MASLD & MASH: Emerging Therapeutics to Enhance Standard of Care

Metabolic dysfunction–associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD),^1-4 is a multifaceted disorder that involves hepatic fat accumulation and at least one of five cardiometabolic risk factors.^5,6 MASLD represents a spectrum of pathologies that, in some patients, will progress from simple steatosis to metabolic dysfunction–associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH),⁵ to cirrhosis and hepatocellular carcinoma (HCC).⁷ 

The global prevalence of MASLD is an estimated 30% and reportedly increasing.⁸ In the US, up to 80 million individuals may have MASLD, and this prevalence is also rising, particularly among children and adolescents.⁹

MASLD is closely related to systemic metabolic diseases.¹⁰ Obesity is a well-known risk factor, and the prevalence of MASLD increases as BMI increases; however, despite being closely linked with obesity, MASLD can also manifest in non-obese individuals.⁷ Genetics may play a part in disease development.¹⁰ In addition to cardiovascular disease, MASLD is also an independent risk factor for type 2 diabetes, metabolic syndrome, chronic kidney disease, and malignant tumors.¹⁰

Diet modification and regular exercise are the standard treatments for MASLD.¹¹ In recent years, a line of evidence has suggested a close linkage between the intestine and MASLD/MASH.^9,12 Accordingly, nutritional therapies and the gut microbiome have emerged as potential therapeutic targets in combating these diseases.^9,13-19 What is the connection between nutrition, the gut microbiota, and MASLD/MASH, and can personalized therapies that include intermittent fasting and probiotic supplementation affect the clinical measures of these diseases?

Gut Microbiota & MASLD/MASH

Recent breakthroughs in the understanding of the pathogenesis of MASLD/MASH have pointed to gastrointestinal dysbiosis as an underlying factor.^14,15,20 A dysbiotic environment can lead to a series of problems, including the overgrowth of detrimental bacteria, increased gut barrier permeability, bacterial translocation, and the flow of metabolites to the liver.¹⁵This plays a critical role in MASLD onset and progression via the gut-liver axis.¹³

When the gut is in a dysbiotic state, this can trigger a series of events that culminate in insulin resistance, inflammation of the liver, and eventually the development of liver fibrosis.¹⁵ In addition, various metabolites produced by intestinal bacteria that reach the liver have been linked to the manifestation of simple steatosis, MASLD, and MASH.¹⁵ A link between MASLD/MASH and the gut microbiome is supported by several recent studies.^9,12,21-24 However, it is important to note that some studies comparing the specific bacterial taxonomic compositions between patients with MASLD and control subjects have contradictory findings.¹² 

Emerging Interventions: From Intermittent Fasting to Probiotics

Intermittent fasting approaches have been discussed in relation to the management of MASLD, yet few fasting-related clinical trials have included MASLD-specific populations, and findings have been inconsistent.^16,17,25 To further the research, randomized controlled trials (RCTs) have specifically assessed the benefits of alternate-day fasting and time-restricted eating for patients diagnosed with MASLD.^18,19 A 2023 RCT is reportedly one of the first studies to examine the effect of intermittent fasting combined with exercise on MASLD outcomes.¹⁸ Overall, the RCT demonstrated the significant effectiveness of alternate-day fasting combined with exercise to reduce hepatic steatosis, body weight, fat mass, waist circumference, alanine transaminase (ALT), fasting insulin, and insulin resistance and to increase insulin sensitivity for patients with obesity and MASLD compared to controls.¹⁸

In addition to intermittent fasting, probiotic and synbiotic supplementation have also been areas of developing research as potential treatments for MASLD/MASH.²⁶ Probiotics have been shown to regulate the composition of intestinal flora and the production of antibacterial factors, as well as change the permeability of the epithelium of the intestine to affect disease development and progression.²⁷ Probiotics may also exert effects on MASLD by modifying endotoxemia, inhibiting the inflammatory response, and regulating the immune system.²⁷

A 2023 systematic review and meta-analysis of 41 randomized controlled trials suggests that the use of prebiotics, probiotics, and synbiotics significantly improved liver steatosis (measured by ultrasound grading) and liver enzymes, including ALT, aspartate transaminase (AST), and gamma-glutamyl transferase (GGT).²⁸ A 2022 systematic review and meta-analysis also suggests that the use of probiotics, prebiotics, and synbiotics may be associated with small to moderate positive effects on glucose, insulin, sugar, lipid, and protein metabolism, as well as levels of total cholesterol and low-density lipoprotein (LDL) cholesterol.²⁷ They can also exert effects on MASLD by modifying endotoxemia, inhibiting inflammatory response, and regulating the immune system.²⁷ Most recently, a 2024 meta-analysis of RCTs found that while probiotics alone did not improve clinical indicators in MASLD patients, synbiotics exhibited several benefits, including reducing liver steatosis.²⁶

Dietary Guidelines for MASLD/MASH

Improved dietary composition by itself, weight loss of 5-10% of the initial body weight, and moderate exercise can make a difference for MASH patients in terms of improvement of all histological features.²⁹ Lifestyle interventions that focus on reduced energy intake and improved dietary patterns are the mainstay of MASLD management.³⁰ Dietary factors and patterns also play a critical role in the modulation of gut microbiota.¹³ Current guidelines highlight nutritional recommendations such as enhancing diet quality by minimizing processed meat, ultra-processed foods, and sugar-sweetened beverages.³¹

The most substantial evidence available for lifestyle intervention in MASLD/MASH is weight reduction and the Mediterranean dietary pattern, which is characterized by a plentiful intake of olive oil, vegetables, fruits, nuts, legumes, whole grains, fish, and seafood and a low intake of red meat and especially processed meat, along with reduced carbohydrate intake, especially sugars.^29,30 A recent 18-month trial with 294 participants suggests the Mediterranean diet may be enhanced by additional green plants rich in polyphenols.²⁹ The green-Mediterranean diet reduced hepatic fat by 39% compared with 20% for the Mediterranean diet, despite similar weight loss, and both diets did better than controls provided only with healthy dietary guidelines. The importance of increased phenolic acid intake (from fruits and vegetables, nuts, green tea, and coffee) is independently associated with lower prevalence of insulin resistance, MASLD, and fibrosis.²⁹

Functional Medicine Considerations

The functional medicine model helps practitioners utilize a comprehensive, whole health approach to identify and understand those factors that may be at the root of an individual patient’s health condition such as an MASLD diagnosis. Prioritizing a collaborative patient-practitioner therapeutic partnership helps clinicians understand the patient’s health journey and develop an effective and sustainable personalized intervention that addresses current health concerns and supports the patient’s future health goals, as well as their preferences in terms of lifestyle adjustments.

The Cardiometabolic Advanced Practice Module (APM)^TM provides a logical method to identify the unique drivers of each patient’s cardiometabolic disease using common lab markers and genetic principles. Learn about the discrete mechanisms that underpin cardiometabolic diseases such as MASLD and how to implement personalized care plans, which may include such interventions as IFM’s Cardiometabolic Food Plan, other nutritional therapeutic approaches, and a personalized exercise prescription. 

Learn more from functional medicine experts at IFM’s upcoming Cardiometabolic Advanced Practice Module.