Butyrate limits inflammatory macrophage niche in NASH
Abstract Immune cell infiltrations with lobular inflammation in the background of steatosis and deregulated gut-liver axis are the cardinal features of non-alcoholic steatohepatitis (NASH). An array of gut microbiota-derived metabolites including short-chain fatty acids (SCFA) multifariously modulat...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-05-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05853-6 |
| _version_ | 1797822617325928448 |
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| author | Ankita Sarkar Priya Mitra Abhishake Lahiri Tanusree Das Jit Sarkar Sandip Paul Partha Chakrabarti |
| author_facet | Ankita Sarkar Priya Mitra Abhishake Lahiri Tanusree Das Jit Sarkar Sandip Paul Partha Chakrabarti |
| author_sort | Ankita Sarkar |
| collection | DOAJ |
| description | Abstract Immune cell infiltrations with lobular inflammation in the background of steatosis and deregulated gut-liver axis are the cardinal features of non-alcoholic steatohepatitis (NASH). An array of gut microbiota-derived metabolites including short-chain fatty acids (SCFA) multifariously modulates NASH pathogenesis. However, the molecular basis for the favorable impact of sodium butyrate (NaBu), a gut microbiota-derived SCFA, on the immunometabolic homeostasis in NASH remains elusive. We show that NaBu imparts a robust anti-inflammatory effect in lipopolysaccharide (LPS) stimulated or classically activated M1 polarized macrophages and in the diet-induced murine NASH model. Moreover, it impedes monocyte-derived inflammatory macrophage recruitment in liver parenchyma and induces apoptosis of proinflammatory liver macrophages (LM) in NASH livers. Mechanistically, by histone deactylase (HDAC) inhibition NaBu enhanced acetylation of canonical NF-κB subunit p65 along with its differential recruitment to the proinflammatory gene promoters independent of its nuclear translocation. NaBu-treated macrophages thus exhibit transcriptomic signatures that corroborate with a M2-like prohealing phenotype. NaBu quelled LPS-mediated catabolism and phagocytosis of macrophages, exhibited a differential secretome which consequently resulted in skewing toward prohealing phenotype and induced death of proinflammatory macrophages to abrogate metaflammation in vitro and in vivo. Thus NaBu could be a potential therapeutic as well as preventive agent in mitigating NASH. |
| first_indexed | 2024-03-13T10:11:45Z |
| format | Article |
| id | doaj.art-a881833cb7f341c08df4f725ada242d9 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-13T10:11:45Z |
| publishDate | 2023-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-a881833cb7f341c08df4f725ada242d92023-05-21T11:28:45ZengNature Publishing GroupCell Death and Disease2041-48892023-05-0114511110.1038/s41419-023-05853-6Butyrate limits inflammatory macrophage niche in NASHAnkita Sarkar0Priya Mitra1Abhishake Lahiri2Tanusree Das3Jit Sarkar4Sandip Paul5Partha Chakrabarti6Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical BiologyDivision of Cell Biology and Physiology, CSIR-Indian Institute of Chemical BiologyDivision of Structural Biology & Bioinformatics, CSIR-Indian Institute of Chemical BiologyDivision of Cell Biology and Physiology, CSIR-Indian Institute of Chemical BiologyElucidataJIS Institute of Advanced Studies & ResearchDivision of Cell Biology and Physiology, CSIR-Indian Institute of Chemical BiologyAbstract Immune cell infiltrations with lobular inflammation in the background of steatosis and deregulated gut-liver axis are the cardinal features of non-alcoholic steatohepatitis (NASH). An array of gut microbiota-derived metabolites including short-chain fatty acids (SCFA) multifariously modulates NASH pathogenesis. However, the molecular basis for the favorable impact of sodium butyrate (NaBu), a gut microbiota-derived SCFA, on the immunometabolic homeostasis in NASH remains elusive. We show that NaBu imparts a robust anti-inflammatory effect in lipopolysaccharide (LPS) stimulated or classically activated M1 polarized macrophages and in the diet-induced murine NASH model. Moreover, it impedes monocyte-derived inflammatory macrophage recruitment in liver parenchyma and induces apoptosis of proinflammatory liver macrophages (LM) in NASH livers. Mechanistically, by histone deactylase (HDAC) inhibition NaBu enhanced acetylation of canonical NF-κB subunit p65 along with its differential recruitment to the proinflammatory gene promoters independent of its nuclear translocation. NaBu-treated macrophages thus exhibit transcriptomic signatures that corroborate with a M2-like prohealing phenotype. NaBu quelled LPS-mediated catabolism and phagocytosis of macrophages, exhibited a differential secretome which consequently resulted in skewing toward prohealing phenotype and induced death of proinflammatory macrophages to abrogate metaflammation in vitro and in vivo. Thus NaBu could be a potential therapeutic as well as preventive agent in mitigating NASH.https://doi.org/10.1038/s41419-023-05853-6 |
| spellingShingle | Ankita Sarkar Priya Mitra Abhishake Lahiri Tanusree Das Jit Sarkar Sandip Paul Partha Chakrabarti Butyrate limits inflammatory macrophage niche in NASH Cell Death and Disease |
| title | Butyrate limits inflammatory macrophage niche in NASH |
| title_full | Butyrate limits inflammatory macrophage niche in NASH |
| title_fullStr | Butyrate limits inflammatory macrophage niche in NASH |
| title_full_unstemmed | Butyrate limits inflammatory macrophage niche in NASH |
| title_short | Butyrate limits inflammatory macrophage niche in NASH |
| title_sort | butyrate limits inflammatory macrophage niche in nash |
| url | https://doi.org/10.1038/s41419-023-05853-6 |
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