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Probiotics Normalize Bowel Flora and Improve Liver Enzymes in Human Alcohol-Induced Liver Injury.

Irina Kirpich^1,2, Natalia Solovieva¹, Svetlana Leikhter¹, Natalia Shidakova¹, Oxsana Lebedeva¹, Matt Cave²

¹ Northern State Medical University, Arkhangelsk, Russia; ² University of Louisville School of Medicine, Louisville, KY, USA

Background and Aims:  Alcoholic liver disease (ALD) remains a major cause of morbidity and mortality in the United States and worldwide. Alcoholic hepatitis occurs in approximately 10-35% of heavy drinkers, and carries with it a long term frequency of cirrhosis which is nine fold higher than milder forms of alcoholic liver disease (McClain and Carithers, 2006). Unfortunately, there is no FDA-approved therapy for ALD. The cornerstones of therapy in ALD are abstinence and the correction of associated malnutrition. Bowel-liver interactions are well described in ALD. Importantly, alcoholism is associated with increased gut permeability, and the frequency of endotoxemia is high (McClain et al., 1999). Lipopolysacharide (LPS) derived from gram negative bowel flora stimulates pro-inflammatory cytokine production in Kupffer cells. Tumor necrosis factor alpha (TNF-a) has emerged as a critical cytokine in ALD (McClain and Cohen, 1989). Limited experimental data suggest a potential role for probiotics in the treatment of ALD. However, the effect of chronic alcohol consumption on the bowel flora and the therapeutic role of probiotics in human alcohol-induced liver injury has not been evaluated. The purpose of the present study was to evaluate the ability of a probiotic supplementation to normalize the bowel flora and improve liver enzymes in patients with alcohol-induced liver injury.

Methods:  Sixty-six adult males with a diagnosis of alcoholism admitted to a psychiatric hospital were enrolled in this study. The day following admission, stool was collected for quantitative culture for E. coli, bifidobacteria, lactobacilli, and enterococci. Plasma was collected for routine liver function tests: ALT and AST (alanine- and aspartate- aminotransferases) activity. Patients were randomized to receive 5 days of probiotic supplementation of Bifidobacterium bifidum and Lactobacillus plantarum 8PA3 vs. standard therapy alone. Stool and plasma were then recollected for comparison.

Results and discussion:  Compared to healthy controls, alcoholic patients had significantly reduced numbers of bifidobacteria, lactobacilli, and enterococci. After 5 days of probiotic therapy, patients had significantly increased numbers of both bifidobacteria and lactobacilli when compared to the standard therapy. Patients treated with probiotics had significantly lower AST and ALT activity at the end of treatment than those treated with standard therapy alone. Potential mechanisms may be found in the experimental studies. The available evidence suggests that probiotics including Lactobacillus spp. and Bifidobacterium spp. are capable of protecting gut mucosal integrity to reduce bacterial translocation, endotoxemia, and pro-inflammatory cytokine in alcoholic liver disease. Nanji et al. first demonstrated that Lactobacillus GG reduced endotoxemia and alcohol-induced liver injury in rats (Nanji et al., 1994). It was later shown in alcohol fed rats, that prebiotic oats reduced gut permeability, endotoxemia, and liver injury (Keshavarzian et al., 2001). More recently, it was demonstrated that increased basal mucosal prostaglandin E2 production was the mechanism of gastric mucosal protection by Lactobacillus GG in alcohol fed rats (Lam et al., 2007).

In conclusion, patients with alcohol-induced liver injury have altered bowel flora when compared to healthy controls. Short-term oral supplementation with Bifidobacterium bifidum and Lactobacillus plantarum 8PA3 was associated with normalization of the bowel flora and greater improvement in alcohol-induced liver injury than standard therapy alone. This suggests that probiotics, and in particular Bifidobacterium bifidum and Lactobacillus plantarum, have a potential short term role in the treatment of ALD.

Keshavarzian, A., Choudhary, S., Holmes, E.W., Yong, S., Banan, A., Jakate, S., and Fields, J.Z. (2001). Preventing gut leakiness by oats supplementation ameliorates alcohol-induced liver damage in rats. The Journal of pharmacology and experimental therapeutics 299, 442-448.

Lam, E.K., Tai, E.K., Koo, M.W., Wong, H.P., Wu, W.K., Yu, L., So, W.H., Woo, P.C., and Cho, C.H. (2007). Enhancement of gastric mucosal integrity by Lactobacillus rhamnosus GG. Life sciences 80, 2128-2136. McClain, C.J., Barve, S., Deaciuc, I., Kugelmas, M., and Hill, D. (1999). Cytokines in alcoholic liver disease. Seminars in liver disease 19, 205-219.

McClain, C.J., and Cohen, D.A. (1989). Increased tumor necrosis factor production by monocytes in alcoholic hepatitis. Hepatology (Baltimore, Md 9, 349-351.

McClain, C.M., and Carithers, R.L. (2006). Alcoholic Liver Disease. In Sleisenger and Fordtran's Gastrointestinal and Liver Disease Pathophysiology / Diagnosis / Management, M. Feldman, L. Friedman, and L. Brandt, eds. (Canada: Saunders Elsevier), pp. 1771-1792.

Nanji, A.A., Khettry, U., and Sadrzadeh, S.M. (1994). Lactobacillus feeding reduces endotoxemia and severity of experimental alcoholic liver (disease). Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y 205, 243-247.

If you want to contact this author:

Irina Kirpich, Ph.D.
University of Louisville Medical Center
Department of Medicine
Hepatology and Gastroenterology Division
511 South Floyd Street
Room #405, MDR Building
Louisville, KY 40202
i0kirp01@louisville.edu