Hyodeoxycholic acid (HDCA) suppresses intestinal epithelial cell proliferation through FXR‐PI3K/AKT pathway, accompanied by alteration of bile acids metabolism profiles induced by gut bacteria
Bile acids (BAs) have been implicated in regulation of intestinal epithelial signaling and function. This study aimed to investigate the effects of hyodeoxycholic acid (HDCA) on intestinal epithelial cell proliferation and explore the underlying mechanisms. IPEC‐J2 cells and weaned piglets were trea...
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| Veröffentlicht in: | The FASEB journal 2020-05, Vol.34 (5), p.7103-7117 |
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| creator | Song, Min Yang, Qiang Zhang, Fenglin Chen, Lin Su, Han Yang, Xiaohua He, Haiwen Liu, Fangfang Zheng, Jisong Ling, Mingfa Lai, Xumin Zhu, Xiaotong Wang, Lina Gao, Ping Shu, Gang Jiang, Qingyan Wang, Songbo |
| description | Bile acids (BAs) have been implicated in regulation of intestinal epithelial signaling and function. This study aimed to investigate the effects of hyodeoxycholic acid (HDCA) on intestinal epithelial cell proliferation and explore the underlying mechanisms. IPEC‐J2 cells and weaned piglets were treated with HDCA and the contributions of cellular signaling pathways, BAs metabolism profiles and gut bacteria were assessed. In vitro, HDCA suppressed IPEC‐J2 proliferation via the BAs receptor FXR but not TGR5. In addition, HDCA inhibited the PI3K/AKT pathway, while knockdown of FXR or constitutive activation of AKT eliminated the inhibitory effects of HDCA, suggesting that FXR‐dependent inhibition of PI3K/AKT pathway was involved in HDCA‐suppressed IPEC‐J2 proliferation. In vivo, dietary HDCA inhibited intestinal expression of proliferative markers and PI3K/AKT pathway in weaned piglets. Meanwhile, HDCA altered the BAs metabolism profiles, with decrease in primary BA and increase in total and secondary BAs in feces, and reduction of conjugated BAs in serum. Furthermore, HDCA increased abundance of the gut bacteria associated with BAs metabolism, and thereby induced BAs profiles alternation, which might indirectly contribute to HDCA‐suppressed cell proliferation. Together, HDCA suppressed intestinal epithelial cell proliferation through FXR‐PI3K/AKT signaling pathway, accompanied by alteration of BAs metabolism profiles induced by gut bacteria. |
| doi_str_mv | 10.1096/fj.201903244R |
| format | Article |
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This study aimed to investigate the effects of hyodeoxycholic acid (HDCA) on intestinal epithelial cell proliferation and explore the underlying mechanisms. IPEC‐J2 cells and weaned piglets were treated with HDCA and the contributions of cellular signaling pathways, BAs metabolism profiles and gut bacteria were assessed. In vitro, HDCA suppressed IPEC‐J2 proliferation via the BAs receptor FXR but not TGR5. In addition, HDCA inhibited the PI3K/AKT pathway, while knockdown of FXR or constitutive activation of AKT eliminated the inhibitory effects of HDCA, suggesting that FXR‐dependent inhibition of PI3K/AKT pathway was involved in HDCA‐suppressed IPEC‐J2 proliferation. In vivo, dietary HDCA inhibited intestinal expression of proliferative markers and PI3K/AKT pathway in weaned piglets. Meanwhile, HDCA altered the BAs metabolism profiles, with decrease in primary BA and increase in total and secondary BAs in feces, and reduction of conjugated BAs in serum. Furthermore, HDCA increased abundance of the gut bacteria associated with BAs metabolism, and thereby induced BAs profiles alternation, which might indirectly contribute to HDCA‐suppressed cell proliferation. Together, HDCA suppressed intestinal epithelial cell proliferation through FXR‐PI3K/AKT signaling pathway, accompanied by alteration of BAs metabolism profiles induced by gut bacteria.</description><identifier>ISSN: 0892-6638</identifier><identifier>EISSN: 1530-6860</identifier><identifier>DOI: 10.1096/fj.201903244R</identifier><identifier>PMID: 32246800</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Bile Acids and Salts - metabolism ; bile acids metabolism profiles ; Cell Line ; Cell Proliferation - drug effects ; Deoxycholic Acid - administration & dosage ; Dietary Supplements ; Female ; FXR‐PI3K/AKT ; Gastrointestinal Microbiome - drug effects ; gut bacteria ; hyodeoxycholic acid (HDCA) ; intestinal epithelial cell proliferation ; Intestinal Mucosa - cytology ; Intestinal Mucosa - drug effects ; Intestinal Mucosa - metabolism ; Male ; Metabolome - drug effects ; Phosphatidylinositol 3-Kinases - metabolism ; Proto-Oncogene Proteins c-akt - metabolism ; Receptors, Cytoplasmic and Nuclear - metabolism ; Signal Transduction - drug effects ; Sus scrofa ; Swine</subject><ispartof>The FASEB journal, 2020-05, Vol.34 (5), p.7103-7117</ispartof><rights>2020 Federation of American Societies for Experimental Biology</rights><rights>2020 Federation of American Societies for Experimental Biology.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3389-9df89a65e4bbd1e4691f6bfd652acf82686f4d33d3fe815572195450907980133</citedby><cites>FETCH-LOGICAL-c3389-9df89a65e4bbd1e4691f6bfd652acf82686f4d33d3fe815572195450907980133</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1096%2Ffj.201903244R$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1096%2Ffj.201903244R$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32246800$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Song, Min</creatorcontrib><creatorcontrib>Yang, Qiang</creatorcontrib><creatorcontrib>Zhang, Fenglin</creatorcontrib><creatorcontrib>Chen, Lin</creatorcontrib><creatorcontrib>Su, Han</creatorcontrib><creatorcontrib>Yang, Xiaohua</creatorcontrib><creatorcontrib>He, Haiwen</creatorcontrib><creatorcontrib>Liu, Fangfang</creatorcontrib><creatorcontrib>Zheng, Jisong</creatorcontrib><creatorcontrib>Ling, Mingfa</creatorcontrib><creatorcontrib>Lai, Xumin</creatorcontrib><creatorcontrib>Zhu, Xiaotong</creatorcontrib><creatorcontrib>Wang, Lina</creatorcontrib><creatorcontrib>Gao, Ping</creatorcontrib><creatorcontrib>Shu, Gang</creatorcontrib><creatorcontrib>Jiang, Qingyan</creatorcontrib><creatorcontrib>Wang, Songbo</creatorcontrib><title>Hyodeoxycholic acid (HDCA) suppresses intestinal epithelial cell proliferation through FXR‐PI3K/AKT pathway, accompanied by alteration of bile acids metabolism profiles induced by gut bacteria</title><title>The FASEB journal</title><addtitle>FASEB J</addtitle><description>Bile acids (BAs) have been implicated in regulation of intestinal epithelial signaling and function. This study aimed to investigate the effects of hyodeoxycholic acid (HDCA) on intestinal epithelial cell proliferation and explore the underlying mechanisms. IPEC‐J2 cells and weaned piglets were treated with HDCA and the contributions of cellular signaling pathways, BAs metabolism profiles and gut bacteria were assessed. In vitro, HDCA suppressed IPEC‐J2 proliferation via the BAs receptor FXR but not TGR5. In addition, HDCA inhibited the PI3K/AKT pathway, while knockdown of FXR or constitutive activation of AKT eliminated the inhibitory effects of HDCA, suggesting that FXR‐dependent inhibition of PI3K/AKT pathway was involved in HDCA‐suppressed IPEC‐J2 proliferation. In vivo, dietary HDCA inhibited intestinal expression of proliferative markers and PI3K/AKT pathway in weaned piglets. Meanwhile, HDCA altered the BAs metabolism profiles, with decrease in primary BA and increase in total and secondary BAs in feces, and reduction of conjugated BAs in serum. Furthermore, HDCA increased abundance of the gut bacteria associated with BAs metabolism, and thereby induced BAs profiles alternation, which might indirectly contribute to HDCA‐suppressed cell proliferation. Together, HDCA suppressed intestinal epithelial cell proliferation through FXR‐PI3K/AKT signaling pathway, accompanied by alteration of BAs metabolism profiles induced by gut bacteria.</description><subject>Animals</subject><subject>Bile Acids and Salts - metabolism</subject><subject>bile acids metabolism profiles</subject><subject>Cell Line</subject><subject>Cell Proliferation - drug effects</subject><subject>Deoxycholic Acid - administration & dosage</subject><subject>Dietary Supplements</subject><subject>Female</subject><subject>FXR‐PI3K/AKT</subject><subject>Gastrointestinal Microbiome - drug effects</subject><subject>gut bacteria</subject><subject>hyodeoxycholic acid (HDCA)</subject><subject>intestinal epithelial cell proliferation</subject><subject>Intestinal Mucosa - cytology</subject><subject>Intestinal Mucosa - drug effects</subject><subject>Intestinal Mucosa - metabolism</subject><subject>Male</subject><subject>Metabolome - drug effects</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Receptors, Cytoplasmic and Nuclear - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Sus scrofa</subject><subject>Swine</subject><issn>0892-6638</issn><issn>1530-6860</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1u1DAAhC0EokvhyBX5WCTS-i9e-7gsLFu1EqgUiVvk-KfxKonT2FHJjUfgmXgUngQv28KNky35m_FoBoCXGJ1iJPmZ250ShCWihLGrR2CBS4oKLjh6DBZISFJwTsUReBbjDiGEEeZPwRElhHGB0AL83M7B2PBt1k1ovYZKewNPtu_Wq9cwTsMw2hhthL5PNibfqxbawafGtj5ftW1bOIxZ6Oyokg89TM0YppsGbr5e_fr-49M5vThbXVzDQaXmTs1vsr8O3aB6bw2sZ6ja9KAMDta-tX8SRNjZpOpsHLv9By4_7EOYSR90N1OCtdJZ7NVz8MSpNtoX9-cx-LJ5f73eFpcfP5yvV5eFplTIQhonpOKlZXVtsGVcYsdrZ3hJlHaC5M4cM5Qa6qzAZbkkWJasRBItpUCY0mNwcvDNgW6nXEfV-bivQPU2TLEiVHAiaCmWGS0OqB5DjKN11TD6To1zhVG1n61yu-rfbJl_dW891Z01f-mHnTLADsBdbmL-v1u1-fyWEMSEpL8BrKemYw</recordid><startdate>202005</startdate><enddate>202005</enddate><creator>Song, Min</creator><creator>Yang, Qiang</creator><creator>Zhang, Fenglin</creator><creator>Chen, Lin</creator><creator>Su, Han</creator><creator>Yang, Xiaohua</creator><creator>He, Haiwen</creator><creator>Liu, Fangfang</creator><creator>Zheng, Jisong</creator><creator>Ling, Mingfa</creator><creator>Lai, Xumin</creator><creator>Zhu, Xiaotong</creator><creator>Wang, Lina</creator><creator>Gao, Ping</creator><creator>Shu, Gang</creator><creator>Jiang, Qingyan</creator><creator>Wang, Songbo</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>202005</creationdate><title>Hyodeoxycholic acid (HDCA) suppresses intestinal epithelial cell proliferation through FXR‐PI3K/AKT pathway, accompanied by alteration of bile acids metabolism profiles induced by gut bacteria</title><author>Song, Min ; Yang, Qiang ; Zhang, Fenglin ; Chen, Lin ; Su, Han ; Yang, Xiaohua ; He, Haiwen ; Liu, Fangfang ; Zheng, Jisong ; Ling, Mingfa ; Lai, Xumin ; Zhu, Xiaotong ; Wang, Lina ; Gao, Ping ; Shu, Gang ; Jiang, Qingyan ; Wang, Songbo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3389-9df89a65e4bbd1e4691f6bfd652acf82686f4d33d3fe815572195450907980133</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Bile Acids and Salts - metabolism</topic><topic>bile acids metabolism profiles</topic><topic>Cell Line</topic><topic>Cell Proliferation - drug effects</topic><topic>Deoxycholic Acid - administration & dosage</topic><topic>Dietary Supplements</topic><topic>Female</topic><topic>FXR‐PI3K/AKT</topic><topic>Gastrointestinal Microbiome - drug effects</topic><topic>gut bacteria</topic><topic>hyodeoxycholic acid (HDCA)</topic><topic>intestinal epithelial cell proliferation</topic><topic>Intestinal Mucosa - cytology</topic><topic>Intestinal Mucosa - drug effects</topic><topic>Intestinal Mucosa - metabolism</topic><topic>Male</topic><topic>Metabolome - drug effects</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Receptors, Cytoplasmic and Nuclear - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>Sus scrofa</topic><topic>Swine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Song, Min</creatorcontrib><creatorcontrib>Yang, Qiang</creatorcontrib><creatorcontrib>Zhang, Fenglin</creatorcontrib><creatorcontrib>Chen, Lin</creatorcontrib><creatorcontrib>Su, Han</creatorcontrib><creatorcontrib>Yang, Xiaohua</creatorcontrib><creatorcontrib>He, Haiwen</creatorcontrib><creatorcontrib>Liu, Fangfang</creatorcontrib><creatorcontrib>Zheng, Jisong</creatorcontrib><creatorcontrib>Ling, Mingfa</creatorcontrib><creatorcontrib>Lai, Xumin</creatorcontrib><creatorcontrib>Zhu, Xiaotong</creatorcontrib><creatorcontrib>Wang, Lina</creatorcontrib><creatorcontrib>Gao, Ping</creatorcontrib><creatorcontrib>Shu, Gang</creatorcontrib><creatorcontrib>Jiang, Qingyan</creatorcontrib><creatorcontrib>Wang, Songbo</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The FASEB journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Song, Min</au><au>Yang, Qiang</au><au>Zhang, Fenglin</au><au>Chen, Lin</au><au>Su, Han</au><au>Yang, Xiaohua</au><au>He, Haiwen</au><au>Liu, Fangfang</au><au>Zheng, Jisong</au><au>Ling, Mingfa</au><au>Lai, Xumin</au><au>Zhu, Xiaotong</au><au>Wang, Lina</au><au>Gao, Ping</au><au>Shu, Gang</au><au>Jiang, Qingyan</au><au>Wang, Songbo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hyodeoxycholic acid (HDCA) suppresses intestinal epithelial cell proliferation through FXR‐PI3K/AKT pathway, accompanied by alteration of bile acids metabolism profiles induced by gut bacteria</atitle><jtitle>The FASEB journal</jtitle><addtitle>FASEB J</addtitle><date>2020-05</date><risdate>2020</risdate><volume>34</volume><issue>5</issue><spage>7103</spage><epage>7117</epage><pages>7103-7117</pages><issn>0892-6638</issn><eissn>1530-6860</eissn><abstract>Bile acids (BAs) have been implicated in regulation of intestinal epithelial signaling and function. This study aimed to investigate the effects of hyodeoxycholic acid (HDCA) on intestinal epithelial cell proliferation and explore the underlying mechanisms. IPEC‐J2 cells and weaned piglets were treated with HDCA and the contributions of cellular signaling pathways, BAs metabolism profiles and gut bacteria were assessed. In vitro, HDCA suppressed IPEC‐J2 proliferation via the BAs receptor FXR but not TGR5. In addition, HDCA inhibited the PI3K/AKT pathway, while knockdown of FXR or constitutive activation of AKT eliminated the inhibitory effects of HDCA, suggesting that FXR‐dependent inhibition of PI3K/AKT pathway was involved in HDCA‐suppressed IPEC‐J2 proliferation. In vivo, dietary HDCA inhibited intestinal expression of proliferative markers and PI3K/AKT pathway in weaned piglets. Meanwhile, HDCA altered the BAs metabolism profiles, with decrease in primary BA and increase in total and secondary BAs in feces, and reduction of conjugated BAs in serum. Furthermore, HDCA increased abundance of the gut bacteria associated with BAs metabolism, and thereby induced BAs profiles alternation, which might indirectly contribute to HDCA‐suppressed cell proliferation. Together, HDCA suppressed intestinal epithelial cell proliferation through FXR‐PI3K/AKT signaling pathway, accompanied by alteration of BAs metabolism profiles induced by gut bacteria.</abstract><cop>United States</cop><pmid>32246800</pmid><doi>10.1096/fj.201903244R</doi><tpages>15</tpages></addata></record> |
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| subjects | Animals Bile Acids and Salts - metabolism bile acids metabolism profiles Cell Line Cell Proliferation - drug effects Deoxycholic Acid - administration & dosage Dietary Supplements Female FXR‐PI3K/AKT Gastrointestinal Microbiome - drug effects gut bacteria hyodeoxycholic acid (HDCA) intestinal epithelial cell proliferation Intestinal Mucosa - cytology Intestinal Mucosa - drug effects Intestinal Mucosa - metabolism Male Metabolome - drug effects Phosphatidylinositol 3-Kinases - metabolism Proto-Oncogene Proteins c-akt - metabolism Receptors, Cytoplasmic and Nuclear - metabolism Signal Transduction - drug effects Sus scrofa Swine |
| title | Hyodeoxycholic acid (HDCA) suppresses intestinal epithelial cell proliferation through FXR‐PI3K/AKT pathway, accompanied by alteration of bile acids metabolism profiles induced by gut bacteria |
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