Effect of Saturated Fat (Desi Ghee) on Gut-Liver Axis in Alcoholic Hepatitis

Alcoholic Hepatitis Clinical Trial

— SFAH  

Official title:

Effect of Saturated Fat (Desi Ghee) on Gut-Liver Axis in Alcoholic Hepatitis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04084522
• Other study ID #: ILBS-SAH-01
• Status: Completed
• Phase: N/A
• Start date: October 1, 2019
• Est. completion date: January 31, 2022

Study information

• Verified date: February 2022
• Source: Institute of Liver and Biliary Sciences, India
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: January 31, 2022
• Est. primary completion date: January 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

All patients with Severe Alcoholic Hepatitis

• Aged between 18-60 years
• Having Maddrey Score of >32
• Last Intake of alcohol from 1 day to 60days
• Patients who agree for complete alcohol abstinence from the day of enrollment Exclusion Criteria: Patients with-
• Maddrey Score of <32 and >100
• Comorbidities- Diabetes, Hypertension, Coronary Artery Disease, Chronic Kidney Disease, Hypothyroid
• Continuing Alcohol intake- Non-compliant patients
• Constipation
• On Laxatives until 1 month prior to study
• On probiotics until 1 month prior to study

Related Conditions & MeSH terms

• Alcoholic Hepatitis
• Hepatitis
• Hepatitis A
• Hepatitis, Alcoholic

Intervention

Dietary Supplement:
• Saturated Fat- Desi Ghee (Clarified Butter)
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
Soyabean Oil consists of around 84% of unsaturated fat and is the most widely used source of unsaturated fat used in the area.

Locations

Country	Name	City	State
India	Institute of Liver and Biliary Sciences	New Delhi	Delhi

Sponsors (1)

Lead Sponsor	Collaborator
Institute of Liver and Biliary Sciences, India

Country where clinical trial is conducted

India, 

References & Publications (11)

Chen P, Torralba M, Tan J, Embree M, Zengler K, Stärkel P, van Pijkeren JP, DePew J, Loomba R, Ho SB, Bajaj JS, Mutlu EA, Keshavarzian A, Tsukamoto H, Nelson KE, Fouts DE, Schnabl B. Supplementation of saturated long-chain fatty acids maintains intestinal eubiosis and reduces ethanol-induced liver injury in mice. Gastroenterology. 2015 Jan;148(1):203-214.e16. doi: 10.1053/j.gastro.2014.09.014. Epub 2014 Sep 16. — View Citation

Edenberg HJ. The genetics of alcohol metabolism: role of alcohol dehydrogenase and aldehyde dehydrogenase variants. Alcohol Res Health. 2007;30(1):5-13. Review. — View Citation

Hritz I, Mandrekar P, Velayudham A, Catalano D, Dolganiuc A, Kodys K, Kurt-Jones E, Szabo G. The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88. Hepatology. 2008 Oct;48(4):1224-31. doi: 10.1002/hep.22470. — View Citation

Keshavarzian A, Farhadi A, Forsyth CB, Rangan J, Jakate S, Shaikh M, Banan A, Fields JZ. Evidence that chronic alcohol exposure promotes intestinal oxidative stress, intestinal hyperpermeability and endotoxemia prior to development of alcoholic steatohepatitis in rats. J Hepatol. 2009 Mar;50(3):538-47. doi: 10.1016/j.jhep.2008.10.028. Epub 2008 Dec 29. — View Citation

Kirpich IA, Feng W, Wang Y, Liu Y, Barker DF, Barve SS, McClain CJ. The type of dietary fat modulates intestinal tight junction integrity, gut permeability, and hepatic toll-like receptor expression in a mouse model of alcoholic liver disease. Alcohol Clin Exp Res. 2012 May;36(5):835-46. doi: 10.1111/j.1530-0277.2011.01673.x. Epub 2011 Dec 7. — View Citation

Kirpich IA, Petrosino J, Ajami N, Feng W, Wang Y, Liu Y, Beier JI, Barve SS, Yin X, Wei X, Zhang X, McClain CJ. Saturated and Unsaturated Dietary Fats Differentially Modulate Ethanol-Induced Changes in Gut Microbiome and Metabolome in a Mouse Model of Alcoholic Liver Disease. Am J Pathol. 2016 Apr;186(4):765-76. doi: 10.1016/j.ajpath.2015.11.017. — View Citation

Kirpich IA, Solovieva NV, Leikhter SN, Shidakova NA, Lebedeva OV, Sidorov PI, Bazhukova TA, Soloviev AG, Barve SS, McClain CJ, Cave M. Probiotics restore bowel flora and improve liver enzymes in human alcohol-induced liver injury: a pilot study. Alcohol. 2008 Dec;42(8):675-82. doi: 10.1016/j.alcohol.2008.08.006. — View Citation

Mutlu E, Keshavarzian A, Engen P, Forsyth CB, Sikaroodi M, Gillevet P. Intestinal dysbiosis: a possible mechanism of alcohol-induced endotoxemia and alcoholic steatohepatitis in rats. Alcohol Clin Exp Res. 2009 Oct;33(10):1836-46. doi: 10.1111/j.1530-0277.2009.01022.x. Epub 2009 Jul 23. — View Citation

Nanji AA, Jokelainen K, Tipoe GL, Rahemtulla A, Dannenberg AJ. Dietary saturated fatty acids reverse inflammatory and fibrotic changes in rat liver despite continued ethanol administration. J Pharmacol Exp Ther. 2001 Nov;299(2):638-44. — View Citation

Su GL, Rahemtulla A, Thomas P, Klein RD, Wang SC, Nanji AA. CD14 and lipopolysaccharide binding protein expression in a rat model of alcoholic liver disease. Am J Pathol. 1998 Mar;152(3):841-9. — View Citation

Zhong W, Li Q, Xie G, Sun X, Tan X, Sun X, Jia W, Zhou Z. Dietary fat sources differentially modulate intestinal barrier and hepatic inflammation in alcohol-induced liver injury in rats. Am J Physiol Gastrointest Liver Physiol. 2013 Dec;305(12):G919-32. doi: 10.1152/ajpgi.00226.2013. Epub 2013 Oct 10. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	To study the serum pro- inflammatory marker, TNF-alpha in patients with severe alcoholic hepatitis	The collected blood sample would be assessed for TNF- alpha levels by using Quantikine ELISA kit	2 months
Other	To study the serum pro- inflammatory marker, IL-6 in patients with severe alcoholic hepatitis	The collected blood sample would be assessed for IL-6 levels by using Quantikine ELISA kit	2 months
Other	To study the serum pro- inflammatory marker, NF-kB in patients with severe alcoholic hepatitis	The collected blood sample would be assessed for NF-kB levels by using Quantikine ELISA kit	2 months
Other	To study the serum anti- inflammatory marker,adiponectin in patients with severe alcoholic hepatitis	The collected blood sample would be assessed for adiponectin levels by using Quantikine ELISA kit	2 months
Other	To study the serum anti- inflammatory marker, IL-10 in patients with severe alcoholic hepatitis	The collected blood sample would be assessed for IL-10 levels by using Quantikine ELISA kit	2 months
Other	To observe the expression of gut microbiome specific genes in patients with severe alcoholic hepatitis	The stool sample collected would be assessed for Fab genes (G and F) expression using 16s ribosomal gene sequencing.	2 months
Other	To observe Clinical benefit in patients of severe alcoholic hepatitis	Clinical benefit in terms of resolution of signs & symptoms to be observed.	2 months
Other	To observe Clinical benefit in patients of severe alcoholic hepatitis	Clinical benefit in terms of improvement in Bilirubin levels to be observed	2 months
Other	To observe Clinical benefit in patients of severe alcoholic hepatitis	Clinical benefit in terms of reduction of AST & ALT levels to be observed	2 months
Other	To observe Clinical benefit in patients of severe alcoholic hepatitis	Clinical benefit in terms of reduction Maddrey Score to be observed	2 months
Other	To observe the Nutritional status in patients with Severe Alcoholic hepatitis	Body composition analysis by BIA (Bioelectrical impedance analysis) for nutritional screening of the patients	2 months
Primary	To determine the improvement in cirrhosis dysbiosis ratio (CDR) associated with saturated fat in patients with severe alcoholic hepatitis.	The stool sample of the patients would be processed by 16s ribosomal RNA Gene sequencing to observe the diversity, abundance an evenness of the microbial community and thereafter Cirrhosis dysbiosis ratio (CDR) would be calculated at the starting and the end of the study i.e at baseline and at the end of two months.	2 months
Secondary	To study the serum endotoxin (lipoploysacchride) levels in patients with severe alcoholic hepatitis	The collected blood sample would be assessed for endotoxin levels by using Toxin Sensor TM Chromogenic LAL Endotoxin Assay Kit	2 months

External Links

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