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. 2017 Dec;243(4):431-441.
doi: 10.1002/path.4983. Epub 2017 Nov 1.

Hepatic inflammation caused by dysregulated bile acid synthesis is reversible by butyrate supplementation

Lili Sheng  1 , Prasant Kumar Jena  1 , Ying Hu  1 , Hui-Xin Liu  1 , Nidhi Nagar  1   2 , Karen M Kalanetra  3 , Samuel William French  4 , Samuel Wheeler French  5 , David A Mills  3 , Yu-Jui Yvonne Wan  1
Affiliations

Hepatic inflammation caused by dysregulated bile acid synthesis is reversible by butyrate supplementation

Lili Sheng et al. J Pathol. 2017 Dec.

Abstract

Dysregulated bile acid (BA) synthesis or reduced farnesoid X receptor (FXR) levels are found in patients having metabolic diseases, autoimmune hepatitis, and liver cirrhosis or cancer. The objective of this study was to establish the relationship between butyrate and dysregulated BA synthesis-induced hepatitis as well as the effect of butyrate in reversing the liver pathology. Wild-type (WT) and FXR knockout (KO) male mice were placed on a control (CD) or western diet (WD) for 15 months. In the presence or absence of butyrate supplementation, feces obtained from 15-month-old WD-fed FXR KO mice, which had severe hepatitis and liver tumors, were transplanted to 7-month-old WD-fed FXR KO for 3 months. Hepatic phenotypes, microbiota profile, and BA composition were analyzed. Butyrate-generating bacteria and colonic butyrate concentration were reduced due to FXR inactivation and further reduced by WD intake. In addition, WD-fed FXR KO male mice had the highest concentration of hepatic β-muricholic acid (β-MCA) and bacteria-generated deoxycholic acid (DCA) accompanied by serious hepatitis. Moreover, dysregulated BA and reduced SCFA signaling co-existed in both human liver cancers and WD-fed FXR KO mice. Microbiota transplantation using butyrate-deficient feces derived from 15-month-old WD-fed FXR KO mice increased hepatic lymphocyte numbers as well as hepatic β-MCA and DCA concentrations. Furthermore, butyrate supplementation reduced hepatic β-MCA as well as DCA and eliminated hepatic lymphocyte infiltration. In conclusion, reduced butyrate contributes to the development of hepatitis in the FXR KO mouse model. In addition, butyrate reverses dysregulated BA synthesis and its associated hepatitis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: FXR; gut microbiota; hepatitis; liver cancer; probiotics; short-chain fatty acids.

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Conflict of interest statement

No conflicts of interest were declared.

Figures

Figure 1
Figure 1
Histological and phenotypic changes in control diet (CD) and western diet (WD)-fed wild-type and FXR KO mice. (A) Representative liver morphology and H&E-stained liver sections (original magnification 40×). (B) Body weight. (C) Percentage of liver to body weight ratio. (D) Serum endotoxin level. (E) Flow cytometric analysis of spleen TNF macrophages. n = 8 per group. Data are expressed as mean ± SD. One-way ANOVA with Tukey’s correction. *p < 0.05; **p< 0.01; ***p < 0.001.
Figure 2
Figure 2
Hepatic (A) and colon (B) gene expression in control diet (CD) and western diet (WD)-fed wild-type and FXR KO mice. n = 8 per group. Data are expressed as mean ± SD. One-way ANOVA with Tukey’s correction. *p < 0.05; **p < 0.01; ***p < 0.001.
Figure 3
Figure 3
Alteration of gutmicrobiota and butyrate concentration in control diet (CD) and western diet (WD)-fed wild-type and FXR KOmice. (A) Fecal microbiota changes at phylum level. (B) Relative abundance of fecal microbiota changes at family level. (C) Targeted functional quantitative PCR analysis of microbial genes. Copy number per ng DNA was calculated in each group and the relative changes to CD-fed WT mice are shown. n = 8 per group. (D) NMR analysis of butyrate concentration in colon contents. n = 5 per group. (E) Correlation between Erysipelotrichaceae abundance and butyrate concentration in the colon contents, as well as Desulfovibrionaceae abundance and serum endotoxin LPS. Each dot represents one mouse. The straight line represents the best-fit line obtained by linear regression analysis. *p < 0.05; **p < 0.01; ***p < 0.001.
Figure 4
Figure 4
Gene expression in human normal livers and HCC specimens as well as in wild-type male mice with and without butyrate supplementation. (A) The mRNA level of genes involved in the FXR signaling pathway and SCFA receptors in HCCs (T, n = 14) and normal liver tissues (N, n = 14) (left figure for each gene). In the 28 liver specimens studied, ten pairs were derived from HCC and adjacent normal tissues of the same patients (right figure for each gene). Colonic (B) and hepatic (C) gene expression in 2-month-old wild-type male mice with and without sodium butyrate supplementation (1 g/kg body weight, oral gavage, daily for 7 days). n = 4 per group. (D) Hepatic protein levels of the same mice described in C. Data are expressed as mean ± SD. Two-tailed Student’s t-test. *p < 0.05; **p < 0.01; ***p < 0.001.
Figure 5
Figure 5
Effect of butyrate in WD-fed FXR KO male mice with and without fecal microbiota transplantation (FMT). (A) Representative liver morphology and H&E-stained liver sections (original magnification 40×). (B) Hepatic lymphocyte infiltration score was graded on a scale of 0 (absent), 1 (rare), 2 (mild), 3 (moderate), and 4 (severe). (C) NMR analysis of butyrate concentration in colon contents. (D) Hepatic gene expression. (E) Western blot analysis of the indicated hepatic protein levels. (F) Western blot of MAPK pathways in the liver. (G) Colon gene expression. n = 3 per group. Data are expressed as mean ± SD. One-way ANOVA with Tukey’s correction. *p < 0.05; **p < 0.01; ***p < 0.001.
Figure 6
Figure 6
Hepatic bile acid profile. (A) Relative concentration of hepatic total bile acid (TBA) and individual bile acids in CD- and WD-fed WT and FXR KO mice. n = 8 per group. (B) Relative concentration of hepatic TBA and individual bile acids in mice with and without fecal microbiota transplantation (FMT). n = 3 per group. (C) Relative copy number of fecal baiJ. n = 3 per group. (D) Correlation between the concentration of hepatic BAs and colonic butyrate as well as serum LPS level in all the studied mice. Each dot represents one mouse (n = 32). The straight line represents the best-fit line obtained by linear regression analysis. Data are expressed as mean ± SD. One-way ANOVA with Tukey’s correction. *p < 0.05; **p < 0.01; ***p < 0.001.
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References

    1. Li T, Chiang JY. Bile acids as metabolic regulators. Curr Opin Gastroenterol. 2015;31:159–165. - PMC - PubMed
    1. Li T, Chiang JY. Bile acid signaling in metabolic disease and drug therapy. Pharmacol Rev. 2014;66:948–983. - PMC - PubMed
    1. Lefebvre P, Cariou B, Lien F, et al. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev. 2009;89:147–191. - PubMed
    1. Liu HX, Keane R, Sheng L, et al. Implications of microbiota and bile acid in liver injury and regeneration. J Hepatol. 2015;63:1502–1510. - PMC - PubMed
    1. Liu N, Meng Z, Lou G, et al. Hepatocarcinogenesis in FXR−/− mice mimics human HCC progression that operates through HNF1α regulation of FXR expression. Mol Endocrinol. 2012;26:775–785. - PMC - PubMed

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