Gut Microbial Metabolism and Nonalcoholic Fatty Liver Disease

Sharpton, Suzanne R.; Yong, Germaine Jia Min; Terrault, Norah A.; Lynch, Susan V.

doi:10.1002/hep4.1284

Cited by 29 publications

(32 citation statements)

References 143 publications

(299 reference statements)

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“…Beyond diet, the gut microbiome has also been implicated in the pathology of obese-associated fatty liver, particularly via modulation of bile acids (5,19). Synthesized within the liver, bile acids are secreted in the small intestine.…”

Section: Discussionmentioning

confidence: 99%

“…Both undernutrition and gut microbes shape health trajectories, including systemic metabolic activity (12,13,16). Indeed, the gut microbiome has been implicated in fatty liver as changes in microbial composition and function, notably alterations of bacterium-mediated bile acid metabolism, have been reported in obese-associated NAFLD (5,19). However, the precise influence of fecal-oral contamination on the etiology, pathology, and persistence of undernutrition-triggered fatty liver remains largely unexplored.…”

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confidence: 99%

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Dietary Intervention Reverses Fatty Liver and Altered Gut Microbiota during Early-Life Undernutrition

et al. 2020

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Nonalcoholic fatty liver disease (NAFLD), largely studied as a condition of overnutrition, also presents in undernourished populations. Like NAFLD, undernutrition disrupts systemic metabolism and has been linked to gut microbiota dysbiosis. Indeed, chronic exposures to fecal microbes contribute to undernutrition pathology in regions with poor sanitation. Despite a growing prevalence of fatty liver disease, the influence of undernutrition and the gut microbiota remain largely unexplored. Here, we utilize an established murine model (C57BL/6J mice placed on a malnourished diet that received iterative Escherichia coli/Bacteroidales gavage [MBG mice]) that combines a protein/fat-deficient diet and iterative exposure to specific, fecal microbes. Fecal-oral contamination exacerbates triglyceride accumulation in undernourished mice. MBG livers exhibit diffuse lipidosis accompanied by striking shifts in fatty acid, glycerophospholipid, and retinol metabolism. Multiomic analyses revealed metabolomic pathways linked to the undernourished gut microbiome and hepatic steatosis, including phenylacetate metabolism. Intriguingly, fatty liver features were observed only in the early-life, but not adult, MBG model despite similar liver metabolomic profiles. Importantly, we demonstrate that dietary intervention largely mitigates aberrant metabolomic and microbiome features in MBG mice. These findings indicate a crucial window in early-life development that, when disrupted by nutritional deficiency, may significantly influence liver function. Our work provides a multifaceted study of how diet and gut microbes inform fatty liver progression and reversal during undernutrition. IMPORTANCE Nonalcoholic fatty liver disease (NAFLD) remains a global epidemic, but it is often studied in the context of obesity and aging. Nutritional deficits, however, also trigger hepatic steatosis, influencing health trajectories in undernourished pediatric populations. Here, we report that exposure to specific gut microbes impacts fatty liver pathology in mice fed a protein/fat-deficient diet. We utilize a multiomics approach to (i) characterize NAFLD in the context of early undernutrition and (ii) examine the impact of diet and gut microbes in the pathology and reversal of hepatic steatosis. We provide compelling evidence that an early-life, critical development window facilitates undernutrition-induced fatty liver pathology. Moreover, we demonstrate that sustained dietary intervention largely reverses fatty liver features and microbiome shifts observed during early-life malnutrition.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Dietary Intervention Reverses Fatty Liver and Altered Gut Microbiota during Early-Life Undernutrition

et al. 2020

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“…The role of the intestinal microflora, the microbiome, has taken a center stage as a co-pathogenic mechanism in many diseases and is discussed later [53][54][55][56][57]. Both temperature and latitude itself have been suggested to alter the microbiome.…”

Section: Other Possible Effects Of Latitudementioning

confidence: 99%

“…Whether low-grade inflammatory response in the obese host promotes intestinal microbiome changes or bacterial alterations promote obesity is still unclear although lean/ obese bacterial differences are discernable and fecal transplant from obese animal models can induce obesity [55,84,85]. Similarly, in IBD, the intestinal microbiome reflects or plays a pathogenic role in disease causation.…”

Section: Microbiome Effectsmentioning

confidence: 99%

Relationship(s) between obesity and inflammatory bowel diseases: possible intertwined pathogenic mechanisms

Szilagyi

2019

Clin J Gastroenterol

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The inflammatory bowel diseases, Crohn's and ulcerative colitis have increased in incidence and prevalence from the mideighteen to the late nineteen centuries. From then to the current twenty-first century there has been a more rapid expansion of these disease to areas previously experiencing low rates. This latter expansion coincides with the current obesity pandemic which also began toward the end of the last century. Although the two diseases have radically different frequencies, there are interesting links between them. Four areas link the diseases. On an epidemiological level, IBD tends to follow a northsouth gradient raising the importance of vitamin D in protection. Obesity has very weak relationship with latitude, but both diseases follow adult lactase distributions colliding in this plane. Is it possible that obesity (a low vitamin D condition with questionable response to supplements) reduces effects in IBD? On a pathogenic level, pro-inflammatory processes mark both IBD and obesity. The similarity raises the question of whether obesity could facilitate the development of IBD. Features of the metabolic syndrome occur in both, with or without obesity in IBD. The fourth interaction between the two diseases is the apparent effect of obesity on the course of IBD. There are suggestions that obesity may reduce the efficacy of biologic agents. Yet there is some suggestion also that obesity may reduce the need for hospitalization and surgery. The apparent co-expansion of both obesity and IBD suggests similar environmental changes may be involved in the promotion of both.

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“…Through reabsorption and distribution, SCFA can affect intestinal barrier health, which is very important in the pathogenesis of NAFLD. Destruction of the gut barrier has been associated with the translocation of lipopolysaccharides (LPS), leading to endotoxemia that drives NAFLD progression [34]. SCFAs, mainly butyrate and propionate, reduce gut inflammation and preserve gut barrier integrity, potentially limiting the translocation of LPS [35].…”

Section: Discussionmentioning

confidence: 99%

Gut microbiota and butyrate contribute to nonalcoholic fatty liver disease in premenopause due to estrogen deficiency

Liu

Qingsong

et al. 2020

Preprint

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Background：The incidence of nonalcoholic fatty liver disease (NAFLD) in postmenopausal women has increased significantly. NAFLD can be effectively inhibited by estrogen, but the severe side effects, especially the increased risk of malignant tumors, limit its application. Thus, it is of great clinical significance to explore the mechanism by which estrogen inhibits NAFLD. Gut microbiota and its metabolites short chain fatty acids (SCFA) have been shown to play important roles in the development of NAFLD.Objective：In this study, we investigated the impact of estrogen deficiency on the gut microbiome and SCFA in both NAFLD patients and an experimental NAFLD model in premenopause.Methods：The levels of estrogen，insulin and leptin was measured using ELISA. Gut microbiota was analyzed by 16S rRNA gene sequence analysis. Tissue sections were stained with hematoxylin and eosin. SCFAs were determined with Agilent 6890 N gas chromatography (GC). We quantified mRNA levels of genes in our study by quantitative real time-PCR. Additionally, Western Blotting was used to validate protein expression.Results：We showed that female NAFLD patients had much lower estrogen levels. Estrogen deficient mice, due to ovariectomy (OVX), suffered more severe liver steatosis with an elevated body weight, abdominal fat weight, and serum triglycerides with deterioration in histological hepatic steatosis. Altered gut microbiota composition and decreased butyrate content were found in patients with NAFLD and in OVX mice. Furthermore, fecal microbiota transplantation (FMT) or supplementing with butyrate markedly alleviated NAFLD in OVX mice. The production of antimicrobial peptides (AMP) RegIIIg, β-defensins 1, 3 and the expression of intestinal epithelial tight junction, including ZO-1 and occludin5, were decreased in the OVX mice compared to control mice. Upregulation of PPAR-ɣ and VLDLR and downregulation of PPAR-ɑ indicated that OVX mice suffered from abnormal lipid metabolism.Conclusions：These data indicate that changes in the gut microbiota and SCFA caused by estrogen reduction, together with a disorder in AMP production and lipid metabolism, promote NAFLD, thus provide microbiota derived SCFAs as new therapeutic targets for the clinical prevention and treatment of NAFLD.

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Gut Microbial Metabolism and Nonalcoholic Fatty Liver Disease

Cited by 29 publications

References 143 publications

Dietary Intervention Reverses Fatty Liver and Altered Gut Microbiota during Early-Life Undernutrition

Dietary Intervention Reverses Fatty Liver and Altered Gut Microbiota during Early-Life Undernutrition

Relationship(s) between obesity and inflammatory bowel diseases: possible intertwined pathogenic mechanisms

Gut microbiota and butyrate contribute to nonalcoholic fatty liver disease in premenopause due to estrogen deficiency

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