Modulation of the gut microbiota impacts nonalcoholic fatty liver disease: a potential role for bile acids

Aafke W.F. Janssen, Tom Houben, Saeed Katiraei, Wieneke Dijk, Lily Boutens, Nieke van der Bolt, Zeneng Wang, J.M. Brown, Stanley L. Hazen, Stéphane Mandard, Ronit Shiri-Sverdlov, Folkert Kuipers, Ko Willems van Dijk, Jacques Vervoort, Rinke Stienstra, Guido J.E.J. Hooiveld, Sander Kersten

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Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, yet the pathogenesis of NAFLD is only partially understood. Here, we investigated the role of the gut bacteria in NAFLD by stimulating the gut bacteria via feeding mice the fermentable dietary fiber, guar gum (GG), and suppressing the gut bacteria via chronic oral administration of antibiotics. GG feeding profoundly altered the gut microbiota composition, in parallel with reduced diet-induced obesity and improved glucose tolerance. Strikingly, despite reducing adipose tissue mass and inflammation, GG enhanced hepatic inflammation and fibrosis, concurrent with markedly elevated plasma and hepatic bile acid levels. Consistent with a role of elevated bile acids in the liver phenotype, treatment of mice with taurocholic acid stimulated hepatic inflammation and fibrosis. In contrast to GG, chronic oral administration of antibiotics effectively suppressed the gut bacteria, decreased portal secondary bile acid levels, and attenuated hepatic inflammation and fibrosis. Neither GG nor antibiotics influenced plasma lipopolysaccharide levels. In conclusion, our data indicate a causal link between changes in gut microbiota and hepatic inflammation and fibrosis in a mouse model of NAFLD, possibly via alterations in bile acids.
Original languageEnglish
Pages (from-to)1399-1416
JournalJournal of Lipid Research
Volume58
Issue number7
DOIs
Publication statusPublished - 2017

Fingerprint

guar gum
Bile Acids and Salts
Liver
Modulation
Inflammation
Bacteria
Fibrosis
Anti-Bacterial Agents
Oral Administration
Plasmas
Taurocholic Acid
Dietary Fiber
Nutrition
Lipopolysaccharides
Non-alcoholic Fatty Liver Disease
Gastrointestinal Microbiome
Adipose Tissue
Liver Diseases
Obesity
Tissue

Cite this

Janssen, Aafke W.F. ; Houben, Tom ; Katiraei, Saeed ; Dijk, Wieneke ; Boutens, Lily ; van der Bolt, Nieke ; Wang, Zeneng ; Brown, J.M. ; Hazen, Stanley L. ; Mandard, Stéphane ; Shiri-Sverdlov, Ronit ; Kuipers, Folkert ; Willems van Dijk, Ko ; Vervoort, Jacques ; Stienstra, Rinke ; Hooiveld, Guido J.E.J. ; Kersten, Sander. / Modulation of the gut microbiota impacts nonalcoholic fatty liver disease: a potential role for bile acids. In: Journal of Lipid Research. 2017 ; Vol. 58, No. 7. pp. 1399-1416.
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title = "Modulation of the gut microbiota impacts nonalcoholic fatty liver disease: a potential role for bile acids",
abstract = "Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, yet the pathogenesis of NAFLD is only partially understood. Here, we investigated the role of the gut bacteria in NAFLD by stimulating the gut bacteria via feeding mice the fermentable dietary fiber, guar gum (GG), and suppressing the gut bacteria via chronic oral administration of antibiotics. GG feeding profoundly altered the gut microbiota composition, in parallel with reduced diet-induced obesity and improved glucose tolerance. Strikingly, despite reducing adipose tissue mass and inflammation, GG enhanced hepatic inflammation and fibrosis, concurrent with markedly elevated plasma and hepatic bile acid levels. Consistent with a role of elevated bile acids in the liver phenotype, treatment of mice with taurocholic acid stimulated hepatic inflammation and fibrosis. In contrast to GG, chronic oral administration of antibiotics effectively suppressed the gut bacteria, decreased portal secondary bile acid levels, and attenuated hepatic inflammation and fibrosis. Neither GG nor antibiotics influenced plasma lipopolysaccharide levels. In conclusion, our data indicate a causal link between changes in gut microbiota and hepatic inflammation and fibrosis in a mouse model of NAFLD, possibly via alterations in bile acids.",
author = "Janssen, {Aafke W.F.} and Tom Houben and Saeed Katiraei and Wieneke Dijk and Lily Boutens and {van der Bolt}, Nieke and Zeneng Wang and J.M. Brown and Hazen, {Stanley L.} and St{\'e}phane Mandard and Ronit Shiri-Sverdlov and Folkert Kuipers and {Willems van Dijk}, Ko and Jacques Vervoort and Rinke Stienstra and Hooiveld, {Guido J.E.J.} and Sander Kersten",
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Janssen, AWF, Houben, T, Katiraei, S, Dijk, W, Boutens, L, van der Bolt, N, Wang, Z, Brown, JM, Hazen, SL, Mandard, S, Shiri-Sverdlov, R, Kuipers, F, Willems van Dijk, K, Vervoort, J, Stienstra, R, Hooiveld, GJEJ & Kersten, S 2017, 'Modulation of the gut microbiota impacts nonalcoholic fatty liver disease: a potential role for bile acids', Journal of Lipid Research, vol. 58, no. 7, pp. 1399-1416. https://doi.org/10.1194/jlr.M075713

Modulation of the gut microbiota impacts nonalcoholic fatty liver disease: a potential role for bile acids. / Janssen, Aafke W.F.; Houben, Tom; Katiraei, Saeed; Dijk, Wieneke; Boutens, Lily; van der Bolt, Nieke; Wang, Zeneng; Brown, J.M.; Hazen, Stanley L.; Mandard, Stéphane; Shiri-Sverdlov, Ronit; Kuipers, Folkert; Willems van Dijk, Ko; Vervoort, Jacques; Stienstra, Rinke; Hooiveld, Guido J.E.J.; Kersten, Sander.

In: Journal of Lipid Research, Vol. 58, No. 7, 2017, p. 1399-1416.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Modulation of the gut microbiota impacts nonalcoholic fatty liver disease: a potential role for bile acids

AU - Janssen, Aafke W.F.

AU - Houben, Tom

AU - Katiraei, Saeed

AU - Dijk, Wieneke

AU - Boutens, Lily

AU - van der Bolt, Nieke

AU - Wang, Zeneng

AU - Brown, J.M.

AU - Hazen, Stanley L.

AU - Mandard, Stéphane

AU - Shiri-Sverdlov, Ronit

AU - Kuipers, Folkert

AU - Willems van Dijk, Ko

AU - Vervoort, Jacques

AU - Stienstra, Rinke

AU - Hooiveld, Guido J.E.J.

AU - Kersten, Sander

PY - 2017

Y1 - 2017

N2 - Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, yet the pathogenesis of NAFLD is only partially understood. Here, we investigated the role of the gut bacteria in NAFLD by stimulating the gut bacteria via feeding mice the fermentable dietary fiber, guar gum (GG), and suppressing the gut bacteria via chronic oral administration of antibiotics. GG feeding profoundly altered the gut microbiota composition, in parallel with reduced diet-induced obesity and improved glucose tolerance. Strikingly, despite reducing adipose tissue mass and inflammation, GG enhanced hepatic inflammation and fibrosis, concurrent with markedly elevated plasma and hepatic bile acid levels. Consistent with a role of elevated bile acids in the liver phenotype, treatment of mice with taurocholic acid stimulated hepatic inflammation and fibrosis. In contrast to GG, chronic oral administration of antibiotics effectively suppressed the gut bacteria, decreased portal secondary bile acid levels, and attenuated hepatic inflammation and fibrosis. Neither GG nor antibiotics influenced plasma lipopolysaccharide levels. In conclusion, our data indicate a causal link between changes in gut microbiota and hepatic inflammation and fibrosis in a mouse model of NAFLD, possibly via alterations in bile acids.

AB - Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, yet the pathogenesis of NAFLD is only partially understood. Here, we investigated the role of the gut bacteria in NAFLD by stimulating the gut bacteria via feeding mice the fermentable dietary fiber, guar gum (GG), and suppressing the gut bacteria via chronic oral administration of antibiotics. GG feeding profoundly altered the gut microbiota composition, in parallel with reduced diet-induced obesity and improved glucose tolerance. Strikingly, despite reducing adipose tissue mass and inflammation, GG enhanced hepatic inflammation and fibrosis, concurrent with markedly elevated plasma and hepatic bile acid levels. Consistent with a role of elevated bile acids in the liver phenotype, treatment of mice with taurocholic acid stimulated hepatic inflammation and fibrosis. In contrast to GG, chronic oral administration of antibiotics effectively suppressed the gut bacteria, decreased portal secondary bile acid levels, and attenuated hepatic inflammation and fibrosis. Neither GG nor antibiotics influenced plasma lipopolysaccharide levels. In conclusion, our data indicate a causal link between changes in gut microbiota and hepatic inflammation and fibrosis in a mouse model of NAFLD, possibly via alterations in bile acids.

U2 - 10.1194/jlr.M075713

DO - 10.1194/jlr.M075713

M3 - Article

VL - 58

SP - 1399

EP - 1416

JO - Journal of Lipid Research

JF - Journal of Lipid Research

SN - 0022-2275

IS - 7

ER -