Journal article
The emergence of inflammatory microglia during gut inflammation is not affected by FFAR2 expression in intestinal epithelial cells or peripheral myeloid cells
Brain, behavior, and immunity, v 118, pp 423-436
May 2024
PMID: 38467381
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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•Intestinal inflammation was associated with inflammatory gene expression in microglia.•FFAR2 was deleted on intestinal epithelial cells or peripheral myelid cells to study GBA signaling.•Microglia activation during gut inflammation was not exacerbated by the loss of FFAR2.•In healthy conditions, microglia activation increased with the loss of FFAR2.•The role of FFAR2 may differ between homeostatic and inflammatory conditions.
Gut inflammation can trigger neuroinflammation and is linked to mood disorders. Microbiota-derived short-chain fatty acids (SCFAs) can modulate microglia, yet the mechanism remains elusive. Since microglia do not express free-fatty acid receptor (FFAR)2, but intestinal epithelial cells (IEC) and peripheral myeloid cells do, we hypothesized that SCFA-mediated FFAR2 activation within the gut or peripheral myeloid cells may impact microglia inflammation. To test this hypothesis, we developed a tamoxifen-inducible conditional knockout mouse model targeting FFAR2 exclusively on IEC and induced intestinal inflammation with dextran sodium sulfate (DSS), a well-established colitis model. Given FFAR2′s high expression in myeloid cells, we also investigated its role by selectively deleting it in these populations of cells. In an initial study, male and female wild-type mice received 0 or 2% DSS for 5d and microglia were isolated 3d later to assess inflammatory status. DSS induced intestinal inflammation and upregulated inflammatory gene expression in microglia, indicating inflammatory signaling via the gut-brain axis. Despite the lack of significant effects of sex in the intestinal phenotype, male mice showed higher microglial inflammatory response than females. Subsequent studies using FFAR2 knockout models revealed that FFAR2 expression in IECs or immune myeloid cells did not affect DSS-induced colonic pathology (i.e. clinical and histological scores and colon length), or colonic expression of inflammatory genes. However, FFAR2 knockout led to an upregulation of several microglial inflammatory genes in control mice and downregulation in DSS-treated mice, suggesting that FFAR2 may constrain neuroinflammatory gene expression under healthy homeostatic conditions but may permit it during intestinal inflammation. No interactions with sex were observed, suggesting sex does not play a role on FFAR2 potential function in gut-brain communication in the context of colitis. To evaluate the role of FFAR2 activated by microbiota-derived SCFAs, we employed the same knockout and DSS models adding fermentable dietary fiber (0 or 2.5% inulin for 8 wks). Despite no genotype or fiber main effects, contrary to our hypothesis, inulin feeding augmented DSS-induced inflammation and signs of colitis, suggesting context-dependent effects of fiber. These findings highlight microglial involvement in colitis-associated neuroinflammation and advance our understanding of FFAR2′s role in the gut-brain axis. Although not integral, we observed that the role of FFAR2 differs between homeostatic and inflammatory conditions, underscoring the need to consider different inflammatory conditions and disease contexts when investigating the role of FFAR2 and SCFAs in the gut-brain axis.
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Details
- Title
- The emergence of inflammatory microglia during gut inflammation is not affected by FFAR2 expression in intestinal epithelial cells or peripheral myeloid cells
- Creators
- Maria Elisa Caetano-Silva - University of Illinois at Urbana ChampaignLaurie Rund - University of Illinois Urbana-ChampaignMario Vailati-Riboni - University of Illinois Urbana-ChampaignStephanie Matt - Drexel UniversityKatiria Soto-Diaz - University of Illinois at Urbana ChampaignJon Beever - University of Tennessee at KnoxvilleJacob M. Allen - University of Illinois Urbana-ChampaignJeffrey A. Woods - University of Illinois Urbana-ChampaignAndrew J. Steelman - University of Illinois Urbana-ChampaignRodney W. Johnson - University of Illinois Urbana-Champaign
- Publication Details
- Brain, behavior, and immunity, v 118, pp 423-436
- Publisher
- Elsevier
- Number of pages
- 14
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:001214157600001
- Scopus ID
- 2-s2.0-85188507579
- Other Identifier
- 991021902600304721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Immunology
- Neurosciences
- Psychiatry