TY - JOUR
T1 - Indole supplementation ameliorates MCD-induced NASH in mice
AU - Zhu, Bilian
AU - Li, Honggui
AU - Lu, Bangchao
AU - Guo, Xinlei
AU - Wu, Chiashan
AU - Wang, Fen
AU - Li, Qingsheng
AU - Xie, Linglin
AU - Glaser, Shannon
AU - Francis, Heather
AU - Alpini, Gianfranco
AU - Wu, Chaodong
N1 - Funding Information:
This work was supported in whole or in part by grants from the National Institutes of Health ( DK124854 to C.W. (Chaodong)), and the Hickam Endowed Chair, Gastroenterology, Medicine, Indiana University, the Indiana University Health – Indiana University School of Medicine Strategic Research Initiative to G.A. and H.F., the SRCS and VA Merit award to G.A. (5I01BX000574), and RCS and VA Merit award to H.F. (1I01BX003031) from the United States Department of Veteran's Affairs, Biomedical Laboratory Research and Development Service and NIH grants (DK108959 and DK110421 (HF), DK054811, DK115184, DK076898, DK107310, DK110035, and AA028711) to G.A. and S.G. Also, C.W. (Chaodong) is supported by the Hatch Program of the National Institutes of Food and Agriculture (NIFA).
Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/9
Y1 - 2022/9
N2 - Indole is a microbiota metabolite that functions to protect against obesity-associated non-alcoholic fatty liver disease. The present study examined the extent to which indole supplementation alleviates the severity of non-alcoholic steatohepatitis (NASH), which is the advanced form of non-alcoholic fatty liver disease. In C57BL/6J mice, feeding a methionine- and choline-deficient diet (MCD) resulted in significant weight loss, overt hepatic steatosis, and massive aggregations of macrophages in the liver compared with control diet-fed mice. Upon indole supplementation, the severity of MCD-induced hepatic steatosis and inflammation, as well as liver fibrosis, was significantly decreased compared with that of MCD-fed and control-treated mice. In vitro, indole treatment caused significant decreases in lipopolysaccharide-induced proinflammatory responses in hepatocytes incubated with either basal or MCD-mimicking media. However, indole treatment only significantly decreased lipopolysaccharide-induced proinflammatory responses in bone marrow-derived macrophages incubated with basal, but not MCD-mimicking media. These differential effects suggest that, relative to the responses of macrophages to indole, the responses of hepatocytes to indole appeared to make a greater contribution to indole alleviation of NASH, in particular liver inflammation. While indole supplementation decreased liver expression of desmin in MCD-fed mice, treatment of LX2 cells (a line of hepatic stellate cells) with indole also decreased the expression of various markers of hepatic stellate cell fibrogenic activation. Lastly, indole supplementation decreased intestinal inflammation in MCD-fed mice, suggesting that decreased intestinal inflammation also was involved in indole alleviation of NASH. Collectively, these results demonstrate that indole supplementation alleviates MCD-induced NASH, which is attributable to, in large part, indole suppression of hepatocyte proinflammatory responses and hepatic stellate cell fibrogenic activation, as well as intestinal proinflammatory responses.
AB - Indole is a microbiota metabolite that functions to protect against obesity-associated non-alcoholic fatty liver disease. The present study examined the extent to which indole supplementation alleviates the severity of non-alcoholic steatohepatitis (NASH), which is the advanced form of non-alcoholic fatty liver disease. In C57BL/6J mice, feeding a methionine- and choline-deficient diet (MCD) resulted in significant weight loss, overt hepatic steatosis, and massive aggregations of macrophages in the liver compared with control diet-fed mice. Upon indole supplementation, the severity of MCD-induced hepatic steatosis and inflammation, as well as liver fibrosis, was significantly decreased compared with that of MCD-fed and control-treated mice. In vitro, indole treatment caused significant decreases in lipopolysaccharide-induced proinflammatory responses in hepatocytes incubated with either basal or MCD-mimicking media. However, indole treatment only significantly decreased lipopolysaccharide-induced proinflammatory responses in bone marrow-derived macrophages incubated with basal, but not MCD-mimicking media. These differential effects suggest that, relative to the responses of macrophages to indole, the responses of hepatocytes to indole appeared to make a greater contribution to indole alleviation of NASH, in particular liver inflammation. While indole supplementation decreased liver expression of desmin in MCD-fed mice, treatment of LX2 cells (a line of hepatic stellate cells) with indole also decreased the expression of various markers of hepatic stellate cell fibrogenic activation. Lastly, indole supplementation decreased intestinal inflammation in MCD-fed mice, suggesting that decreased intestinal inflammation also was involved in indole alleviation of NASH. Collectively, these results demonstrate that indole supplementation alleviates MCD-induced NASH, which is attributable to, in large part, indole suppression of hepatocyte proinflammatory responses and hepatic stellate cell fibrogenic activation, as well as intestinal proinflammatory responses.
KW - Indole
KW - Intestinal inflammation
KW - Liver fibrosis
KW - Macrophages
KW - Methionine- and choline-deficient diet
KW - Non-alcoholic steatohepatitis
UR - http://www.scopus.com/inward/record.url?scp=85131383001&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85131383001&partnerID=8YFLogxK
U2 - 10.1016/j.jnutbio.2022.109041
DO - 10.1016/j.jnutbio.2022.109041
M3 - Article
C2 - 35568098
AN - SCOPUS:85131383001
VL - 107
JO - Journal of Nutritional Biochemistry
JF - Journal of Nutritional Biochemistry
SN - 0955-2863
M1 - 109041
ER -