Promotes Intestinal Epithelial IL-18 Production Through Activation of the HIF1α Pathway

Overview

Journal Front Microbiol

Specialty Microbiology

Date 2024 Jan 1

PMID 38163085

Authors

Raphael R Fagundes

Gabriela Bravo-Ruiseco

Shixian Hu

Sarah J Kierans

Rinse K Weersma

Cormac T Taylor

Gerard Dijkstra

Hermie J M Harmsen

Klaas Nico Faber

Affiliations

Soon will be listed here.

Abstract

Introduction: Intestinal epithelial cells produce interleukin-18 (IL-18), a key factor in promoting epithelial barrier integrity. Here, we analyzed the potential role of gut bacteria and the hypoxia-inducible factor 1α (HIF1α) pathway in regulating mucosal expression in inflammatory bowel disease (IBD).

Methods: Mucosal samples from patients with IBD ( = 760) were analyzed for bacterial composition, levels and HIF1α pathway activation. Wild-type Caco-2 and CRISPR/Cas9-engineered Caco-2--null cells were cocultured with in a "Human oxygen-Bacteria anaerobic" system and analyzed by RNA sequencing.

Results: Mucosal mRNA levels correlated positively with the abundance of mucosal-associated butyrate-producing bacteria, in particular , and with HIF1α pathway activation in patients with IBD. HIF1α-mediated expression of , either by a pharmacological agonist (dimethyloxallyl glycine) or , was abrogated in Caco-2--null cells.

Conclusion: Butyrate-producing gut bacteria like regulate mucosal expression in a HIF1α-dependent manner that may aid in mucosal healing in IBD.

Citing Articles

Biological characteristics, immune infiltration and drug prediction of PANoptosis related genes and possible regulatory mechanisms in inflammatory bowel disease.

Zhang M, Liu T, Luo L, Xie Y, Wang F Sci Rep. 2025; 15(1):2033.

PMID: 39814753 PMC: 11736032. DOI: 10.1038/s41598-024-84911-1.

Bacterial extracellular vesicles at the interface of gut microbiota and immunity.

Melo-Marques I, Cardoso S, Empadinhas N Gut Microbes. 2024; 16(1):2396494.

PMID: 39340209 PMC: 11444517. DOI: 10.1080/19490976.2024.2396494.

Crosstalk between hypoxia-inducible factor-1α and short-chain fatty acids in inflammatory bowel disease: key clues toward unraveling the mystery.

Xiao J, Guo X, Wang Z Front Immunol. 2024; 15:1385907.

PMID: 38605960 PMC: 11007100. DOI: 10.3389/fimmu.2024.1385907.

References

Hu S, Uniken Venema W, Westra H, Vich Vila A, Barbieri R, Voskuil M . Inflammation status modulates the effect of host genetic variation on intestinal gene expression in inflammatory bowel disease. Nat Commun. 2021; 12(1):1122. PMC: 7892863. DOI: 10.1038/s41467-021-21458-z. View

Nowarski R, Jackson R, Gagliani N, de Zoete M, Palm N, Bailis W . Epithelial IL-18 Equilibrium Controls Barrier Function in Colitis. Cell. 2015; 163(6):1444-56. PMC: 4943028. DOI: 10.1016/j.cell.2015.10.072. View

Lapiere A, Geiger M, Robert V, Demarquay C, Auger S, Chadi S . Prophylactic treatment prevents the acute breakdown of colonic epithelial barrier in a preclinical model of pelvic radiation disease. Gut Microbes. 2020; 12(1):1-15. PMC: 7524396. DOI: 10.1080/19490976.2020.1812867. View

Synnestvedt K, Furuta G, Comerford K, Louis N, Karhausen J, Eltzschig H . Ecto-5'-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia. J Clin Invest. 2002; 110(7):993-1002. PMC: 151145. DOI: 10.1172/JCI15337. View

Manor O, Dai C, Kornilov S, Smith B, Price N, Lovejoy J . Health and disease markers correlate with gut microbiome composition across thousands of people. Nat Commun. 2020; 11(1):5206. PMC: 7562722. DOI: 10.1038/s41467-020-18871-1. View

Liu X, Lu J, Liu Z, Zhao J, Sun H, Wu N . Intestinal Epithelial Cell-Derived LKB1 Suppresses Colitogenic Microbiota. J Immunol. 2018; 200(5):1889-1900. PMC: 6814173. DOI: 10.4049/jimmunol.1700547. View

Hu S, Bourgonje A, Gacesa R, Jansen B, Bjork J, Bangma A . Mucosal host-microbe interactions associate with clinical phenotypes in inflammatory bowel disease. Nat Commun. 2024; 15(1):1470. PMC: 10874382. DOI: 10.1038/s41467-024-45855-2. View

Mo Z, Yu L, Cao Z, Hu H, Luo S, Zhang S . Identification of a Hypoxia-Associated Signature for Lung Adenocarcinoma. Front Genet. 2020; 11:647. PMC: 7324800. DOI: 10.3389/fgene.2020.00647. View

Zheng L, Kelly C, Battista K, Schaefer R, Lanis J, Alexeev E . Microbial-Derived Butyrate Promotes Epithelial Barrier Function through IL-10 Receptor-Dependent Repression of Claudin-2. J Immunol. 2017; 199(8):2976-2984. PMC: 5636678. DOI: 10.4049/jimmunol.1700105. View

10.

Kim S, Becker J, Bechheim M, Kaiser V, Noursadeghi M, Fricker N . Characterizing the genetic basis of innate immune response in TLR4-activated human monocytes. Nat Commun. 2014; 5:5236. DOI: 10.1038/ncomms6236. View

11.

Jang G, Jeon J, Cho S, Shin D, Kim C, Jeong E . Transglutaminase 2 suppresses apoptosis by modulating caspase 3 and NF-kappaB activity in hypoxic tumor cells. Oncogene. 2009; 29(3):356-67. DOI: 10.1038/onc.2009.342. View

12.

Kelly C, Zheng L, Campbell E, Saeedi B, Scholz C, Bayless A . Crosstalk between Microbiota-Derived Short-Chain Fatty Acids and Intestinal Epithelial HIF Augments Tissue Barrier Function. Cell Host Microbe. 2015; 17(5):662-71. PMC: 4433427. DOI: 10.1016/j.chom.2015.03.005. View

13.

Yasuda K, Nakanishi K, Tsutsui H . Interleukin-18 in Health and Disease. Int J Mol Sci. 2019; 20(3). PMC: 6387150. DOI: 10.3390/ijms20030649. View

14.

Cummins E, Keogh C, Crean D, Taylor C . The role of HIF in immunity and inflammation. Mol Aspects Med. 2016; 47-48:24-34. DOI: 10.1016/j.mam.2015.12.004. View

15.

Du W, Zhang L, Brett-Morris A, Aguila B, Kerner J, Hoppel C . HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism. Nat Commun. 2017; 8(1):1769. PMC: 5701259. DOI: 10.1038/s41467-017-01965-8. View

16.

Ebersole J, Novak M, Orraca L, Martinez-Gonzalez J, Kirakodu S, Chen K . Hypoxia-inducible transcription factors, HIF1A and HIF2A, increase in aging mucosal tissues. Immunology. 2018; 154(3):452-464. PMC: 6002220. DOI: 10.1111/imm.12894. View

17.

Wiercinska-Drapalo A, Flisiak R, Jaroszewicz J, Prokopowicz D . Plasma interleukin-18 reflects severity of ulcerative colitis. World J Gastroenterol. 2005; 11(4):605-8. PMC: 4250821. DOI: 10.3748/wjg.v11.i4.605. View

18.

Jiang Y, Zhou J, Zou D, Hou D, Zhang H, Zhao J . Overexpression of Limb-Bud and Heart (LBH) promotes angiogenesis in human glioma via VEGFA-mediated ERK signalling under hypoxia. EBioMedicine. 2019; 48:36-48. PMC: 6838451. DOI: 10.1016/j.ebiom.2019.09.037. View

19.

Harrison O, Srinivasan N, Pott J, Schiering C, Krausgruber T, Ilott N . Epithelial-derived IL-18 regulates Th17 cell differentiation and Foxp3⁺ Treg cell function in the intestine. Mucosal Immunol. 2015; 8(6):1226-36. PMC: 4368110. DOI: 10.1038/mi.2015.13. View

20.

Moens F, De Vuyst L . Inulin-type fructan degradation capacity of Clostridium cluster IV and XIVa butyrate-producing colon bacteria and their associated metabolic outcomes. Benef Microbes. 2017; 8(3):473-490. DOI: 10.3920/BM2016.0142. View