Effect of Saturated Fat (Desi Ghee) on Gut-Liver Axis in Alcoholic Hepatitis
Condition: Alcoholic Hepatitis
MeSH terms: Hepatitis A; Hepatitis; Hepatitis, Alcoholic
Study type: Interventional

Summary: 
      The pathogenesis of the alcoholic liver disease (ALD) is a complex interplay of various
      etiopathological factors other than direct alcohol toxicity. These factors include
      inflammation & oxidative stress, dysbiosis, intestinal hyperpermeability, and endotoxemia.
      Dietary fats not only improve nutritional status in ALD but specific properties of saturated
      fats (SF) have the potential to favourably modulate these causative factors. This project has
      two parts, in the animal study 10 groups of murine model of alcoholic hepatitis (AH) would be
      given SF in the form of Desi Ghee and in the human study patients with AH would be randomized
      into two groups, one with SF ( Desi Ghee) and the other with usual unsaturated fat (cooking
      oil). In all effect of SF on gut microbiota, hepatic steatosis, TLR-4 expression, serum
      adiponectin, endotoxin levels, intestinal tight junction proteins and inflammatory markers in
      murine models of AH, along with hepatic morbidity & lipid profile, in patients with ALD would
      be studied.
    

Detailed description: 
      Alcohol is one of the predominant causes of liver diseases and liver-related deaths
      worldwide. 10% of heavy drinkers consuming more than 30g /day of alcohol for 5 years develop
      alcoholic liver disease (ALD). The liver acts as a major organ in alcohol metabolism. Alcohol
      is metabolized to acetaldehyde, the key toxin in alcohol mediated liver injury which gets
      converted to reactive oxygen species (ROS) through oxidative pathway thus leading to
      hepatocyte injury. Several experimental and human studies have shown that alcohol also causes
      intestinal bacterial overgrowth, intestinal mucosal damage and enhances intestinal
      permeability, leading to translocation of bacteria and their by-products (like LPS) in the
      portal circulation. Bacteria further stimulate the production of ROS and pro-inflammatory
      cytokines like TNF-alpha, IL-6, & chemokines, thus further damaging the liver. Alcohol intake
      not only causes bacterial overgrowth but also brings a qualitative change in the type of
      bacteria. The number of gram-negative bacteria like Enterobacteriaceae / Proteobacteria -
      E.Coli, Firmicutes -Enterococcocus, Bacteriodetes- Fusobacteria and Staphylococaceae
      -Staphylococcus increase whereas the number of gram-positive bacteria viz. Firmicutes
      -Lactobacillus, Ruminococcaceae, Lachnospiraceae; Actinobacteria -Bifidobacterium decrease.
      This change is termed dysbiosis. Thus alcohol-related liver injury is potentiated by
      alcohol-induced gut barrier dysfunction and ensuing cascade of events, involving dysbiosis.
      Studies suggest that probiotic administration decreased alcohol-induced dysbiosis, TNF- alpha
      & IL-6 levels, and improves gut leakiness & liver inflammation. Probiotics also restore the
      level of lactobacilli thus creating more acidic environment, lowering the intestinal pH &
      stabilizing mucosal barrier, thereby preventing microbial translocation & blocking TLR-4
      signaling cascade and attenuating liver injury. Hence there is evidence that suggests to
      targeting dysbiosis improves alcohol-related liver disease. Studies have also shown that
      lactobacilli use saturated fat (SF) for its growth and supplementing SF improves gut
      lactobacilli levels and subsequently decreases the progression of ALD. Low levels of
      microbial long-chain saturated fat caused due to alcohol compromise the growth of
      lactobacillus and hence disrupt gut barrier integrity. A large multicentre epidemiologic
      study in chronic alcoholics with comparable per capita alcohol intake has shown that intake
      of saturated fat is associated with lower mortality rates as compared to unsaturated fats
      (USF) Diet rich in SF has been found to prevent ethanol-induced changes viz. an increase in
      proteobacteria & liver steatosis, which were actually increased with the consumption of USF.
      Yet another study reported that the SF diet improved intestinal tight junction expression and
      alleviated intestinal inflammation caused due to ethanol intake. Supplementation of
      long-chain fatty SF to ethanol injured mice with increased intestinal permeability restored
      metabolic homeostasis with decreased intestinal bad bacteria levels where supposedly
      saturated fat serves as a vitamin B substitute and promotes the growth of lactobacilli
      species which ameliorates alcoholic liver injury.

      Alcohol induced disruption in the intestinal tight junction protein levels, endotoxemia and
      hepatic LPS signaling were found to be alleviated by SF in the form of medium chain
      triglycerides. Dietary SF (e.g., palm oil or MCT oil) reversed the established experimental
      ALD in rats, and improved liver histological changes despite continued intragastric ethanol
      administration.

      Hence the supplementation of SF in ALD is a logical manoeuvre within the nutritional therapy
      of this disease, as almost 90% of these patients are malnourished primarily due to a reduced
      diet intake. Fats are concentrated source of energy which makes the food palatable, hence
      making the attainment of higher calorie (35-40 kcal/kg body weight/day) target possible. With
      this background use of SF in ALD is a promising modality in the medical armamentarium, given
      the fact that nutrition remains the cornerstone of the overall therapy.
    

Intervention name(s): Saturated Fat- Desi Ghee (Clarified Butter); Soyabean Oil
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): Desi Ghee which is also known as clarified butter contains around 70% of saturated fat. in India it is one of the important culinary items which promotes longevity and protects against various diseases, attributing numerous health benefits. Ghee consumption has also significant hypolipidemic and hypocholesterolemic effects.; Soyabean Oil consists of around 84% of unsaturated fat and is the most widely used source of unsaturated fat used in the area.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Alcoholic Hepatitis; Gut Microbiota; Dysbiosis; Malnutrition; Saturated Fat