Gut microbiota-mediated generation of saturated fatty acids elicits inflammation in the liver in murine high-fat diet-induced steatohepatitis

Shoji Yamada, Nobuhiko Kamada, Takeru Amiya, Nobuhiro Nakamoto, Toshiaki Nakaoka, Masaki Kimura, Yoshimasa Saito, Chieko Ejima, Takanori Kanai, Hidetsugu Saito

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background: The gut microbiota plays crucial roles in the development of non-alcoholic steatohepatitis (NASH). However, the precise mechanisms by which alterations of the gut microbiota and its metabolism contributing to the pathogenesis of NASH are not yet fully elucidated. Methods: Mice were fed with a recently reported new class of high-fat diet (HFD), steatohepatitis-inducing HFD (STHD)-01 for 9weeks. The composition of the gut microbiota was analyzed by T-RFLP. Luminal metabolome was analyzed using capillary electrophoresis and liquid chromatography time-of-flight mass spectrometry (CE- and LC-TOFMS). Results: Mice fed the STHD-01 developed NASH-like pathology within a short period. Treatment with antibiotics prevented the development of NASH by STHD-01. The composition of the gut microbiota and its metabolic activities were markedly perturbed in the STHD-01-fed mice, and antibiotic administration normalized these changes. We identified that long-chain saturated fatty acid and n-6 fatty acid metabolic pathways were significantly altered by STHD-01. Of note, the changes in gut lipidome caused by STHD-01 were mediated by gut microbiota, as the depletion of the gut microbiota could reverse the perturbation of these metabolic pathways. A saturated long-chain fatty acid, palmitic acid, which accumulated in the STHD-01 group, activated liver macrophages and promoted TNF-α expression. Conclusions: Lipid metabolism by the gut microbiota, particularly the saturation of fatty acids, affects fat accumulation in the liver and subsequent liver inflammation in NASH.

Original languageEnglish
Article number136
JournalBMC Gastroenterology
Volume17
Issue number1
DOIs
Publication statusPublished - 2017 Nov 29

Fingerprint

High Fat Diet
Fatty Liver
Fatty Acids
Inflammation
Liver
Metabolic Networks and Pathways
Gastrointestinal Microbiome
Anti-Bacterial Agents
Metabolome
Palmitic Acid
Capillary Electrophoresis
Lipid Metabolism
Liquid Chromatography
Restriction Fragment Length Polymorphisms
Mass Spectrometry
Fats
Macrophages
Pathology

Keywords

  • Fat accumulation
  • Fat transportation
  • Gut microbiota
  • Long-chain saturated fatty acids
  • Non-alcoholic steatohepatitis

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Gut microbiota-mediated generation of saturated fatty acids elicits inflammation in the liver in murine high-fat diet-induced steatohepatitis. / Yamada, Shoji; Kamada, Nobuhiko; Amiya, Takeru; Nakamoto, Nobuhiro; Nakaoka, Toshiaki; Kimura, Masaki; Saito, Yoshimasa; Ejima, Chieko; Kanai, Takanori; Saito, Hidetsugu.

In: BMC Gastroenterology, Vol. 17, No. 1, 136, 29.11.2017.

Research output: Contribution to journalArticle

@article{49ffa8e62c7245c085cebcf02b64df4f,
title = "Gut microbiota-mediated generation of saturated fatty acids elicits inflammation in the liver in murine high-fat diet-induced steatohepatitis",
abstract = "Background: The gut microbiota plays crucial roles in the development of non-alcoholic steatohepatitis (NASH). However, the precise mechanisms by which alterations of the gut microbiota and its metabolism contributing to the pathogenesis of NASH are not yet fully elucidated. Methods: Mice were fed with a recently reported new class of high-fat diet (HFD), steatohepatitis-inducing HFD (STHD)-01 for 9weeks. The composition of the gut microbiota was analyzed by T-RFLP. Luminal metabolome was analyzed using capillary electrophoresis and liquid chromatography time-of-flight mass spectrometry (CE- and LC-TOFMS). Results: Mice fed the STHD-01 developed NASH-like pathology within a short period. Treatment with antibiotics prevented the development of NASH by STHD-01. The composition of the gut microbiota and its metabolic activities were markedly perturbed in the STHD-01-fed mice, and antibiotic administration normalized these changes. We identified that long-chain saturated fatty acid and n-6 fatty acid metabolic pathways were significantly altered by STHD-01. Of note, the changes in gut lipidome caused by STHD-01 were mediated by gut microbiota, as the depletion of the gut microbiota could reverse the perturbation of these metabolic pathways. A saturated long-chain fatty acid, palmitic acid, which accumulated in the STHD-01 group, activated liver macrophages and promoted TNF-α expression. Conclusions: Lipid metabolism by the gut microbiota, particularly the saturation of fatty acids, affects fat accumulation in the liver and subsequent liver inflammation in NASH.",
keywords = "Fat accumulation, Fat transportation, Gut microbiota, Long-chain saturated fatty acids, Non-alcoholic steatohepatitis",
author = "Shoji Yamada and Nobuhiko Kamada and Takeru Amiya and Nobuhiro Nakamoto and Toshiaki Nakaoka and Masaki Kimura and Yoshimasa Saito and Chieko Ejima and Takanori Kanai and Hidetsugu Saito",
year = "2017",
month = "11",
day = "29",
doi = "10.1186/s12876-017-0689-3",
language = "English",
volume = "17",
journal = "BMC Gastroenterology",
issn = "1471-230X",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Gut microbiota-mediated generation of saturated fatty acids elicits inflammation in the liver in murine high-fat diet-induced steatohepatitis

AU - Yamada, Shoji

AU - Kamada, Nobuhiko

AU - Amiya, Takeru

AU - Nakamoto, Nobuhiro

AU - Nakaoka, Toshiaki

AU - Kimura, Masaki

AU - Saito, Yoshimasa

AU - Ejima, Chieko

AU - Kanai, Takanori

AU - Saito, Hidetsugu

PY - 2017/11/29

Y1 - 2017/11/29

N2 - Background: The gut microbiota plays crucial roles in the development of non-alcoholic steatohepatitis (NASH). However, the precise mechanisms by which alterations of the gut microbiota and its metabolism contributing to the pathogenesis of NASH are not yet fully elucidated. Methods: Mice were fed with a recently reported new class of high-fat diet (HFD), steatohepatitis-inducing HFD (STHD)-01 for 9weeks. The composition of the gut microbiota was analyzed by T-RFLP. Luminal metabolome was analyzed using capillary electrophoresis and liquid chromatography time-of-flight mass spectrometry (CE- and LC-TOFMS). Results: Mice fed the STHD-01 developed NASH-like pathology within a short period. Treatment with antibiotics prevented the development of NASH by STHD-01. The composition of the gut microbiota and its metabolic activities were markedly perturbed in the STHD-01-fed mice, and antibiotic administration normalized these changes. We identified that long-chain saturated fatty acid and n-6 fatty acid metabolic pathways were significantly altered by STHD-01. Of note, the changes in gut lipidome caused by STHD-01 were mediated by gut microbiota, as the depletion of the gut microbiota could reverse the perturbation of these metabolic pathways. A saturated long-chain fatty acid, palmitic acid, which accumulated in the STHD-01 group, activated liver macrophages and promoted TNF-α expression. Conclusions: Lipid metabolism by the gut microbiota, particularly the saturation of fatty acids, affects fat accumulation in the liver and subsequent liver inflammation in NASH.

AB - Background: The gut microbiota plays crucial roles in the development of non-alcoholic steatohepatitis (NASH). However, the precise mechanisms by which alterations of the gut microbiota and its metabolism contributing to the pathogenesis of NASH are not yet fully elucidated. Methods: Mice were fed with a recently reported new class of high-fat diet (HFD), steatohepatitis-inducing HFD (STHD)-01 for 9weeks. The composition of the gut microbiota was analyzed by T-RFLP. Luminal metabolome was analyzed using capillary electrophoresis and liquid chromatography time-of-flight mass spectrometry (CE- and LC-TOFMS). Results: Mice fed the STHD-01 developed NASH-like pathology within a short period. Treatment with antibiotics prevented the development of NASH by STHD-01. The composition of the gut microbiota and its metabolic activities were markedly perturbed in the STHD-01-fed mice, and antibiotic administration normalized these changes. We identified that long-chain saturated fatty acid and n-6 fatty acid metabolic pathways were significantly altered by STHD-01. Of note, the changes in gut lipidome caused by STHD-01 were mediated by gut microbiota, as the depletion of the gut microbiota could reverse the perturbation of these metabolic pathways. A saturated long-chain fatty acid, palmitic acid, which accumulated in the STHD-01 group, activated liver macrophages and promoted TNF-α expression. Conclusions: Lipid metabolism by the gut microbiota, particularly the saturation of fatty acids, affects fat accumulation in the liver and subsequent liver inflammation in NASH.

KW - Fat accumulation

KW - Fat transportation

KW - Gut microbiota

KW - Long-chain saturated fatty acids

KW - Non-alcoholic steatohepatitis

UR - http://www.scopus.com/inward/record.url?scp=85035339275&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85035339275&partnerID=8YFLogxK

U2 - 10.1186/s12876-017-0689-3

DO - 10.1186/s12876-017-0689-3

M3 - Article

C2 - 29187142

AN - SCOPUS:85035339275

VL - 17

JO - BMC Gastroenterology

JF - BMC Gastroenterology

SN - 1471-230X

IS - 1

M1 - 136

ER -