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. 2021 Aug 31;12(4):e0115521.
doi: 10.1128/mBio.01155-21. Epub 2021 Jul 6.

Ileal Bile Acid Transporter Inhibitor Improves Hepatic Steatosis by Ameliorating Gut Microbiota Dysbiosis in NAFLD Model Mice

Masahiro Matsui  1 , Shinya Fukunishi  1 , Takashi Nakano  2 , Takaaki Ueno  3 , Kazuhide Higuchi  1 , Akira Asai  1
Affiliations

Ileal Bile Acid Transporter Inhibitor Improves Hepatic Steatosis by Ameliorating Gut Microbiota Dysbiosis in NAFLD Model Mice

Masahiro Matsui et al. mBio. .

Abstract

Nonalcoholic fatty liver disease (NAFLD), characterized by excessive fat deposition in the liver unrelated to alcohol consumption, is highly prevalent worldwide. However, effective therapeutic agents approved for NAFLD treatment are lacking. An ileal bile acid transporter inhibitor (IBATi), which represents a new mode of treatment of chronic idiopathic constipation, leads to increased delivery of bile acids to the colon. We investigated the effect of IBATi against NAFLD through modification of the gut microbiota in mice. IBATi treatment significantly suppressed body weight gain, liver dysfunction, and serum low-density lipoprotein levels and significantly decreased NAFLD activity scores in high-fat diet (HFD) mice. Treatment with IBATi ameliorated the decreased hepatic cholesterol 7-a-monooxygenase (Cyp7a1) and increased ileal fibroblast growth factor 15 (Fgf15) mRNA expression in HFD mice. Further, IBATi treatment changed the α-diversity in the gut microbiota reduced by HFD, which was analyzed in feces using 16S rRNA sequencing. To establish the mechanism underlying improvement in NAFLD induced by IBATi, we recolonized antibiotic solution-treated mice by fecal microbiome transplantation (FMT) using stool from HFD or HFD plus IBATi mice. This is the first report that fecally transplanted gut microbiota from HFD plus IBATi mice prevented hepatic steatosis caused by HFD. In conclusion, IBATi improved hepatic steatosis by ameliorating gut microbiota dysbiosis in NAFLD model mice, suggesting a potential therapeutic agent for NAFLD treatment. IMPORTANCE NAFLD is an increasingly recognized condition that may progress to liver cirrhosis and hepatocellular carcinoma, and community surveys have assessed that the prevalence is 14 to 32% worldwide. The first line of treatment for NAFLD is lifestyle modification to achieve weight reduction, particularly through diet and exercise. However, weight reduction is difficult to achieve and maintain, and pharmacological agents approved for the treatment of NAFLD are lacking. This study investigated the influence of the gut microbiota and the effect of an IBATi on NAFLD using a murine model. Treatment with IBATi significantly improved NAFLD in HFD mice. Further, fecal microbiome transplantation using stool from HFD plus IBATi mice prevented hepatic steatosis caused by HFD. Our study makes a significant contribution to the literature because the study findings suggest a potential treatment strategy for NAFLD patients by ameliorating gut microbiota dysbiosis.

Keywords: gut microbiome; ileal bile acid transporter inhibitor; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis.

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Figures

FIG 1
FIG 1
Effects of IBATi administration on gut microbiota. (A) Shannon index (OTU evenness estimation) in each treatment group. (B) PCoA plot of unweighted Bray-Curtis data for each treatment group. (C) Microbial composition at the family level in each group. (D) Relative abundance at the family level by linear discriminant analysis effect size (LEfSe) in each group. (E) Ratio of Firmicutes to Bacteroidetes in each group. Values are expressed as the mean ± SEM of three or five mice in each group. Significant differences compared with the control diet group are denoted by an asterisk (P < 0.05), and those with the HFD group are denoted by a dagger symbol (P < 0.05).
FIG 2
FIG 2
Effects of fecal microbiota transplantation (FMT) from HFD plus IBATi mice on hepatic steatosis. (A) Time course of mouse body weights and liver weight/body weight ratios of groups (n = 6) who received FMT from HFD mice or HFD plus IBATi mice. (B) Representative photographs of mice and livers from each group. (C) Representative hematoxylin & eosin (HE)-stained liver sections of each group. (D) Representative oil red O-stained liver sections of each group. (E) NAFLD activity scores (NAS) of liver sections of each group. (F) Fibrosis stage of each group.
FIG 3
FIG 3
Biochemical parameters of mice with fecal microbiota transplantation (FMT). (A) Serum biochemical parameters from groups (n = 6) who received FMT from HFD mice or HFD plus IBATi mice assayed using ELISA. (B and C) Hepatic mRNA (B) and ileal mRNA (C) expression from each group measured by reverse transcription-quantitative PCR (RT-PCR). (D) Fecal bile acid pool composition profiling of each group of mice was assayed by mass spectrometry.
FIG 4
FIG 4
Influence of fecal microbiota transplantation (FMT) on gut microbiota. (A) Shannon index (OTU evenness estimation) in groups who received FMT from HFD mice or HFD plus IBATi mice. (B) PCoA plot of unweighted Bray-Curtis data for both FMT groups. (C) Microbial composition at the family level in each FMT group. (D) Relative abundance at the family level by LEfSe in each FMT group. (E) Ratio of Firmicutes/Bacteroidetes in each FMT group. Values are expressed as the mean ± SEM of three mice in each group.
FIG 5
FIG 5
Effects of fecal microbiota transplantation (FMT) from HFD plus IBATi mice on hepatic steatosis in long-term antibiotics mice. Mice receiving long-term antibiotics (6 weeks) were transplanted with gut microbiota from HFD or HFD plus IBATi groups of mice (n = 5 each), and both groups of mice were fed HFD for 4 weeks. (A) Time course of mouse body weights and liver weight/body weight ratios (n = 5). (B) Representative photographs of mice and livers from both groups after 4 weeks. (C) Representative hematoxylin and eosin (H&E)-stained liver sections of both groups. (D) Representative oil red O-stained liver sections of both groups. (E) NAFLD activity scores (NAS) of liver sections of both groups. (F) Fibrosis stage of both groups.
FIG 6
FIG 6
Therapeutic effects of IBATi on HFD-induced NAFLD. (A) Time course of mouse body weights and liver weight/body weight ratios of HFD mice treated without (control) and with IBATi (IBATi-Tx) (n = 6). (B) Representative photographs of mice and livers from each group. (C) Representative hematoxylin & eosin (HE)-stained liver sections from each group. (D) Representative oil red O-stained liver sections from each group. (E) NAFLD activity score (NAS) of liver sections from each group. (F) Fibrosis stage of each group.
FIG 7
FIG 7
Biochemical parameters of IBATi-TX mice. (A) Biochemical parameters of sera from HFD mice treated without (control) and with IBATi (IBATi-Tx) assayed using ELISA (n = 6). (B and C) Hepatic mRNA (B) and ileal mRNA (C) expression in each group measured by RT-PCR. (D) Fecal bile acid pool composition profiling of each group of mice was assayed by mass spectrometry.
FIG 8
FIG 8
Effects of IBATi treatment on gut microbiota. (A) Shannon index (OTU evenness estimation) of HFD mice treated without (control) and with IBATi (IBATi-Tx). (B) PCoA plot of unweighted Bray-Curtis data for both groups. (C) Microbial composition at the family level in both groups. (D) Relative abundance at family level by LEfSe in both groups. (E) Ratio of Firmicutes/Bacteroidetes in both groups. Values are expressed as the mean ± SEM of three mice in each group.
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