Probiotics as a complementary therapeutic approach in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD) is currently recognized as one of the most common causes of chronic liver disease. It involves a spectrum of conditionsthat include pure steatosis without inflammation, steatohepatitis, fibrosis and cirrhosis. The key factor in the pathophysiology of NAFLD is insulin resistance that determines lipid accumulation in the hepatocytes and, thus, oxidative stress, which is followed by inflammatory response. However, NAFLD pathogenesis is still largely unknown and has been extensively investigated. Although life style modification with the aim of losing weight has been advocated to treat this disorder, its effectiveness is limited; additionally, there is no specific pharmacologic treatment until nowadays. Recent evidence suggests that the gut microbiota may play a role in the development of insulin resistance, hepatic steatosis, necroinflammation and fibrosis. Differences in gut microbiota between NAFLD patients and lean individuals as well as presence of small intestinal bacterial overgrowth in NAFLD subjects have been demonstrated. Furthermore, some data indicate that the immunoregulatory effects of probiotics may be beneficial in NAFLD treatment as they modulate the intestinal microbiota; improve epithelial barrier function and strengthen the intestinal wall decreasing its permeability; reduce bacterial translocation and endotoxemia; improve intestinal inflammation; and reduce oxidative and inflammatory liver damage. In this article, we review the clinical trials on the use of probiotics in the treatment of NAFLD and discuss the effects of these agents and their efficacy as an emerging therapeutic resource to treat NAFLD patients.

PNPLA3 and TM6SF2 polymorphisms in Brazilian patients with nonalcoholic fatty liver disease

BACKGROUND Nonalcoholic fatty liver disease(NAFLD)is becoming the most common chronic liver disease worldwide,with significant morbidity associated with nonalcoholic steatohepatitis(NASH).Genome-wide association studies demonstrated that the variants rs738409 C/G in the PNPLA3 and rs58542926 C/T in the TM6SF2 genes are determinants of inter-individual and ethnicity-related differences in hepatic fat content and NAFLD progression.AIM To investigate PNPLA3 and TM6SF2 genotype frequency and their association with NAFLD development and progression in Brazilian patients.METHODS This cross-sectional case-control study enrolled 285 individuals from the Gastroenterology and Hepatology clinics at a university hospital in Brazil.The case patients(n=148)were confirmed to have NAFLD by the identification of hepatic steatosis on ultrasonography and exclusion of other causes of liver disease.According to the clinical protocol,patients underwent liver biopsy when at high risk for NASH and/or advanced fibrosis(n=65).Steatohepatitis was confirmed in 54 patients.Individuals who did not have biopsy indication or NASH on histology were considered to have simple steatosis(n=94).The control group(n=137)was selected among patients that attended the Intestinal Disease clinic and was composed of subjects without abnormalities on abdominal ultrasonography and normal liver biochemical tests.All individuals underwent PNPLA3 and TM6SF2 genotype analysis.RESULTS PNPLA3 CC,CG and GG genotype frequencies were 37%,44%and 19%,respectively,in NAFLD patients and were 58%,31%and 10%in controls(P<0.001).In a model adjusted for gender,age,body mass index and type 2 diabetes mellitus,the G allele increased the chance of NAFLD(OR=1.69,95%CI:1.21-2.36,P=0.002)and NASH(OR=3.50,95%CI:1.84-6.64,P<0.001).The chance of NASH was even higher with GG homozygosis(OR=5.53,95%CI:2.04-14.92,P=0.001).No association was found between G allele and the features of metabolic syndrome.In histological assessment,PNPLA3 genotype was not associated with steatosis grade,although GG homozygosis increased the chance of significant NASH activity(OR=17.11,95%CI:1.87-156.25,P=0.01)and fibrosis(OR=7.42,95%CI:1.55-34.47,P=0.01)in the same adjusted model.TM6SF2 CC,CT and TT genotype frequencies were 83%,15%and 0.7%,respectively,in NAFLD patients and were 84%,16%and 0.7%in controls(P=0.78).The T allele presence was not associated with NAFLD or NASH,and was not associated with histological features.CONCLUSION PNPLA3 may be involved in susceptibility and progression of NAFLD and NASH in the Brazilian population.More advanced histological liver disease was associated with the G allele.The TM6SF2 genetic variants were not associated with NAFLD susceptibility and progressive histological forms in the population studied,but further studies are required to confirm these findings.