TY - JOUR
T1 - Ablation of liver Fxr results in an increased colonic mucus barrier in mice
AU - Ijssennagger, Noortje
AU - van Rooijen, Kristel S.
AU - Magnúsdóttir, Stefanía
AU - Ramos Pittol, José M.
AU - Willemsen, Ellen C.L.
AU - de Zoete, Marcel R.
AU - Baars, Matthijs J.D.
AU - Stege, Paul B.
AU - Colliva, Carolina
AU - Pellicciari, Roberto
AU - Youssef, Sameh A.
AU - de Bruin, Alain
AU - Vercoulen, Yvonne
AU - Kuipers, Folkert
AU - van Mil, Saskia W.C.
N1 - Funding Information:
NI is supported by the MLDS Career Development grant ( CDG16-04 ) and by the Wilhelmina Children’s Hospital Research Fund. NI and YV are supported by the Unusual Collaborations Grant from CUCo (Center for Unusual Collaborations; Strategic Alliance between Eindhoven University of Technology, Wageningen University & Research, Utrecht University, and the University Medical Center Utrecht). MRdZ is supported by a VIDI grant from the Netherlands Organization for Scientific Research (ZonMW, grant 917.15.377 ) and the Utrecht Exposome Hub of Utrecht Life Sciences . MB and YV are supported by NWO Gravitation 024.001.028 . SvM is supported by the Netherlands Organization for Scientific Research (NWO) project ZonMW VICI ( 917.11.365 ) and project ZonMW Aspasia program ( 015.015.013 ).
Funding Information:
NI is supported by the MLDS Career Development grant (CDG16-04) and by the Wilhelmina Children's Hospital Research Fund. NI and YV are supported by the Unusual Collaborations Grant from CUCo (Center for Unusual Collaborations; Strategic Alliance between Eindhoven University of Technology, Wageningen University & Research, Utrecht University, and the University Medical Center Utrecht). MRdZ is supported by a VIDI grant from the Netherlands Organization for Scientific Research (ZonMW, grant 917.15.377) and the Utrecht Exposome Hub of Utrecht Life Sciences. MB and YV are supported by NWO Gravitation 024.001.028. SvM is supported by the Netherlands Organization for Scientific Research (NWO) project ZonMW VICI (917.11.365) and project ZonMW Aspasia program (015.015.013).
Publisher Copyright:
© 2021 The Author(s)
PY - 2021/10
Y1 - 2021/10
N2 - Background & Aims: The interorgan crosstalk between the liver and the intestine has been the focus of intense research. Key in this crosstalk are bile acids, which are secreted from the liver into the intestine, interact with the microbiome, and upon absorption reach back to the liver. The bile acid-activated farnesoid X receptor (Fxr) is involved in the gut-to-liver axis. However, liver-to-gut communication and the roles of bile acids and Fxr remain elusive. Herein, we aim to get a better understanding of Fxr-mediated liver-to-gut communication, particularly in colon functioning. Methods: Fxr floxed/floxed mice were crossed with cre-expressing mice to yield Fxr ablation in the intestine (Fxr-intKO), liver (Fxr-livKO), or total body (Fxr-totKO). The effects on colonic gene expression (RNA sequencing), the microbiome (16S sequencing), and mucus barrier function by ex vivo imaging were analysed. Results: Despite relatively small changes in biliary bile acid concentration and composition, more genes were differentially expressed in the colons of Fxr-livKO mice than in those of Fxr-intKO and Fxr-totKO mice (3272, 731, and 1824, respectively). The colons of Fxr-livKO showed increased expression of antimicrobial genes, Toll-like receptors, inflammasome-related genes and genes belonging to the ‘Mucin-type O-glycan biosynthesis’ pathway. Fxr-livKO mice have a microbiome profile favourable for the protective capacity of the mucus barrier. The thickness of the inner sterile mucus layer was increased and colitis symptoms reduced in Fxr-livKO mice. Conclusions: Targeting of FXR is at the forefront in the battle against metabolic diseases. We show that ablation of Fxr in the liver greatly impacts colonic gene expression and increased the colonic mucus barrier. Increasing the mucus barrier is of utmost importance to battle intestinal diseases such as inflammatory bowel disease, and we show that this might be done by antagonising FXR in the liver. Lay summary: This study shows that the communication of the liver to the intestine is crucial for intestinal health. Bile acids are key players in this liver-to-gut communication, and when Fxr, the master regulator of bile acid homoeostasis, is ablated in the liver, colonic gene expression is largely affected, and the protective capacity of the mucus barrier is increased.
AB - Background & Aims: The interorgan crosstalk between the liver and the intestine has been the focus of intense research. Key in this crosstalk are bile acids, which are secreted from the liver into the intestine, interact with the microbiome, and upon absorption reach back to the liver. The bile acid-activated farnesoid X receptor (Fxr) is involved in the gut-to-liver axis. However, liver-to-gut communication and the roles of bile acids and Fxr remain elusive. Herein, we aim to get a better understanding of Fxr-mediated liver-to-gut communication, particularly in colon functioning. Methods: Fxr floxed/floxed mice were crossed with cre-expressing mice to yield Fxr ablation in the intestine (Fxr-intKO), liver (Fxr-livKO), or total body (Fxr-totKO). The effects on colonic gene expression (RNA sequencing), the microbiome (16S sequencing), and mucus barrier function by ex vivo imaging were analysed. Results: Despite relatively small changes in biliary bile acid concentration and composition, more genes were differentially expressed in the colons of Fxr-livKO mice than in those of Fxr-intKO and Fxr-totKO mice (3272, 731, and 1824, respectively). The colons of Fxr-livKO showed increased expression of antimicrobial genes, Toll-like receptors, inflammasome-related genes and genes belonging to the ‘Mucin-type O-glycan biosynthesis’ pathway. Fxr-livKO mice have a microbiome profile favourable for the protective capacity of the mucus barrier. The thickness of the inner sterile mucus layer was increased and colitis symptoms reduced in Fxr-livKO mice. Conclusions: Targeting of FXR is at the forefront in the battle against metabolic diseases. We show that ablation of Fxr in the liver greatly impacts colonic gene expression and increased the colonic mucus barrier. Increasing the mucus barrier is of utmost importance to battle intestinal diseases such as inflammatory bowel disease, and we show that this might be done by antagonising FXR in the liver. Lay summary: This study shows that the communication of the liver to the intestine is crucial for intestinal health. Bile acids are key players in this liver-to-gut communication, and when Fxr, the master regulator of bile acid homoeostasis, is ablated in the liver, colonic gene expression is largely affected, and the protective capacity of the mucus barrier is increased.
KW - Colon
KW - Farnesoid X receptor
KW - Gut microbiome
KW - Intestine-specific Fxr-KO mouse
KW - Liver-gut axis
KW - Liver-specific Fxr-KO mouse
KW - Mucus layer
KW - Liver–gut axis
UR - http://www.scopus.com/inward/record.url?scp=85122762768&partnerID=8YFLogxK
U2 - 10.1016/j.jhepr.2021.100344
DO - 10.1016/j.jhepr.2021.100344
M3 - Article
C2 - 34604725
SN - 2589-5559
VL - 3
SP - 1
EP - 10
JO - JHEP reports : innovation in hepatology
JF - JHEP reports : innovation in hepatology
IS - 5
M1 - 100344
ER -