Nonalcoholic Fatty Liver Disease Is Exacerbated in High-Fat Diet-Fed Gnotobiotic Mice by Colonization with the Gut Microbiota from Patients with Nonalcoholic Steatohepatitis

Chiu, Chien Chao; Ching, Yung Hao; Li, Yen Peng; Liu, Ju Yun; Huang, Yen Te; Huang, Yi Wen; Yang, Shwu Huey; Huang, Wen Ching; Chuang, Hsiao-Li

doi:10.3390/nu9111220

Cited by 129 publications

(100 citation statements)

References 57 publications

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“…Importantly, LPS is known to leak through damaged intestinal epithelial barrier under inflammatory conditions 36 and circulate to the liver through the portal vein. This is accompanied by an increase in the levels of PPARγ [37][38][39] , causing obesity and metabolic diseases via an inflammatory immune response 40 . Importantly, the hepatic expression of PPARγ is highly associated with NAFLD in humans and experimental mouse models 41 .…”

Section: Discussionmentioning

confidence: 99%

Lactobacillus plantarum LMT1-48 exerts anti-obesity effect in high-fat diet-induced obese mice by regulating expression of lipogenic genes

Choi¹,

Dong²,

Jeong³

et al. 2020

Sci Rep

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Obesity is a major health problem and is known to be closely associated with metabolic diseases. Abnormal hepatic accumulation of fat causes fatty liver or hepatic steatosis, and long-term consumption of a high-fat diet is known to be a key obesity-causing factor. Recent studies have demonstrated that probiotics such as Lactobacillus strains, exert an anti-obesity effect by regulating adipogenesis. However, it is still unknown how the consumption of probiotics can reduce abdominal fat volume by regulating the hepatic expression of lipogenic genes. Therefore, we evaluated the effect of long-term ingestion of L. plantarum LMT1-48 on the expression of lipogenic genes in high-fat diet (HFD)-fed mice. We observed that treatment of 3T3-L1 adipocytes with L. plantarum LMT1-48 extract inhibited their differentiation and lipid accumulation by downregulating lipogenic genes, namely, PPARγ, C/EBPα, FAS, and FABP4. Interestingly, administration of L. plantarum LMT1-48 reduced liver weight and liver triglycerides concurrently with the downregulation of the lipogenic genes PPARγ, HSL, SCD-1, and FAT/CD36 in the liver, resulting in the reduction of body weight and fat volume in HFDfed obese mice. Notably, we also observed that the administration of at least 10 6 CFU of L. plantarum LMT1-48 significantly lowered body weight and abdominal fat volume in modified diet-fed mouse models. Collectively, these data suggest that L. plantarum LMT1-48 is a potential healthy food for obese people. Obesity is a major health problem and causes many diseases, including cardiovascular diseases, type 2 diabetes, and liver diseases 1,2. In particular, obesity is closely associated with abnormal accumulation of free fatty acids (FFA) in the liver, resulting in fatty liver or hepatic steatosis 3-5. Fatty liver is classified as microvesicular and macrovesicular fat through the histological accumulation of >5% triglycerides in hepatocytes 6. The major causes of fatty liver are related to drug use, metabolic syndrome, and alcohol consumption 7,8. Insulin resistance is the primary cause of metabolic disorders leading to fat accumulation. Insulin-suppressed hormone-sensitive lipases (HSLs) in adipocytes are activated due to insulin resistance, while triglycerides in adipocytes are released into the blood in the form of fatty acids. Free fatty acids released into the blood increase the fatty acid inflow into the liver, whereby hepatic fat accumulation increases. The mechanism underlying the development of nonalcoholic fatty liver is not fully understood yet, but hepatic fat accumulation is considered a feature of insulin resistance with abdominal obesity and is closely related to metabolic syndrome 9,10. Consequently, long-term consumption of high-fat enriched diets increases the body weight as well as hepatic fat accumulation and hepatic adipocyte proliferation in mammals, thereby leading to obesity 11,12. Interestingly, recent studies have demonstrated that human probiotic strains play an important role in modulating immune responses 13,14 and exert an...

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Section: Discussionmentioning

confidence: 99%

Lactobacillus plantarum LMT1-48 exerts anti-obesity effect in high-fat diet-induced obese mice by regulating expression of lipogenic genes

Choi¹,

Dong²,

Jeong³

et al. 2020

Sci Rep

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show abstract

“…The decisive role of microbiota in NAFLD development is further confirmed by a study where differences in microbiota composition between the NAFLD-resistant and NAFLDsusceptible phenotypes were identified (Le Roy et al, 2013). In another study, high-fat diet-fed germ-free mice inoculated with microbiota of NASH patients, rather than healthy donors, showed an exacerbated NASH phenotype, as manifested by increased liver steatosis and inflammation (Chiu et al, 2017). Further exciting evidence comes from recent studies using human donors.…”

Section: Causal Evidence To Microbiome Involvement In the Pathogenesimentioning

confidence: 99%

“…Furthermore, mice receiving microbiota from the same donor but after weight loss exhibit normal liver physiology (Wang et al, 2018). In another study, high-fat diet-fed germ-free mice inoculated with microbiota of NASH patients, rather than healthy donors, showed an exacerbated NASH phenotype, as manifested by increased liver steatosis and inflammation (Chiu et al, 2017). Based on these promising animal models, future studies are needed to establish a definite cause-effect link between dysbiosis and human NAFLD.…”

Section: Causal Evidence To Microbiome Involvement In the Pathogenesimentioning

confidence: 99%

The role of the microbiome in NAFLD and NASH

et al. 2018

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Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of cardiometabolic syndrome, which often also includes obesity, diabetes, and dyslipidemia. It is rapidly becoming the most prevalent liver disease worldwide. A sizable minority of NAFLD patients develop nonalcoholic steatohepatitis (NASH), which is characterized by inflammatory changes that can lead to progressive liver damage, cirrhosis, and hepatocellular carcinoma. Recent studies have shown that in addition to genetic predisposition and diet, the gut microbiota affects hepatic carbohydrate and lipid metabolism as well as influences the balance between pro‐inflammatory and anti‐inflammatory effectors in the liver, thereby impacting NAFLD and its progression to NASH. In this review, we will explore the impact of gut microbiota and microbiota‐derived compounds on the development and progression of NAFLD and NASH, and the unexplored factors related to potential microbiome contributions to this common liver disease.

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“…Co-housing inflammasome-deficient mice with wild-type mice increased the susceptibility of wild-type mice to NASH, so fatty liver risk might be affected by the surrounding faecal microbiota 11. Moreover, epididymal fat weight, hepatic steatosis, multifocal necrosis and infiltration of liver by inflammatory cells were significantly increased in germ-free mice colonised with faeces from patients with NASH and then fed a high-fat diet (HFD) 12. These results indicate that risk of NAFL and NASH can be transmitted, apparently by the faecal microbiota.…”

Section: Introductionmentioning

confidence: 99%

Small metabolites, possible big changes: a microbiota-centered view of non-alcoholic fatty liver disease

Chu

Duan

Yang

et al. 2018

Gut

257

217

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The spectrum of non-alcoholic fatty liver disease (NAFLD) ranges from simple hepatic steatosis, commonly associated with obesity, to non-alcoholic steatohepatitis, which can progress to fibrosis, cirrhosis and hepatocellular carcinoma. NAFLD pathophysiology involves environmental, genetic and metabolic factors, as well as changes in the intestinal microbiota and their products. Dysfunction of the intestinal barrier can contribute to NAFLD development and progression. Although there are technical limitations in assessing intestinal permeability in humans and the number of patients in these studies is rather small, fewer than half of the patients have increased intestinal permeability and translocation of bacterial products. Microbe-derived metabolites and the signalling pathways they affect might play more important roles in development of NAFLD. We review the microbial metabolites that contribute to the development of NAFLD, such as trimethylamine, bile acids, short-chain fatty acids and ethanol. We discuss the mechanisms by which metabolites produced by microbes might affect disease progression and/or serve as therapeutic targets or biomarkers for NAFLD.

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Nonalcoholic Fatty Liver Disease Is Exacerbated in High-Fat Diet-Fed Gnotobiotic Mice by Colonization with the Gut Microbiota from Patients with Nonalcoholic Steatohepatitis

Cited by 129 publications

References 57 publications

Lactobacillus plantarum LMT1-48 exerts anti-obesity effect in high-fat diet-induced obese mice by regulating expression of lipogenic genes

Lactobacillus plantarum LMT1-48 exerts anti-obesity effect in high-fat diet-induced obese mice by regulating expression of lipogenic genes

The role of the microbiome in NAFLD and NASH

Small metabolites, possible big changes: a microbiota-centered view of non-alcoholic fatty liver disease

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