians managing patients with MASLD, traditional care has relied heavily on cross-sectional evaluations—staging liver fibrosis or inflammation at a single point in time. However, as Prof. Dufour notes during the discussion, static lesion staging offers an imperfect picture of disease progression and fails to capture how a patient’s trajectory changes over years of follow-up.

Prof. Boursier explains that while non-invasive tests (NIVs) like FibroScan (vibration-controlled transient elastography) and blood-based biomarkers like the Fibrosis-4 (FIB-4) index were originally created for diagnostic staging, longitudinal research confirms they also serve as powerful prognostic markers. Single measurements alone, however, cannot easily convey a patient’s long-term trend to the treating physician. Integrating baseline parameters with subsequent longitudinal measurements allows clinicians to track disease dynamics and deliver true risk stratification.

2. Scientific Breakthrough: The VCTE-Prognosis Cohort and JLCM

To address this gap, Prof. Boursier and his co-authors evaluated data from the international VCTE-Prognosis cohort, encompassing 13,627 adult patients with MASLD. Across a median follow-up period of 4.0 years, researchers tracked repeated non-invasive test measurements alongside hard clinical outcomes, specifically liver-related events (LREs) defined as cirrhosis decompensation or hepatocellular carcinoma.

Using an advanced statistical technique known as Joint Latent Class Modeling (JLCM), the team combined longitudinal test dynamics with baseline survival factors. The model incorporates five core clinical variables:

• Age and Sex: Baseline demographic factors that adjust baseline risk trajectories.
• Liver Stiffness Trajectory: Sequential FibroScan (VCTE) measurements tracked over time.
• FIB-4 Index Dynamics: Longitudinal changes in serum biomarker scoring.
• Platelet Counts: Key hematologic indicators of portal hypertension and disease severity.

How the Model Predicts Patient Outcomes:

• Inputs: Patient age, sex, longitudinal FibroScan (liver stiffness) dynamics, FIB-4 index trajectory, and platelet counts.
• Statistical Engine: Joint Latent Class Modeling (JLCM) integrating baseline survival and biomarker trajectories.
• Personalized Output: Concrete event probabilities (ranging from 0% to 100%) for developing liver-related events at 5-year and 10-year time horizons.

Key Study Finding: The joint latent class model demonstrated superior predictive accuracy compared to traditional static measurements. In validation analyses, the model achieved an integrated area under the receiver operating characteristic curve (AUROC) that increased from 88.2% at baseline to 92.2% at the 5-year follow-up visit. Furthermore, the JLCM successfully identified 61% to 80% of patients who subsequently experienced liver-related events as high risk, significantly outperforming single-point liver stiffness measurements (39%–56%) and FIB-4 scores alone (32%–60%).

3. Practical Implications: A Cardiology-Style Paradigm Shift

A central theme of the interview is how this dynamic risk model reshapes daily patient care and physician-patient communication. Prof. Boursier draws a direct comparison to cardiovascular medicine, where clinicians do not focus solely on anatomical vessel stenosis but instead use risk equations to guide preventive therapy.

Transforming Patient Communication and Resource Allocation

Rather than explaining complex histological jargon such as MASH grades or stage-specific fibrosis lesions, physicians can discuss concrete, understandable clinical outcomes. Telling a patient their 5-year risk of liver cancer or decompensation is under 2% provides clear, actionable context.

The table below summarizes how dynamic risk modeling shifts clinical practice compared to traditional diagnostic approaches:

Clinical Dimension	Traditional Diagnostic Approach	Dynamic JLCM Risk Model Approach
Primary Focus	Staging histological lesions (e.g., fibrosis stage at one visit)	Predicting hard clinical outcomes (liver cancer, decompensation)
Data Utilization	Single snapshot test value at presentation	Multi-visit longitudinal trajectory combining history and baseline data
Core Variables	Standalone FibroScan score or FIB-4 index	Combined age, sex, FibroScan trajectory, FIB-4 trajectory, and platelets
Patient Dialogue	Explaining complex tissue histology concepts	Sharing concrete event probabilities (0%–100%) over 5 and 10 years
Care Delivery	Uniform surveillance schedules for broad patient groups	Targeted surveillance for high-risk; reassurance for low-risk patients

As Prof. Dufour emphasizes, this individualized approach offers immense reassurance to the large population of MASLD patients whose test trends remain stable and low-risk over time. Concurrently, it empowers healthcare teams to concentrate intensive monitoring and novel pharmacological treatments on the subset of high-risk individuals who need them most.

Watch the Full “Ask the Author” Video Interview

The Swiss NASH Foundation invites all hepatologists, gastroenterologists, primary care providers, and patient advocates to watch this insightful 6-minute interview. By moving from static diagnostic snapshots to dynamic prognostic modeling, clinical hepatology takes a major step toward personalized, precision care.

The Swiss NASH Foundation remains committed to bringing you the latest scientific breakthroughs, expert commentary, and educational resources in steatotic liver disease. Stay connected with our platform for future clinical updates and video features.

Thank you to our sponsors

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Ask the author session

The global landscape of metabolic dysfunction-associated steatotic liver disease (MASLD) and its more progressive form, metabolic dysfunction-associated steatohepatitis (MASH), is evolving at an unprecedented pace. For years, therapeutic options for individuals living with liver fat accumulation, inflammation, and fibrosis were limited primarily to lifestyle interventions. Today, targeted medical therapies are demonstrating remarkable clinical efficacy.

Among the most promising novel therapeutics is survodutide, a first-in-class dual glucagon receptor and glucagon-like peptide-1 (GLP-1) receptor agonist. Recently published in Nature Medicine, the results of the pivotal Phase 3 SYNCHRONIZE-MASLD trial highlight the extraordinary potential of this molecule to clear hepatic fat and promote weight loss.

To unpack these clinical findings, the Swiss NASH Foundation is pleased to highlight an insightful “Ask the Author” video interview featuring lead study investigator Prof. Lee Kaplan, Director of the Obesity and Metabolism Institute in Boston. Below, we explore the science behind survodutide, the key trial outcomes, and why this study represents a major step forward for the global liver health community.

👉 You can watch the full interview below between Prof. Lee Kaplan and Prof. Jean-François Dufour — don’t miss it.

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1. Unlocking Dual Agonism: GLP-1 and Glucagon Working in Harmony

Survodutide represents a novel class of metabolic therapeutics designed to engage two distinct biological pathways simultaneously: the GLP-1 receptor and the glucagon receptor. While GLP-1 receptor agonists have transformed obesity and type 2 diabetes management by enhancing satiety and glycemic control, adding glucagon receptor activation introduces a direct, powerful driver of liver lipid metabolism.

As Prof. Lee Kaplan explains in his interview, survodutide is engineered with a specific 8:1 balance—exhibiting eightfold greater potency at the GLP-1 receptor than at the glucagon receptor. This calibrated ratio is crucial: it delivers the metabolic benefits of glucagon on liver metabolism while preventing the disruption of blood glucose homeostasis that high-dose glucagon activation might otherwise trigger.

The synergistic mechanism operates across key physiological pathways:

• GLP-1 Receptor Agonism: Suppresses central appetite, improves insulin secretion, delays gastric emptying, and reduces body weight.
• Glucagon Receptor Agonism: Stimulates hepatic energy expenditure, increases mitochondrial fatty acid oxidation, and directly accelerates the clearance of accumulated lipids from hepatocytes.

2. Rigorous Trial Design: Target Population and “At-Risk MASLD”

The SYNCHRONIZE-MASLD trial was a randomized, double-blind, placebo-controlled Phase 3 study conducted over 48 weeks across clinical sites in the United States and Spain. The study evaluated 216 adult participants (131 female and 85 male) with obesity—defined as a body mass index (BMI) of ≥30 kg/m², or ≥27 kg/m² with at least one obesity-related complication—and confirmed at-risk MASLD.

A notable strength of the trial was its pragmatic recruitment framework. Rather than requiring invasive liver biopsies for all participants, the study team adopted a clinical definition termed “at-risk MASLD”:

• Non-Invasive Qualification (~90% of cohort): Participants were identified using non-invasive liver tests (NITs) indicating a high probability of liver inflammation or progressive MASH.
• Biopsy Confirmation (~10% of cohort): A subset had pre-existing biopsy confirmation of MASH.

Participants were randomized in a 2:1 ratio to receive once-weekly subcutaneous injections of survodutide 6.0 mg (146 participants) or placebo (70 participants). The trial established two co-primary endpoints evaluated from baseline to week 48: achieving a ≥30% reduction in liver fat content (LFC) measured by Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF), and the percentage change in overall body weight.

3. Key Efficacy Findings: Deep Liver Fat Clearance and Weight Loss

The SYNCHRONIZE-MASLD trial met both co-primary endpoints with high statistical significance (P < 0.0001 across all primary analyses). Survodutide demonstrated clear superiority over placebo in both liver fat reduction and weight reduction.

The table below outlines the primary efficacy results at 48 weeks using both the efficacy estimand (evaluating treatment response while on study drug) and the treatment regimen estimand (evaluating all randomized participants regardless of treatment adherence):

Endpoint / Clinical Metric	Survodutide 6.0 mg	Placebo	Statistical Significance
≥30% Liver Fat Reduction (Efficacy Estimand)	84.2%	24.3%	P < 0.0001
≥30% Liver Fat Reduction (Treatment Regimen)	68.5%	28.6%	P < 0.0001
Mean Body Weight Change (Efficacy Estimand)	-12.2%	-1.0%	P < 0.0001
Mean Body Weight Change (Treatment Regimen)	-8.7%	-1.4%	P < 0.0001

Beyond meeting the baseline 30% reduction threshold, survodutide induced rapid and profound reductions in liver fat. As highlighted by Prof. Kaplan, a majority of patients receiving survodutide achieved a 50% loss of liver fat, and a substantial majority achieved a 70% loss of liver fat.

4. Why Glucagon Agonism Changes the Game for MASH Resolution

Understanding the clinical thresholds of liver fat clearance is essential for evaluating the therapeutic impact of next-generation liver treatments. In hepatology research, specific degrees of liver fat reduction correlate directly with histological improvements:

• 30% Liver Fat Reduction: Corresponds with meaningful clinical improvement in MASH inflammation and ballooning.
• 50% Liver Fat Reduction: Correlates with histological regression of liver fibrosis.
• 70% Liver Fat Reduction: Representative of full normalization of liver fat content.

Prof. Kaplan notes that while established GLP-1 receptor agonists (such as semaglutide) and dual GLP-1/GIP agonists (such as tirzepatide) effectively improve MASH through weight loss and metabolic modulation, they rarely achieve the rapid 50% to 70% liver fat clearance seen with glucagon-containing dual or triple agonists. The direct hepatic action of glucagon agonism provides a distinct metabolic advantage, accelerating fat exit from liver cells far beyond what weight loss alone typically delivers.

5. Safety, Tolerability, and the Future Pipeline

Evaluating the safety profile of intensive metabolic therapy is paramount for long-term patient management. In the SYNCHRONIZE-MASLD trial:

• Adverse Events: The most frequent side effects reported with survodutide were gastrointestinal (such as nausea and diarrhea), occurring predominantly during the initial dose-escalation phase and generally ranging from mild to moderate severity.
• Gallstone Risk Evaluation: Rapid fat mobilization from the liver raised theoretical questions regarding increased biliary cholesterol output and gallstone formation. However, across a pooled dataset of approximately 1,800 patients in three Phase 3 trials (covering obesity with diabetes, obesity without diabetes, and MASLD), survodutide treatment was not associated with an increased risk of gallstones.

The Road Ahead: The LIVERAGE Program

The findings from SYNCHRONIZE-MASLD serve as a stepping stone toward dedicated histological outcomes trials. Boehringer Ingelheim and Zealand Pharma are advancing the LIVERAGE clinical trial program—a suite of biopsy-driven Phase 3 studies specifically evaluating MASH resolution and fibrosis improvement. Top-line results from the LIVERAGE program are anticipated in late 2027 or early 2028.

Additionally, data from a massive Cardiovascular Outcomes Trial (CVOT) enrolling 5,500 patients will provide further insights into the broader systemic and cardiometabolic protection offered by survodutide.

6. Watch the Full “Ask the Author” Video Interview

We invite all members of the Swiss NASH Foundation community, patients, clinicians, and researchers to watch the complete “Ask the Author” video interview with Prof. Lee Kaplan to hear his full analysis of the trial design, mechanism of action, and future clinical implications.

• Watch the Video Interview on YouTube: Prof. Lee Kaplan Discusses Survodutide and SYNCHRONIZE-MASLD Results
• Read the Full Publication in Nature Medicine: Nature Medicine Article (DOI: 10.1038/s41591-026-04479-3)
• Access PubMed Indexing: PubMed ID: 42252333

The Swiss NASH Foundation remains committed to bringing you the latest scientific breakthroughs, expert commentary, and educational resources in steatotic liver disease. Stay connected with our platform for future clinical updates and video features.

Thank you to our sponsors

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Ask the author session

Glucagon-like peptide-1 receptor (GLP1R) agonists have transformed clinical care across type 2 diabetes, obesity, and hepatology. However, hepatologists and endocrinologists frequently encounter a clinical puzzle: patient response to GLP-1 therapy is highly individual, with some individuals showing no response at all. Natural genetic variations—specifically missense variants in the GLP1R gene—can alter receptor function and cell signaling, influencing both disease susceptibility and individual drug response.

👉 You can watch the full interview below between Prof. Jana Selent and Prof. Jean-François Dufour — don’t miss it.

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The Breakthrough: Bringing Cellular Context to AI

In a recent landmark study published in Diabetologia, Prof. Jana Selent from the University Pompeu Fabra in Barcelona introduced a novel computational framework called GPCRVP (or the GPCR score). While existing artificial intelligence models such as AlphaMissense and REVEL can predict variant effects, they frequently produce false predictions because they evaluate proteins in isolation without their natural cellular environment.

To bridge this gap, Prof. Selent’s team combined machine-learning predictors with all-atom molecular dynamics (MD) computer simulations of GLP1R embedded in a native-like cell membrane.

Key Clinical Takeaways

Please find below the main insights:

• 78% Fewer False Positives: By factoring in the lipid membrane, allosteric communication, and mutation-induced structural changes, GPCRVP achieved a ~78% reduction in false-positive predictions compared to AlphaMissense alone.
• Predicting Receptor Function: The score reliably forecasts whether a specific variant impairs crucial receptor functions, such as signal transduction, insulin release, and body weight regulation.
• Accelerating Precision Medicine: The predictor provides actionable insights into variant impact without requiring time-consuming and expensive laboratory experiments, helping clinicians anticipate patient risk for obesity or type 2 diabetes and avoid trial-and-error prescribing.

Watch the “Ask the Author” Interview

Want to understand how computational biology and membrane-aware AI modeling are shaping the future of personalized metabolic and liver care?

🎥 Watch our full “Ask the Author” interview with Prof. Jana Selent to hear directly from the lead author about the science behind the GPCR score and its potential for precision medicine.

Associated publication: “The GPCR^VP score reliably predicts the impact of GLP1R human variants on receptor function”

Thank you to our sponsors

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Ask the author session

What if the secret to understanding cancer’s aggressiveness lies not just within the tumor itself, but in the environment where it grows?

In a recent “Ask the Author” session, we had the pleasure of hosting Dr. Yiming Peng-Winkler, a researcher from the Laboratory for Tumor Evolution and Metastasis in Leuven, to discuss his team’s groundbreaking study published in Nature: “Steatosis shapes prognosis-defining liver metastasis heterogeneity in Colorectal Cancer”

👉 You can watch the full interview below — don’t miss it.

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The Mystery of Metastatic Growth Patterns

Colorectal cancer (CRC) often spreads to the liver, but not all metastases behave the same way. Clinicians have long observed different “histological growth patterns” under the microscope. One specific type, known as the replacement growth pattern, is particularly aggressive and associated with a much poorer prognosis—a 5-year survival rate of less than 44.2%, compared to 73.4% for other types.

Until now, it was unclear what drove this dangerous form of cancer. Dr. Peng-Winkler’s research provides a startling answer: the metabolic state of the liver itself.

Fatty Liver: A Scaffolding for Cancer

The study reveals that steatosis (fatty liver disease) is not just a passive condition. Instead, it actively shapes how cancer cells grow. In both patient cohorts and mouse models, Dr. Peng-Winkler found that a fatty liver causally promotes the replacement growth pattern.

The mechanism is fascinating:

• Cancer cells in a steatotic liver use available fatty acids to stabilize a notorious oncoprotein called MYC.
• MYC then triggers the synthesis of proline and collagen.
• This collagen acts as a physical scaffold, allowing cancer cells to infiltrate and replace healthy liver tissue.

A New Frontier for Precision Oncology

This research has profound implications for clinical practice, especially since steatosis affects roughly 25% of the population. Dr. Peng-Winkler suggests that assessing liver fat could become a vital part of risk stratification for CRC patients. Furthermore, it opens the door to therapies targeting metabolic pathways—like MYC or collagen production—to suppress these aggressive metastases.

As Dr. Peng-Winkler notes, precision oncology must look beyond the tumor and consider the metabolic conditions of the host organ.

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Ready to dive deeper into the science? Watch the full video interview to hear Dr. Yiming Peng-Winkler explain the translational design of this study, the experimental models used to prove causality, and his vision for the future of cancer treatment.

Thank you to our sponsors

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Ask the author session

We have all heard about the transformative impact of semaglutide on weight loss, but a groundbreaking new study suggests its benefits for the liver might be far more direct—and independent of the scale—than we ever imagined.

In our latest “Ask the Author” session, we sit down with Dr. González Rellán from the Lunenfeld Tanenbaum Research Institute to discuss her team’s recent publication in Cell Metabolism. Their research tackles a long-standing controversy in the field: Does semaglutide improve liver health simply because patients lose weight, or is there a direct hepatic mechanism at play?

👉 You can watch the full interview below — don’t miss it.

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The “Weight-Independent” Breakthrough

Using innovative genetic mouse models, Dr. González Rellán and her team were able to dissociate weight loss from drug action. They discovered that semaglutide significantly improved liver inflammation and fibrosis even in mice that did not lose any weight.

The secret lies in a specific population of liver sinusoidal endothelial cells (LSECs) located in the pericentral region of the liver. These cells express the GLP-1 receptor, and the study proved that when these receptors are selectively removed, the liver-protective benefits of semaglutide vanish—even if the subject continues to lose weight.

Why This Matters for Patients

This discovery has profound implications for how we treat Metabolic Dysfunction-Associated Steatohepatitis (MASH). During the interview, Dr. González Rellán highlights two critical groups of patients who could benefit from these findings:

• Non-responders: Patients who take GLP-1 agonists but do not experience substantial weight loss.
• Lean MASH: Patients who already have a healthy weight but suffer from severe liver disease.

As Dr. González Rellán explains, “Weight loss alone may not fully capture the full therapeutic benefit of semaglutide”. This opens the door for new dosing strategies that focus on liver repair rather than just maximizing weight loss.

Watch the Full Interview

Are you ready to dive deeper into the transcriptomics and proteomics behind this discovery? Curious about how the ESSENCE trial clinical data aligns with these findings?

Click here to watch the full interview with Dr. González Rellán and learn how the intrahepatic GLP-1 receptor is orchestrating a new era of liver health.

Thank you to our sponsors

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Ask the author session

Could the same medication used for weight loss and diabetes provide a new path for those struggling with alcohol use disorder?

In a compelling new “Ask the Author” session, Professor Fink-Jensen from the Mental Health Institute in Copenhagen joins us to discuss a groundbreaking study: “Once-weekly semaglutide versus placebo in patients with alcohol use disorder and comorbid obesity: a randomised, double-blind, placebo-controlled trial“

👉 You can watch the full interview on our website—don’t miss it.

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The Intersection of Obesity and Alcohol Use

The study addresses a critical gap in clinical care for patients with MetALD—those who navigate both obesity and high alcohol consumption. Professor Fink-Jensen notes that over 20% of individuals with a BMI over 30 also engage in high-risk alcohol use, highlighting an urgent need for targeted therapeutic interventions.

Inside the 26-Week Trial

Led by first author Dr. Mette Kruse Klausen, the research team conducted a rigorous six-month study involving treatment-seeking participants with moderate to severe alcohol use disorder and a BMI of 30 or higher. Every participant received cognitive-based psychotherapy, while half were randomized to receive 2.4 mg of once-weekly semaglutide and the other half received a placebo.

The trial’s methodology was particularly unique: because matching placebo pens were unavailable, the team had to ensure the double-blind design by blindfolding participants and providing headphones with music during their weekly hospital visits for injections.ease.

Remarkable Results

The findings, published in this recent trial, are highly promising for the future of addiction medicine:

• A Significant Drop in Heavy Drinking: The primary endpoint was a reduction in “heavy drinking days” (defined as four units/day for women or five for men).
• 50% Lower Consumption: While both groups saw improvements, those on semaglutide dropped from an average of 17 heavy drinking days per month to just five—a 50% lower value compared to the placebo group.
• Reward Center Impact: Professor Fink-Jensen explains that previous brain imaging research with first-generation GLP-1 agonists (exenatide) showed changes in the brain’s reward center when exposed to alcohol cues, specifically in participants with a BMI over 30.

Why You Should Watch the Full Interview

Is it time to start using GLP-1 agonists for alcohol use disorder in clinical practice? While the data is strongest for patients with a BMI above 30, this trial opens new perspectives on treating the comorbid population of MetALD patients.

Watch the full video interview to hear Professor Fink-Jensen dive deeper into the clinical management of these patients, the safety profile of the medication, and what this means for the future of treatment.

Thank you to our sponsors

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Ask the author session

Metabolic dysfunction–associated steatotic liver disease (MASLD) continues to challenge clinicians and researchers worldwide. While much is known about its links to obesity, insulin resistance, and lifestyle factors, a new perspective is emerging—one that shifts our attention to when metabolic dysfunction happens, not just how.

In a recent “Ask the Author” session, Thomas Marjot shares groundbreaking findings from his latest publication in Cell Metabolism, offering a fresh and thought-provoking understanding of Metabolic dysfunction-associated steatotic liver disease.

👉 You can watch the full interview on our website—don’t miss it.

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A 24-Hour View of Metabolism

Traditionally, MASLD has been studied as a static condition. But Dr. Marjot and his team took a different approach: they examined metabolic processes across a full 24-hour cycle in patients with MASLD and compared them to overweight controls.

Using advanced metabolic phenotyping techniques—including insulin infusion studies and stable isotope tracing—they were able to map how key metabolic pathways fluctuate between day and night.

The Key Finding: Nighttime Matters Most

The results reveal something striking: MASLD is strongly diurnal, with metabolic dysfunction peaking at night.

During nighttime, patients exhibit:

• Increased insulin resistance (both hepatic and peripheral)
• Elevated de novo lipogenesis (fat production in the liver)
• Higher exposure to circulating fatty acids
• Reduced insulin availability due to decreased secretion and increased clearance

This creates a “perfect storm” for liver fat accumulation while the body is least equipped to handle it.

Even more compelling, these abnormalities persist even after weight loss and reduction in liver fat, suggesting that nighttime dysfunction is not just a consequence—but a primary driver of the disease.

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What Does This Mean for Patients and Clinicians?

These findings could reshape how MASLD is managed in clinical practice:

1. Timing of Medication

Current therapies target metabolic pathways—but rarely consider when drugs are administered. This research suggests that evening dosing may enhance effectiveness by targeting peak dysfunction.

2. Lifestyle Interventions

• Evening exercise may help counteract poor nighttime muscle metabolism
• Reducing large evening meals could prevent overwhelming an already compromised metabolic system

3. Rethinking Clinical Measurements

Metabolic markers such as insulin resistance or glucose tolerance may vary significantly depending on the time of day. Incorporating chronobiology into clinical assessments could improve accuracy and interpretation.

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Why You Should Watch the Full Session

This blog only scratches the surface of a rich and insightful discussion. In the full video, Dr. Marjot explains:

• The study design in detail
• The physiological mechanisms behind nighttime dysfunction
• The broader implications for research and therapeutic development

👉 Watch the full “Ask the Author” session to hear directly from the expert.

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Dive Deeper into the Science

For those interested in the full scientific details, the published paper provides comprehensive insights into:

• Diurnal changes in lipid and glucose metabolism
• Molecular pathways involved in MASLD progression
• Potential therapeutic targets identified through integrated proteomics

👉 Read the full paper to explore the data and methodology behind these findings.

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A New Way of Thinking About MASLD

This research challenges a long-standing assumption: that metabolic diseases behave the same way throughout the day. By highlighting the importance of timing, it opens the door to more precise and potentially more effective interventions.

As the field evolves, one thing becomes clear—in MASLD, the night shift may be where the real story unfolds.

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👉 Watch the full interview with Dr. Thomas Marjot now here on the Swiss NASH Foundation website.

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Ask the author session

Understanding how our gut influences our brain is one of the most exciting frontiers in metabolic and liver-related research. For people living with MASLD/MASH (formerly NAFLD/NASH), obesity, and metabolic dysfunction, new insights into the gut–brain–liver axis are emerging every year.

One particularly compelling example is the recent paper published in GUT by Dr. Virginia Mela and colleagues: “Microbiota fasting-related changes ameliorate cognitive decline in obesity and boost ex vivo microglial function through the gut-brain axis.”

In our latest Ask the Author session, Prof. Jean-François Dufour sat down with Dr. Mela to explore the study’s design, findings, and what they could mean for individuals at risk of fatty liver disease. The conversation is rich, accessible, and highly relevant for anyone interested in the interplay between nutrition, inflammation, cognition, and metabolic liver disease.

👉 You can watch the full interview on our website—don’t miss it.

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A Closer Look: Three Diets, One Key Question

Dr. Mela and her team conducted a randomized controlled trial involving 96 participants with obesity. Participants were assigned to one of three well-defined dietary interventions for three months:

• Mediterranean diet (rich in olive oil, fish, legumes, vegetables)
• Ketogenic diet (very low carbohydrate, high fat)
• Alternate-day fasting (restricted intake on fasting days; controlled intake on non-fasting days)

The goals?

1. To determine how these diets affect weight loss
2. To explore whether they can improve cognitive performance, given the well-established link between obesity and cognitive decline

All participants underwent detailed metabolic, inflammatory, microbiota, and cognitive assessments before and after the intervention period.

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What They Discovered: Alternate-Day Fasting Stands Out

While all three diets produced similar weight loss—and the ketogenic diet led to the greatest reduction in fat mass—the alternate-day fasting diet had the most impressive effect on cognitive improvement.

Dr. Mela explains that this benefit appears to be driven by several biological changes:

1. Reduced systemic inflammation

Inflammatory markers fell significantly after the alternate-day fasting intervention, suggesting a broad anti-inflammatory effect.

2. Improved microglial function

Microglia—the brain’s resident immune cells—showed healthier, more functional behavior after exposure to participants’ post-diet biological samples.

3. Favorable shifts in gut microbiota

Alternate-day fasting increased specific beneficial bacterial taxa that correlated with cognitive improvements.

4. Increased riboflavin production

A standout finding was the rise in riboflavin, a microbiota-derived metabolite known for anti-inflammatory and immunomodulatory effects—potentially linking gut changes to brain improvements.

Prof. Dufour highlighted how elegant and multidimensional the study is, bridging microbiota composition, metabolites, brain immune cell activity, and cognition.

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What Does This Mean for MASLD/MASH?

With new drugs entering the MASLD/MASH treatment landscape, lifestyle strategies remain essential. Dr. Mela emphasizes that dietary interventions like alternate-day fasting may play a powerful preventive role:

They help minimize metabolic dysfunction and inflammation—two key drivers of fatty liver disease progression. While diet alone may be insufficient in later disease stages, integrating such patterns early could reduce risk, support metabolic health, and potentially complement future pharmacotherapies.

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Why You Should Watch the Full Interview

This conversation is not just about nutrition—it’s about how strategic dietary patterns reshape the microbiota, influence immune function in the brain, and potentially protect metabolic health.

Whether you’re:

• living with MASLD/MASH,
• a clinician advising patients,
• a researcher in the metabolic field, or
• simply someone curious about the gut–brain axis,

this interview offers science-based insights delivered in a clear and engaging way.

👉 Watch the full interview with Dr. Virginia Mela now here on the Swiss NASH Foundation website.
It’s an inspiring look at how dietary science continues to evolve—and how it may help us prevent and better understand metabolic liver disease.