Hepatic Mitochondria-Gut Microbiota Interactions in Metabolism-Associated Fatty Liver Disease

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Abstract

The prevalence of metabolism-associated fatty liver disease (MAFLD) represents an urgent pandemic, complicated by a higher risk of morbidity and mortality as well as an increased socio-economic burden. There is growing evidence proving the impact of gut microbiota modifications on the development and progression of MAFLD through changes in metabolic pathways, modulation of the immune response, and activation of pro-inflammatory signals. Concurrently, metabolites produced by gut microbiota consisting of short chain fatty acids and bile acids contribute to the regulation of hepatic homeostasis by interacting with mitochondria. Evolving research indicates that innovative therapeutic targets for MAFLD may focus on gut microbiota–mitochondria interplay to regulate hepatic homeostasis. Recent investigations have explored the potential of new treatment strategies, such as prebiotics, probiotics, and metabolites, to change the composition of gut microbiota and simultaneously exert a positive impact on mitochondrial function to improve MAFLD. This review summarizes the significance of mitochondria and reports modifications in the composition of gut microbiota and its metabolites in MAFLD in order to illustrate the fascinating interplay between liver mitochondria and intestinal microbiota, discussing the potential effects of innovative treatments to modulate gut microbiota.

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The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism.

Gijs den Besten, Karen van Eunen, Albert Groen … (2013)

Short-chain fatty acids (SCFAs), the end products of fermentation of dietary fibers by the anaerobic intestinal microbiota, have been shown to exert multiple beneficial effects on mammalian energy metabolism. The mechanisms underlying these effects are the subject of intensive research and encompass the complex interplay between diet, gut microbiota, and host energy metabolism. This review summarizes the role of SCFAs in host energy metabolism, starting from the production by the gut microbiota to the uptake by the host and ending with the effects on host metabolism. There are interesting leads on the underlying molecular mechanisms, but there are also many apparently contradictory results. A coherent understanding of the multilevel network in which SCFAs exert their effects is hampered by the lack of quantitative data on actual fluxes of SCFAs and metabolic processes regulated by SCFAs. In this review we address questions that, when answered, will bring us a great step forward in elucidating the role of SCFAs in mammalian energy metabolism.

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What is the Healthy Gut Microbiota Composition? A Changing Ecosystem across Age, Environment, Diet, and Diseases

Emanuele Rinninella, Pauline Raoul, Marco Cintoni … (2019)

Each individual is provided with a unique gut microbiota profile that plays many specific functions in host nutrient metabolism, maintenance of structural integrity of the gut mucosal barrier, immunomodulation, and protection against pathogens. Gut microbiota are composed of different bacteria species taxonomically classified by genus, family, order, and phyla. Each human’s gut microbiota are shaped in early life as their composition depends on infant transitions (birth gestational date, type of delivery, methods of milk feeding, weaning period) and external factors such as antibiotic use. These personal and healthy core native microbiota remain relatively stable in adulthood but differ between individuals due to enterotypes, body mass index (BMI) level, exercise frequency, lifestyle, and cultural and dietary habits. Accordingly, there is not a unique optimal gut microbiota composition since it is different for each individual. However, a healthy host–microorganism balance must be respected in order to optimally perform metabolic and immune functions and prevent disease development. This review will provide an overview of the studies that focus on gut microbiota balances in the same individual and between individuals and highlight the close mutualistic relationship between gut microbiota variations and diseases. Indeed, dysbiosis of gut microbiota is associated not only with intestinal disorders but also with numerous extra-intestinal diseases such as metabolic and neurological disorders. Understanding the cause or consequence of these gut microbiota balances in health and disease and how to maintain or restore a healthy gut microbiota composition should be useful in developing promising therapeutic interventions.

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Non-alcoholic fatty liver disease – A global public health perspective

Zobair Younossi (2018)

As the epidemics of obesity and type 2 diabetes mellitus increase worldwide, the prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing proportionately. The subtype of NAFLD which can be characterised as non-alcoholic steatohepatitis (NASH) is a potentially progressive liver disease that can lead to cirrhosis, hepatocellular carcinoma, liver transplantation, and death. NAFLD is also associated with extrahepatic manifestations such as chronic kidney disease, cardiovascular disease and sleep apnoea. NAFLD and NASH carry a large economic burden and create poor health-related quality of life. Despite this important burden, we are only beginning to understand its mechanisms of pathogenesis and the contribution of environmental and genetic factors to the risk of developing a progressive course of disease. Research is underway to identify appropriate non-invasive diagnostic methods and effective treatments. Although the risk of liver-related mortality is increased in patients with NAFLD and liver fibrosis stages F3 or F4, the leading cause of death is cardiovascular disease. Given the rapidly growing global burden of NAFLD and NASH, efforts must continue to find accurate non-invasive diagnostic and prognostic biomarkers, to develop effective treatments for individuals with advanced NASH and prevention methods for individuals at high risk of NAFLD and progressive liver disease.