Evidence of an allostatic response by intestinal tissues following induction of joint inflammation.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Arthritis, Experimental*/pathology ; Arthritis, Experimental*/immunology ; Arthritis, Experimental*/chemically induced ; Inflammation*/pathology ; Intestinal Mucosa*/metabolism ; Intestinal Mucosa*/pathology ; Arthritis, Rheumatoid*/pathology; Ileum/pathology ; Ileum/metabolism ; Ileum/immunology ; Colon/pathology ; Colon/metabolism ; Colon/immunology ; Synovial Membrane/pathology ; Synovial Membrane/metabolism ; Animals ; Rats ; Male ; Freund's Adjuvant ; Gastrointestinal Microbiome

Disrupted intestinal epithelial barrier function has been proposed to be integral to rheumatoid arthritis (RA) progression and pathogenesis. To further define the molecular pathways in synovial inflammation and the response of the intestinal tissues, we have used a rat model of mono-joint inflammatory arthritis, induced by intra-articular injection of Complete Freund's adjuvant (CFA). The predominant inflammatory response of a single injection of the adjuvant into the knee joint resulted in rapid and reproducible formation of a fibrotic myeloid-infiltrated synovial pannus. Our aim was to determine how intestinal tissues, including the proximal and distal ileum and distal colon, responded to inflammatory changes in the synovium in a temporally coordinated manner by comparing their transcriptomic landscapes using RNASeq analyses. We confirmed the timeline of joint inflammation by knee joint swelling measurement, increased synovial fluid levels of bikunin (a component of both the acute phase protein pre-alpha-inhibitor and inter-alpha-inhibitor) and demonstrated a self-correcting response of trabecular and cortical bone to the CFA challenge. Intestine-specific responses were monitored by 16S microbiome amplicon sequencing, histopathology for mucus layer integrity, and immune cell immunohistochemistry. We present data that shows the intestinal tissue displays an allostatic response to the acute joint inflammation and was region specific. The ileum primarily responded with increased mucus secretion and silencing of T-cell specific pathways, whereas the colon showed a transient upregulation of macrophages, with a broader suppression of immune related and metabolic pathway related transcripts. Interestingly, many neuropathways were activated early but then suppressed later in both the ileum and colon. There were only insignificant changes in the fecal microbiome composition in ileum or colon post-CFA administration. In summary, our data show for the first time a suppression of intestinal inflammatory and immune responses following the induction of joint inflammation and only minimal and transient changes in the microbiome. The results help clarify the molecular responses of intestinal tissues to inflammatory stresses that accompany the pathogenesis of inflammatory joint diseases.
(Copyright: © 2026 Moran et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The authors have declared that no competing interests exist.

Front Immunol. 2019 Jul 03;10:1462. (PMID: 31333642)
Cell. 2024 Feb 15;187(4):914-930.e20. (PMID: 38280375)
J Orthop Res. 2017 Jul;35(7):1404-1413. (PMID: 27584936)
Acta Pharmacol Sin. 2023 Feb;44(2):454-464. (PMID: 35918412)
Cell. 2023 Jun 22;186(13):2823-2838.e20. (PMID: 37236193)
Curr Osteoporos Rep. 2023 Feb;21(1):21-31. (PMID: 36441432)
J Bone Miner Res. 2023 Mar;38(3):359-369. (PMID: 36651575)
Cell Host Microbe. 2023 Jul 12;31(7):1087-1100. (PMID: 37442097)
Circ Res. 2025 May 23;136(11):1382-1406. (PMID: 40403109)
Int J Mol Sci. 2023 Aug 01;24(15):. (PMID: 37569682)
Bioinformatics. 2014 Apr 1;30(7):923-30. (PMID: 24227677)
Adv Exp Med Biol. 2020;1204:57-73. (PMID: 32152943)
Methods Mol Biol. 2018;1783:149-169. (PMID: 29767361)
FASEB J. 2003 Jul;17(10):1277-85. (PMID: 12832292)
BMB Rep. 2014 Oct;47(10):540-5. (PMID: 25154721)
Psychother Psychosom. 2021;90(1):11-27. (PMID: 32799204)
Nutr Res. 2020 Nov;83:30-48. (PMID: 33010588)
Sci Rep. 2016 Jun 29;6:28653. (PMID: 27353765)
Philos Trans R Soc Lond B Biol Sci. 2023 Nov 20;378(1890):20220240. (PMID: 37778377)
J Cell Sci. 1997 Jun;110 ( Pt 11):1317-24. (PMID: 9202392)
J Stat Theory Appl. 2009;8(3):325-352. (PMID: 27818616)
Inflamm Res. 2010 Aug;59(8):667-78. (PMID: 20349327)
Biochim Biophys Acta Rev Cancer. 2024 May;1879(3):189098. (PMID: 38555001)
Cell Rep. 2022 Jan 4;38(1):110179. (PMID: 34986353)
Nucleic Acids Res. 2012 May;40(10):4288-97. (PMID: 22287627)
Proc Natl Acad Sci U S A. 2016 Oct 18;113(42):11859-11864. (PMID: 27708166)
Mol Metab. 2023 Nov;77:101807. (PMID: 37717665)
Ann N Y Acad Sci. 2014 May;1318:18-26. (PMID: 24579884)
Basic Clin Neurosci. 2017 May-Jun;8(3):173-182. (PMID: 28781725)
Science. 2021 Nov 26;374(6571):1087-1092. (PMID: 34822299)
Nat Methods. 2016 Jul;13(7):581-3. (PMID: 27214047)
Physiol Rev. 2014 Apr;94(2):329-54. (PMID: 24692350)
Gastroenterol Res Pract. 2011;2011:745829. (PMID: 22144996)
Cell Mol Life Sci. 2021 May;78(10):4713-4733. (PMID: 33770200)
Front Pharmacol. 2024 Jan 23;14:1346054. (PMID: 38322703)
Rev Esp Enferm Dig. 2015 Nov;107(11):686-96. (PMID: 26541659)
Antioxidants (Basel). 2023 Feb 14;12(2):. (PMID: 36830038)
Mediators Inflamm. 2021 Dec 10;2021:8817421. (PMID: 34924815)
Eur J Pharmacol. 2011 Oct 1;668(1-2):163-8. (PMID: 21749865)
Ann Med. 2021 Dec;53(1):2380-2390. (PMID: 34933614)
Proc Natl Acad Sci U S A. 2019 Mar 26;116(13):6286-6291. (PMID: 30862736)
Obesity (Silver Spring). 2016 May;24(5):1106-15. (PMID: 27030572)
Pharmacol Res. 2021 Sep;171:105779. (PMID: 34298111)
mSystems. 2024 Mar 19;9(3):e0121423. (PMID: 38364095)
Sci Transl Med. 2022 May 11;14(644):eabj9954. (PMID: 35544595)
Front Immunol. 2021 Apr 16;12:654839. (PMID: 33936082)
Osteoarthritis Cartilage. 2022 Apr;30(4):501-515. (PMID: 34537381)
Scand J Immunol. 1997 Aug;46(2):122-8. (PMID: 9583992)
Cent Eur J Immunol. 2021;46(4):470-473. (PMID: 35125945)
Mol Aspects Med. 2013 Apr-Jun;34(2-3):139-58. (PMID: 23506863)
Front Cell Infect Microbiol. 2023 Jan 27;13:1092118. (PMID: 36779190)
Int J Mol Sci. 2021 Jul 03;22(13):. (PMID: 34281249)
Calcif Tissue Int. 2017 Aug;101(2):193-203. (PMID: 28374176)
Matrix Biol. 2019 May;78-79:60-83. (PMID: 29362135)
J Biol Chem. 2006 Jul 21;281(29):20303-14. (PMID: 16702221)
Biol Res. 2020 Mar 24;53(1):12. (PMID: 32209121)
J Transl Med. 2014 Oct 28;12:293. (PMID: 25347935)
Chronic Stress (Thousand Oaks). 2017 Jan-Dec;1:. (PMID: 28856337)
Trends Immunol. 2018 Sep;39(9):677-696. (PMID: 29716793)
Int J Clin Pract. 2020 Sep;74(9):e13564. (PMID: 32478946)
Free Radic Biol Med. 2017 Mar;104:75-103. (PMID: 28062361)
Bio Protoc. 2015 Oct 20;5(20):. (PMID: 26539560)
Int J Cancer. 1994 May 15;57(4):561-7. (PMID: 7514154)
Matrix Biol. 2023 Aug;121:149-166. (PMID: 37391162)
Nucleic Acids Res. 2013 Jan;41(Database issue):D590-6. (PMID: 23193283)
Cell Death Discov. 2025 Jan 28;11(1):28. (PMID: 39875357)
Expert Rev Gastroenterol Hepatol. 2017 Sep;11(9):821-834. (PMID: 28650209)
Toxicol Appl Pharmacol. 2004 Sep 15;199(3):275-84. (PMID: 15364543)
Nature. 2023 Nov;623(7987):616-624. (PMID: 37938773)
Pain. 2022 May 1;163(5):809-819. (PMID: 34510137)
Cochrane Database Syst Rev. 2015 Oct 22;(10):CD005328. (PMID: 26490760)
Nat Rev Endocrinol. 2023 Jan;19(1):5. (PMID: 36319759)
J Biol Chem. 2013 Sep 6;288(36):25792-25803. (PMID: 23878196)
Front Immunol. 2023 Oct 09;14:1277102. (PMID: 37876938)
Nat Protoc. 2022 Jun;17(6):1518-1552. (PMID: 35478247)
Mol Metab. 2021 Sep;51:101231. (PMID: 33831593)
Genes (Basel). 2018 Jan 08;9(1):. (PMID: 29316729)
Cell. 2022 Mar 31;185(7):1172-1188.e28. (PMID: 35303419)
Int J Clin Exp Pathol. 2014 May 15;7(6):3048-56. (PMID: 25031723)
Inflamm Bowel Dis. 2011 May;17(5):1177-88. (PMID: 20824812)
Nat Commun. 2020 Apr 24;11(1):1995. (PMID: 32332732)
Osteoarthritis Cartilage. 2008 Nov;16(11):1343-55. (PMID: 18524635)
Front Immunol. 2024 May 10;15:1394108. (PMID: 38799455)
Front Immunol. 2018 Apr 13;9:745. (PMID: 29706964)
Cent Eur J Immunol. 2017;42(3):269-273. (PMID: 29204091)
Bioinformatics. 2010 Jan 1;26(1):139-40. (PMID: 19910308)
FEBS J. 2021 Jun;288(12):3694-3714. (PMID: 33460504)
J Inflamm Res. 2024 Feb 19;17:1105-1120. (PMID: 38406325)
Clin Chim Acta. 2023 Nov 1;551:117592. (PMID: 37832905)
Ann Rheum Dis. 2024 Jul 15;83(8):984-997. (PMID: 38503474)
J Clin Invest. 2011 Dec;121(12):4685-99. (PMID: 22056382)
Best Pract Res Clin Rheumatol. 2006 Jun;20(3):451-71. (PMID: 16777576)
Nat Rev Rheumatol. 2021 Apr;17(4):224-237. (PMID: 33674813)
Annu Rev Immunol. 2024 Jun;42(1):289-316. (PMID: 38277691)
Int J Mol Sci. 2024 Mar 13;25(6):. (PMID: 38542216)
Physiol Int. 2019 Sep 1;106(3):195-206. (PMID: 31560235)
J Leukoc Biol. 2021 Sep;110(3):525-537. (PMID: 33884666)
J Histochem Cytochem. 2020 Dec;68(12):907-927. (PMID: 32639183)
Rheumatology (Oxford). 2018 Aug 1;57(8):1461-1471. (PMID: 28968875)
Bioinformatics. 2014 Mar 1;30(5):614-20. (PMID: 24142950)
Brain Res. 2018 Aug 15;1693(Pt B):207-213. (PMID: 29360466)
Med. 2021 Jul 09;2(7):864-883.e9. (PMID: 34296202)
Biomolecules. 2023 Mar 09;13(3):. (PMID: 36979437)
Mucosal Immunol. 2021 Nov;14(6):1259-1270. (PMID: 34211125)
MethodsX. 2022 Feb 09;9:101630. (PMID: 35242614)
Cell Death Differ. 2014 Mar;21(3):427-37. (PMID: 24270408)
Inflammopharmacology. 2024 Oct;32(5):3429-3441. (PMID: 39192161)
Bioinformatics. 2013 Jan 1;29(1):15-21. (PMID: 23104886)
Biochim Biophys Acta Mol Cell Biol Lipids. 2017 Dec;1862(12):1587-1594. (PMID: 28919479)
J Orthop Res. 2018 Jan;36(1):365-376. (PMID: 28646530)
Inflammation. 2021 Aug;44(4):1315-1329. (PMID: 33484396)
BMC Complement Altern Med. 2018 Dec 19;18(1):337. (PMID: 30567538)
Curr Rheumatol Rep. 2019 Aug 29;21(10):52. (PMID: 31468238)
Arthritis Res Ther. 2017 Jun 30;19(1):146. (PMID: 28666464)
Aliment Pharmacol Ther. 2024 Oct;60(8):1062-1074. (PMID: 39166843)
Sci Rep. 2023 Jan 25;13(1):1373. (PMID: 36697459)
Am J Pathol. 2003 Jul;163(1):121-33. (PMID: 12819017)
J Rheumatol. 1999 Jun;26(6):1230-8. (PMID: 10381035)
Hum Mol Genet. 2022 Aug 23;31(16):2810-2819. (PMID: 35349660)
Mil Med Res. 2022 Aug 23;9(1):46. (PMID: 35996168)
Clin Anat. 2023 Oct;36(7):977-985. (PMID: 37191299)
J Affect Disord. 2024 Aug 1;358:416-421. (PMID: 38735581)
Semin Immunol. 2023 Sep;69:101807. (PMID: 37478802)
Neurology. 2022 Oct 4;99(14):e1511-e1526. (PMID: 36192182)
Am J Physiol Gastrointest Liver Physiol. 2021 Sep 1;321(3):G280-G297. (PMID: 34288735)
FASEB J. 2020 Nov;34(11):14302-14317. (PMID: 32931052)
Cochrane Database Syst Rev. 2010 May 12;(5):CD007320. (PMID: 20464751)
Front Immunol. 2018 Nov 05;9:2522. (PMID: 30455690)
Inflammation. 2018 Dec;41(6):2184-2195. (PMID: 30069664)
Molecules. 2018 Apr 24;23(5):. (PMID: 29695052)
Microbiome. 2018 May 17;6(1):90. (PMID: 29773078)
Cells. 2020 Jul 13;9(7):. (PMID: 32668663)
PLoS One. 2012;7(9):e45478. (PMID: 23029038)
Front Cell Infect Microbiol. 2022 Mar 16;12:812596. (PMID: 35372125)
Trends Neurosci. 2019 Oct;42(10):740-752. (PMID: 31488322)
J Bone Miner Metab. 2019 May;37(3):430-440. (PMID: 30097709)
Nat Rev Immunol. 2016 Oct;16(10):639-49. (PMID: 27498766)
Curr Opin Neurobiol. 2019 Aug;57:71-80. (PMID: 30771697)
Immunity. 2018 Dec 18;49(6):1103-1115.e6. (PMID: 30566883)
Front Microbiol. 2023 Oct 27;14:1290858. (PMID: 37965563)
Int Immunopharmacol. 2023 Dec;125(Pt A):111090. (PMID: 37866312)
Gastro Hep Adv. 2023;2(2):261-276. (PMID: 36908772)
Med J Islam Repub Iran. 2020 Mar 25;34:25. (PMID: 32551314)
Ageing Res Rev. 2024 Feb;94:102196. (PMID: 38218463)
J Orthop Translat. 2022 Mar 12;33:142-152. (PMID: 35330945)
Brief Bioinform. 2021 Nov 5;22(6):. (PMID: 34329375)
Sci Rep. 2024 Jan 20;14(1):1811. (PMID: 38245637)
Nutr Metab (Lond). 2023 Apr 4;20(1):22. (PMID: 37016458)
Front Immunol. 2023 Oct 04;14:1274679. (PMID: 37860014)
Biomolecules. 2023 Jan 24;13(2):. (PMID: 36830591)
Cell Adh Migr. 2023 Dec;17(1):1-15. (PMID: 37909712)
Life Sci. 2021 Feb 15;267:118974. (PMID: 33385407)
Arthritis Res Ther. 2020 Mar 6;22(1):42. (PMID: 32143707)
J Biol Chem. 2003 Aug 29;278(35):32710-8. (PMID: 12799384)
Eur Cell Mater. 2021 Apr 21;41:454-470. (PMID: 33881768)
J Agric Food Chem. 2024 Apr 10;72(14):7969-7979. (PMID: 38551374)
Clin Exp Immunol. 2011 Jun;164(3):396-406. (PMID: 21438871)
Curr Mol Pharmacol. 2021;14(5):823-837. (PMID: 33645493)
Cell Mol Immunol. 2004 Dec;1(6):416-24. (PMID: 16293210)
Anal Chem. 2024 Jan 30;96(4):1606-1613. (PMID: 38215004)
Endocrinology. 2021 Apr 1;162(4):. (PMID: 33534908)
Ann Clin Lab Sci. 2024 Sep;54(5):661-670. (PMID: 39537231)
Nat Biotechnol. 2019 Aug;37(8):852-857. (PMID: 31341288)
Oxid Med Cell Longev. 2022 Apr 25;2022:4943965. (PMID: 35509836)
Cell. 2019 Feb 21;176(5):967-981.e19. (PMID: 30739797)
Front Microbiol. 2022 Apr 19;13:841662. (PMID: 35516438)

9007-81-2 (Freund's Adjuvant)

Date Created: 20260123 Date Completed: 20260123 Latest Revision: 20260127

20260130

PMC12829947

10.1371/journal.pone.0338053

41576101