The metabolic links between diet-induced changes in the gut and NASH

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Excessive intake of sucrose is a major driver of obesity and other diseases, such as non-alcoholic fatty liver diseases (NAFLD) and the more severe non-alcoholic steatohepatitis (NASH). In addition, a high-caloric diet induces gut dysbiosis and inflammation, which in turn causes NASH. Recently, scientists reviewed the metabolic association between diet-induced alterations in the gut and NASH. This review is available in iScience.

Study: Diet-induced gut dysbiosis and inflammation: key drivers of obesity driven NASH. Image Credit: Magic mine/Shutterstock
Study: Diet-induced gut dysbiosis and inflammation: key drivers of obesity driven NASH. Image Credit: Magic mine/Shutterstock

Macronutrients and metabolism

Macronutrients, such as proteins, carbohydrates, and fats, are obtained via food consumption. These are absorbed in the intestinal wall, following digestion and metabolic functions in the gut. Subsequently, these macronutrients are transported to distal organs, where they are used as chemical energy necessary for the functioning of organs.

Complex carbohydrates are broken down into monosaccharides (e.g., fructose and glucose), which are then absorbed in glucose transporter 5 (Glut5) and Glut2 (sodium-glucose-linked transporter-1 (SGLT-1). Subsequently, monosaccharides are transported from the intestines to the liver through the mesenteric blood vessels and portal vein.

Proteins are first converted into peptides and finally to amino acids. These are transported to the liver via the portal vein. In the liver, the toxic ammonia is quickly transformed into urea, which is eliminated from the body through urine.

Among the three key dietary fats (phospholipids, triglycerides, and cholesterol derivatives), triglyceride is sequentially digested into monoglycerides and fatty acids. These digested products are absorbed and re-synthesized to triglyceride, which is incorporated into lipoproteins. These lipoproteins are transported from the intestine to the liver by the lymphatics. 

Storage of excessive energy and metabolic dysfunction

In most cases, consumption of a high-fat diet (HFD) and sugar-sweetened beverages (SSBs) results in a positive energy balance. This condition occurs when the energy intake is more than the energy used. The body stores the surplus energy as fat in the adipocytes, which leads to metabolic dysfunction and obesity.

Obesity is related to increased body mass index (BMI), which has been linked with an increased mortality rate in both males and females. Diet-induced obesity (DIO) increases the risk of incidence of many chronic conditions, such as cardiovascular diseases (CVD), type 2 diabetes mellitus (T2DM), and several types of cancers (e.g., liver, breast, and colon). DIO enhances the accumulation of lipid droplets in the liver parenchyma, promoting NAFLD development.

NAFLD includes benign steatosis, characterized by moderately elevated triglyceride levels in hepatocytes. However, NASH is a more severe condition that entails additional inflammation. NASH is associated with more severe liver cirrhosis with fibrosis.

Typically, the progression of NAFLD to NASH is caused by cellular stress (oxidative and endoplasmic reticulum (ER) stress) and inflammation. Interestingly, Bariatric surgery-based studies have revealed that NAFLD was found in 85-95% of obese patients.

The effects of macronutrients on the gut microbiota

Gut microbiota plays an important role in gut energy metabolism. A high sugar and fatty food intake get rapidly absorbed in the small intestine, and a very small amount reaches the colon. As a result, the gut microbes are deprived of essential nutrients for their growth and survival. This finding reveals that consuming a high calorific and sugar diet leads to gut dysbiosis. In contrast, fiber-rich plant-based diet reverses the condition known as gut eubiosis.

Typically, gut dysbiosis is described based on the Firmicutes/Bacteroidetes ratio, where an increased ratio is a marker of microbiota-induced obesity. Western diet, which is regarded as a high-fat diet, induces gut dysbiosis that promotes inflammation and enterocyte ER stress.

Several studies have documented that a high fructose diet (HFrD) downregulates tight junction proteins (TJPs), which subsequently leads to the elevation of hepatic de novo lipogenesis (DNL). These studies have highlighted that DNL is associated with the synthesis of new lipids from glucose and fructose via the activation of the enzyme acetyl-CoA carboxylase (ACC). 

The downregulation of TJPs by HFrD leads to gut barrier deterioration, which promotes leakage of bacterial products (e.g., lipopolysaccharides- LPS) and gut-derived metabolites into the portal circulation. This leakage causes LPS to reach the liver. In the liver, LPS binds to Toll-like receptor 4 (TLR4) on the macrophages and induces the release of inflammatory mediators, causing liver inflammation and the development of NAFLD/NASH.

Therapeutic treatment of NASH

In the US, NASH is the leading cause of liver transplants. Currently, around 30 clinical trials are being conducted to identify potential drug candidates to treat NASH. Some simple preventive measures for NASH include lifestyle modification through a healthy diet, exercise, and bariatric surgery.

Since gut microbiota has been associated with obesity-induced NASH, scientists consider the gut-liver axis as an important therapeutic target. Alterations in the gut microbiota that affect the gut-liver axis influences the incidence of inflammation, hepatic lipid dysregulation, fibrosis, and cirrhosis. 

A dietary restriction approach could also alleviate NASH conditions. Several pharmacological therapeutic interventions, such as Orlistat, IMM-124e, and Faecal microbiota transplantation (FMT), have been explored to treat obesity-induced NASH.

Journal reference:
Dr. Priyom Bose

Written by

Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.


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