Using of probiotics in verities of medical problems is safer and less expensive than antibiotic therapy. According to the currently adopted definition by the Food and Agriculture Organization and World Health Organization, probiotics are: “live microorganisms, when administered in adequate amounts confer a health benefit on the host.”1 Probiotics are used as effective biological factors for modulation of gut microflora, and recently they are suggested as natural means for improving the liver function. The colonized gut flora in healthy individuals is affected by many physiological and environmental factors: nutrition, illness, aging, and stress are the main parameters affecting the imbalance and impairment of the natural pattern of gut mechanism in healthy individuals.2 Therefore, probiotics are suggested as a beneficial agent to better balance the gut flora. Because of the functional link to the intestine, the liver is known as the first-organ barrier against the gut-derived bacterial fractions or metabolites, which are persistently released into the circulation. The kupffer cells as the liver macrophages particularly reduce the amount of bacterial phagocytosis and endotoxins.3
PROBIOTICS AND LIVER DISEASES
Numbers of liver diseases in which probiotics may have a role in its management, these include: alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), hepatic encephalopathy, primary sclerosing cholangitis (PSC), and hepatocellular carcinoma (HCC).
Alcoholic steatohepatitis and severe ALD manifest in approximately one third of heavy drinkers, suggesting that other factors may also play an etiological role. Furthermore, chronic alcoholism elevates the growth of gram-negative bacteria and increases the amount of Lactobacilli and Bifidobacteria.4 The resultant endotoxaemia may stimulate the proinflammatory cytokines, that is, tumor necrosis factor (TNF)-α, interleukin-1, interleukin-6) causing alcoholic steatohepatitis. Treatment with probiotics has been shown to restore the intestinal microflora including Lactobacilli and Bifidobacteria, to reduce endotoxaemia, and to improve liver function.5–7
NAFLD and Nonalcoholic Steatohepatitis (NASH)
NAFLD, usually asymptomatic, is the most common liver disorder in western countries. It is defined as a chronic condition with >5% to 10% of liver augmented by extra fat. The prevalence of NAFLD is rapidly rising, and is becoming a worldwide public health problem.8 Studies have confirmed that NAFLD is associated with high body mass index, components of the metabolic syndrome, and insulin resistance. This disorder represents a spectrum of conditions ranging from fat accumulation alone (steatosis without inflammation) to NASH with macrovesicular steatosis in hepatocytes, associated with inflammation and fibrosis. NAFLD occurs among all ages, both the genders and various ethnic groups, and its prevalence is reported to be 14% to 30% of the general population.9 The prevalence of NAFLD is increasing as is the worldwide trend in obesity and type II diabetes. Among the general adult population, the prevalence is estimated to be 20% to 30%, 15%, and 10% to 40% in western countries,10 Asian countries11 and USA,12 respectively. The pathogenesis of NAFLD, and its development and progression to NASH remains to be determined. According to Day and James, the double “hit” theory can greatly explain the pathway and the mechanisms involved.13 At the “first hit,” the development of simple liver steatosis occurs and is accompanied with systemic factors. Obesity and insulin resistance has been known to have a pivotal role in this phase. Such damage would result in increase in vulnerability to fatty liver changes to subsequent inflammatory products such as bacterial lipopolysaccharide (LPS). The main factors contributing to initiation of the second hit are oxidative stress, subsequent lipid peroxidation, produced proinflammatory cytokines, such as TNF-α, and hormones secreted from adipose tissue. All these factors aggravate the transformation of NAFLD to NASH or even to cirrhosis. Currently, there is limited proven effective treatment for NASH. Since its underlying cause and its prognosis are not well understood, therapeutic modalities considered for patients with NAFLD has typically been focused on the management of associated conditions such as obesity, diabetes mellitus, and hyperlipidemia. The main treatment for NAFLD is lifestyle modification, including weight loss through a combination of decreased energy intake and increased energy expenditure. Recent studies have reported a possible impact of gut microflora overgrowth on the development of NAFLD and NASH.11 Several microbiota inhabit the human gut, and gut microflora have a dual impact on the liver function. The fermentation products such as ethanol, ammonia, and acetaldehyde produced by gut microflora are metabolized in the liver. Moreover, LPS from gram-negative gut microflora is continuously released after bacterial death as endotoxin and transported by a toll-like receptor 4 (TLR-4)-dependent process into intestinal capillaries. This induces cytokines formation and secretion from liver.14 It is suggested that liver injury and fibrosis could be partly caused by exposure to bacterial products such as LPS. TLR-4-bearing stellate cells respond to LPS, producing inflammatory cytokines and chemokines, but also promoting fibrosis. Further research supports the role of TLR-4 in promoting fibrosis. It has been shown that deficiency in myeloid differentiation factor-2, the coreceptor of TLR-4, and TLR-4 expression, may attenuate liver inflammation and fibrosis in mice affected by NASH. Therefore, the relation between gut microflora and NAFLD might be mostly because of the endogenous LPS. Gut microflora have important role in the host physiological function and metabolism through the following mechanism: conversion of procarcinogen into less harmful substances, production of vitamins, degradation of bile acid and cholesterol, as well as facilitating nutrient digestion, especially fermentation of nondigestible carbohydrates.15 Probiotics significantly improved the effect resulted from the cytokines signaling and led to improved insulin signaling.16 There is a suggestive evidence that probiotics might have some role in the treatment of patients with NAFLD by reducing liver transaminases, total cholesterol, TNF-α and improve insulin resistance,17 but more randomized control trials are needed.
The longstanding use of lactulose and more recently rifaximin (a nonabsorbable antibiotic) in the treatment of hepatic encephalopathy suggests involvement of gut microbiota in the management of chronic liver diseases.
Subclinical hepatic encephalopathy was first described in cirrhotic patients who by conventional neurological and mental status examination appeared normal but had abnormalities in psychometric tests. This condition is currently recognized as minimal hepatic encephalopathy (MHE), it is a part of spectrum along hepatic encephalopathy characterized by abnormalities in psychometric and neurophysiological tests without overt clinical symptoms.18 Incidence of MHE ranges from 30% to 84% in patients with chronic liver disease. MHE is an under diagnosed problem, but its effect on daily activities could be profound as it impairs attention span and reaction time. It has been shown that MHE impairs fitness to drive. Similar observations in this subpopulation of cirrhotics confirm that MHE is a strong predictor for traffic violations and accidents. Cirrhotic patients with MHE have poor health related quality of life and impaired daily functioning, and employability, as confirmed by lower scores on the sickness impact profile.
The major treatment modalities for MHE have been similar to that of obvious hepatic encephalopathy which focused on targeting ammonia production and absorption. As the gut microbiota play an important role in the production of ammonia, its modulation using probiotics has been evaluated by several studies as a therapeutic option for MHE which is reported in a recent metanalysis.19 The results of these studies favor the use of probiotics for MHE. This is not true in the case of overt hepatic encephalopathy as a Cochrane report on using of probiotics for hepatic encephalopathy has failed to show any evidence of improvement in clinically significant outcomes, although probiotics reduced plasma ammonia levels.20
PSC is an autoimmune liver disease which involves bile ducts in and out of the liver. Cholestatic features of bile ducts are a result from progressive obliterative fibrosis. Although a close association between PSC and inflammatory bowel disease has been reported, however, its pathogenesis remains unknown. Immune and nonimmune mechanisms are suggested for the pathogenesis of PSC.14 There is a substantial amount of evidence that the lymphocytes located in the gut play a critical role for emerging PSC. In contrast, bacteria residing in the gut may be a part of the cause of PSC through nonimmune routs.14 These microorganisms are able to release toxic compounds. As the administration of antibiotics is an appropriate treatment for some patients with PSC, there is a possibility indicating the role of bacterial flora together with intestinal inflammation in the pathogenesis of PSC.21
Few studies were performed to assess probiotic effects on toxicity of aflatoxin in liver dysfunction and HCC. Diminution of aflatoxin concentration was observed in fecal samples after the administration of Lactobacillus rhamnosus LC705 alone or in combination with Propionibacterium freudenreichii subsp. shermanii.14 In recent in vivo, gene expression changes induced by Lactobacillus rhamnosus was studied and Lactobacillus rhamnosus-GG GG consumption in rats exposed to aflatoxin.22 Concomitant with lowering of the c-myc, bcl2, cyclin D1 and rasp21 expression in treated rats compared with control group, the frequency of tumors in liver was alleviated.
A growing body of evidence suggests a relation between overgrowths of gut microbiota with pathogenesis of some chronic liver diseases. Various experimental studies and clinical trials revealed promising effects of probiotics in improving these diseases; however, given the limited specific strain efficacy and the relatively limited experience in this field, generalization of probiotics as treatment of such conditions needs more trials with large sample size and long-term follow up.
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