<i>Cmtm4</i> deficiency exacerbates colitis by inducing gut dysbiosis and S100a8/9 expression

Qiao Meng; Jing Ning; Jingjing Lu; Jing Zhang; Ming Zu; Jing Zhang; Xiurui Han; Huiling Zheng; Yueqing Gong; Xinyu Hao; Ying Xiong; Fang Gu; Wenling Han; Weiwei Fu; Jun Wang; Shigang Ding

doi:10.1016/j.jgg.2024.03.009

Volume 51 Issue 8

Aug. 2024

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Article Navigation > Journal of Genetics and Genomics > 2024 > 51(8): 811-823

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Cmtm4 deficiency exacerbates colitis by inducing gut dysbiosis and S100a8/9 expression

doi: 10.1016/j.jgg.2024.03.009

Qiao Meng^a,b,
Jing Ning^a,b,
Jingjing Lu^c,d,
Jing Zhang^a,b,
Ming Zu^a,b,
Jing Zhang^a,b,
Xiurui Han^a,b,
Huiling Zheng^a,b,
Yueqing Gong^a,b,
Xinyu Hao^a,b,
Ying Xiong^a,b,
Fang Gu^a,b,
Wenling Han^e,f,
Weiwei Fu^a,b,
Jun Wang^c,
Shigang Ding^a,b

a. Department of Gastroenterology, Peking University Third Hospital, Beijing 100191, China;
b. Beijing Key Laboratory for Helicobacter Pylori Infection and Upper Gastrointestinal Diseases (BZ0371), Beijing 100191, China;
c. CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China;
d. University of Chinese Academy of Sciences, Beijing 100101, China;
e. Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, NHC Key Laboratory of Medical Immunology (Peking University), Beijing 100191, China;
f. Peking University Center for Human Disease Genomics, Beijing 100191, China

Funds:

We thank the National Natural Science Foundation of China (No. 81870386) and the Strategic Priority Research Program of the Chinese Academy of Sciences (No. XDB29020000) who supported this research.

Received Date: 2024-03-26
Accepted Date: 2024-03-28
Rev Recd Date: 2024-03-28

Available Online: 2025-06-06

Publish Date: 2024-04-02

Abstract

Abstract

The dysfunction of innate immunity components is one of the major drivers for ulcerative colitis (UC), and increasing reports indicate that the gut microbiome serves as an intermediate between genetic mutations and UC development. Here, we find that the IL-17 receptor subunit, CMTM4, is reduced in UC patients and dextran sulfate sodium (DSS)-induced colitis. The deletion of CMTM4 (Cmtm4^-/-) in mice leads to a higher susceptibility to DSS-induced colitis than in wild-type, and the gut microbiome significantly changes in composition. The causal role of the gut microbiome is confirmed with a cohousing experiment. We further identify that S100a8/9 is significantly up-regulated in Cmtm4^-/- colitis, with the block of its receptor RAGE that reverses the phenotype associated with the CMTM4 deficiency. CMTM4 deficiency rather suppresses S100a8/9 expression in vitro via the IL17 pathway, further supporting that the elevation of S100a8/9 in vivo is most likely a result of microbial dysbiosis. Taken together, the results suggest that CMTM4 is involved in the maintenance of intestinal homeostasis, suppression of S100a8/9, and prevention of colitis development. Our study further shows CMTM4 as a crucial innate immunity component, confirming its important role in UC development and providing insights into potential targets for the development of future therapies.
- Ulcerative colitis,
- CMTM4,
- Gut microbiota,
- IL-17 receptor C (IL-17RC),
- S100a8/9

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References(62)

References

Ayling, R.M.,Kok, K., 2018. Fecal calprotectin. Adv Clin Chem. 87, 161-190.

Barberio, B., Facchin, S., Patuzzi, I., Ford, A.C., Massimi, D., Valle, G., Sattin, E., Simionati, B., Bertazzo, E., Zingone, F., et al., 2022. A specific microbiota signature is associated to various degrees of ulcerative colitis as assessed by a machine learning approach. Gut Microbes. 14, 2028366.

Berger, C.N., Crepin, V.F., Roumeliotis, T.I., Wright, J.C., Serafini, N., Pevsner-Fischer, M., Yu, L., Elinav, E., Di Santo, J.P., Choudhary, J.S., et al., 2018. The citrobacter rodentium type iii secretion system effector espo affects mucosal damage repair and antimicrobial responses. PLoS Pathog. 14, e1007406.

Burr, M.L., Sparbier, C.E., Chan, Y.C., Williamson, J.C., Woods, K., Beavis, P.A., Lam, E.Y.N., Henderson, M.A., Bell, C.C., Stolzenburg, S., et al., 2017. Cmtm6 maintains the expression of pd-l1 and regulates anti-tumour immunity. Nature. 549, 101-105.

Caruso, R., Mathes, T., Martens, E.C., Kamada, N., Nusrat, A., Inohara, N.,Nunez, G., 2019. A specific gene-microbe interaction drives the development of crohn's disease-like colitis in mice. Sci Immunol. 4, eaaw4341.

Chang, J.T., 2020. Pathophysiology of inflammatory bowel diseases. The New England journal of medicine. 383, 2652-2664.

Chiricozzi, A., Suarez-Farinas, M., Fuentes-Duculan, J., Cueto, I., Li, K., Tian, S., Brodmerkel, C.,Krueger, J.G., 2016. Increased expression of interleukin-17 pathway genes in nonlesional skin of moderate-to-severe psoriasis vulgaris. Br J Dermatol. 174, 136-145.

Costello, S.P., Hughes, P.A., Waters, O., Bryant, R.V., Vincent, A.D., Blatchford, P., Katsikeros, R., Makanyanga, J., Campaniello, M.A., Mavrangelos, C., et al., 2019. Effect of fecal microbiota transplantation on 8-week remission in patients with ulcerative colitis: A randomized clinical trial. Jama. 321, 156-164.

de Souza, H.S.,Fiocchi, C., 2016. Immunopathogenesis of ibd: Current state of the art. Nat Rev Gastroenterol Hepatol. 13, 13-27.

de Vos, W.M., Tilg, H., Van Hul, M.,Cani, P.D., 2022. Gut microbiome and health: Mechanistic insights. Gut. 71, 1020-1032.

Duan, H.J., Li, X.Y., Liu, C.,Deng, X.L., 2020. Chemokine-like factor-like marvel transmembrane domain-containing family in autoimmune diseases. Chin Med J (Engl). 133, 951-958.

Eeckhaut, V., Machiels, K., Perrier, C., Romero, C., Maes, S., Flahou, B., Steppe, M., Haesebrouck, F., Sas, B., Ducatelle, R., et al., 2013. Butyricicoccus pullicaecorum in inflammatory bowel disease. Gut. 62, 1745-1752.

Elmentaite, R., Kumasaka, N., Roberts, K., Fleming, A., Dann, E., King, H.W., Kleshchevnikov, V., Dabrowska, M., Pritchard, S., Bolt, L., et al., 2021. Cells of the human intestinal tract mapped across space and time. Nature. 597, 250-255.

Fite, A., Macfarlane, S., Furrie, E., Bahrami, B., Cummings, J.H., Steinke, D.T.,Macfarlane, G.T., 2013. Longitudinal analyses of gut mucosal microbiotas in ulcerative colitis in relation to patient age and disease severity and duration. J Clin Microbiol. 51, 849-856.

Foley, J.F., 2022. Cmtm4 makes il-17 signaling more complex. Sci Signal. 15, eadf9180.

Galdiero, M.R., Ciaglia, E.,Dal Col, J., 2023. Cmtm4 as a new partner for il-17 receptor: Adding a piece in the puzzle of il17-driven diseases. Allergy. 78, 3282-3284.

Gong, T., Fu, J., Shi, L., Chen, X.,Zong, X., 2021. Antimicrobial peptides in gut health: A review. Front Nutr. 8, 751010.

Ichikawa, M., Williams, R., Wang, L., Vogl, T.,Srikrishna, G., 2011. S100a8/a9 activate key genes and pathways in colon tumor progression. Mol Cancer Res. 9, 133-148.

Jukic, A., Bakiri, L., Wagner, E.F., Tilg, H.,Adolph, T.E., 2021. Calprotectin: From biomarker to biological function. Gut. 70, 1978-1988.

Kaplan, G.G., 2015. The global burden of ibd: From 2015 to 2025. Nat Rev Gastroenterol Hepatol. 12, 720-727.

Karmakar, M., Minns, M., Greenberg, E.N., Diaz-Aponte, J., Pestonjamasp, K., Johnson, J.L., Rathkey, J.K., Abbott, D.W., Wang, K., Shao, F., et al., 2020. N-gsdmd trafficking to neutrophil organelles facilitates il-1β release independently of plasma membrane pores and pyroptosis. Nat Commun. 11, 2212.

Katakura, K., Lee, J., Rachmilewitz, D., Li, G., Eckmann, L.,Raz, E., 2005. Toll-like receptor 9-induced type i ifn protects mice from experimental colitis. J Clin Invest. 115, 695-702.

Klingberg, E., Magnusson, M.K., Strid, H., Deminger, A., Stahl, A., Sundin, J., Simren, M., Carlsten, H., Ohman, L.,Forsblad-d'Elia, H., 2019. A distinct gut microbiota composition in patients with ankylosing spondylitis is associated with increased levels of fecal calprotectin. Arthritis Res Ther. 21, 248.

Knizkova, D., Pribikova, M., Draberova, H., Semberova, T., Trivic, T., Synackova, A., Ujevic, A., Stefanovic, J., Drobek, A., Huranova, M., et al., 2022. Cmtm4 is a subunit of the il-17 receptor and mediates autoimmune pathology. Nat Immunol. 23, 1644-1652.

Liang, W., Zhao, L., Zhang, J., Fang, X., Zhong, Q., Liao, Z., Wang, J., Guo, Y., Liang, H.,Wang, L., 2020. Colonization potential to reconstitute a microbe community in pseudo germ-free mice after fecal microbe transplant from equol producer. Front Microbiol. 11, 1221.

Lima, A.L., Karl, I., Giner, T., Poppe, H., Schmidt, M., Presser, D., Goebeler, M.,Bauer, B., 2016. Keratinocytes and neutrophils are important sources of proinflammatory molecules in hidradenitis suppurativa. Br J Dermatol. 174, 514-521.

Lin, J.F., Chen, J.M., Zuo, J.H., Yu, A., Xiao, Z.J., Deng, F.H., Nie, B.,Jiang, B., 2014. Meta-analysis: Fecal calprotectin for assessment of inflammatory bowel disease activity. Inflamm Bowel Dis. 20, 1407-1415.

Liu, F., Liu, X., Liu, X., Li, T., Zhu, P., Liu, Z., Xue, H., Wang, W., Yang, X., Liu, J., et al., 2019. Integrated analyses of phenotype and quantitative proteome of cmtm4 deficient mice reveal its association with male fertility. Mol Cell Proteomics. 18, 1070-1084.

Loh, J.T., Lee, K.G., Lee, A.P., Teo, J.K.H., Lim, H.L., Kim, S.S., Tan, A.H.,Lam, K.P., 2021. Dok3 maintains intestinal homeostasis by suppressing jak2/stat3 signaling and s100a8/9 production in neutrophils. Cell Death Dis. 12, 1054.

Loy, A., Pfann, C., Steinberger, M., Hanson, B., Herp, S., Brugiroux, S., Gomes Neto, J.C., Boekschoten, M.V., Schwab, C., Urich, T., et al., 2017. Lifestyle and horizontal gene transfer-mediated evolution of mucispirillum schaedleri, a core member of the murine gut microbiota. mSystems. 2, e00171-e00216.

Machiels, K., Joossens, M., Sabino, J., De Preter, V., Arijs, I., Eeckhaut, V., Ballet, V., Claes, K., Van Immerseel, F., Verbeke, K., et al., 2014. A decrease of the butyrate-producing species roseburia hominis and faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut. 63, 1275-1283.

Magro, F., Langner, C., Driessen, A., Ensari, A., Geboes, K., Mantzaris, G.J., Villanacci, V., Becheanu, G., Borralho Nunes, P., Cathomas, G., et al., 2013. European consensus on the histopathology of inflammatory bowel disease. Journal of Crohn's & colitis. 7, 827-851.

Maukonen, J., Kolho, K.L., Paasela, M., Honkanen, J., Klemetti, P., Vaarala, O.,Saarela, M., 2015. Altered fecal microbiota in paediatric inflammatory bowel disease. Journal of Crohn's & colitis. 9, 1088-1095.

Mezzadra, R., Sun, C., Jae, L.T., Gomez-Eerland, R., de Vries, E., Wu, W., Logtenberg, M.E.W., Slagter, M., Rozeman, E.A., Hofland, I., et al., 2017. Identification of cmtm6 and cmtm4 as pd-l1 protein regulators. Nature. 549, 106-110.

Mills, R.H., Dulai, P.S., Vazquez-Baeza, Y., Sauceda, C., Daniel, N., Gerner, R.R., Batachari, L.E., Malfavon, M., Zhu, Q., Weldon, K., et al., 2022. Multi-omics analyses of the ulcerative colitis gut microbiome link bacteroides vulgatus proteases with disease severity. Nat Microbiol. 7, 262-276.

Mitsialis, V., Wall, S., Liu, P., Ordovas-Montanes, J., Parmet, T., Vukovic, M., Spencer, D., Field, M., McCourt, C., Toothaker, J., et al., 2020. Single-cell analyses of colon and blood reveal distinct immune cell signatures of ulcerative colitis and crohn's disease. Gastroenterology. 159, 591-608.e10.

Monteleone, G., Biancone, L., Marasco, R., Morrone, G., Marasco, O., Luzza, F.,Pallone, F., 1997. Interleukin 12 is expressed and actively released by crohn's disease intestinal lamina propria mononuclear cells. Gastroenterology. 112, 1169-1178.

Ng, S.C., Shi, H.Y., Hamidi, N., Underwood, F.E., Tang, W., Benchimol, E.I., Panaccione, R., Ghosh, S., Wu, J.C.Y., Chan, F.K.L., et al., 2017. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: A systematic review of population-based studies. Lancet (London, England). 390, 2769-2778.

Noviello, D., Mager, R., Roda, G., Borroni, R.G., Fiorino, G.,Vetrano, S., 2021. The il23-il17 immune axis in the treatment of ulcerative colitis: Successes, defeats, and ongoing challenges. Front Immunol. 12, 611256.

Paramsothy, S., Kamm, M.A., Kaakoush, N.O., Walsh, A.J., van den Bogaerde, J., Samuel, D., Leong, R.W.L., Connor, S., Ng, W., Paramsothy, R., et al., 2017. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: A randomised placebo-controlled trial. Lancet (London, England). 389, 1218-1228.

Pittayanon, R., Lau, J.T., Leontiadis, G.I., Tse, F., Yuan, Y., Surette, M.,Moayyedi, P., 2020. Differences in gut microbiota in patients with vs without inflammatory bowel diseases: A systematic review. Gastroenterology. 158, 930-946.e1.

Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S.,Medzhitov, R., 2004. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell. 118, 229-241.

Ramos, G.P.,Papadakis, K.A., 2019. Mechanisms of disease: Inflammatory bowel diseases. Mayo Clin Proc. 94, 155-165.

Roeseth, A.G., Schmidt, P.N.,Fagerhol, M.K., 1999. Correlation between faecal excretion of indium-111-labelled granulocytes and calprotectin, a granulocyte marker protein, in patients with inflammatory bowel disease. Scand J Gastroenterol. 34, 50-54.

Schindelin, J., Arganda-Carreras, I., Frise, E., Kaynig, V., Longair, M., Pietzsch, T., Preibisch, S., Rueden, C., Saalfeld, S., Schmid, B., et al., 2012. Fiji: An open-source platform for biological-image analysis. Nat Methods. 9, 676-682.

Scott, N.R., Swanson, R.V., Al-Hammadi, N., Domingo-Gonzalez, R., Rangel-Moreno, J., Kriel, B.A., Bucsan, A.N., Das, S., Ahmed, M., Mehra, S., et al., 2020. S100a8/a9 regulates cd11b expression and neutrophil recruitment during chronic tuberculosis. J Clin Invest. 130, 3098-3112.

Sokol, H., Landman, C., Seksik, P., Berard, L., Montil, M., Nion-Larmurier, I., Bourrier, A., Le Gall, G., Lalande, V., De Rougemont, A., et al., 2020. Fecal microbiota transplantation to maintain remission in crohn's disease: A pilot randomized controlled study. Microbiome. 8, 12.

Sun, J., Chen, H., Kan, J., Gou, Y., Liu, J., Zhang, X., Wu, X., Tang, S., Sun, R., Qian, C., et al., 2020. Anti-inflammatory properties and gut microbiota modulation of an alkali-soluble polysaccharide from purple sweet potato in dss-induced colitis mice. Int J Biol Macromol. 153, 708-722.

Suskind, D.L., Brittnacher, M.J., Wahbeh, G., Shaffer, M.L., Hayden, H.S., Qin, X., Singh, N., Damman, C.J., Hager, K.R., Nielson, H., et al., 2015. Fecal microbial transplant effect on clinical outcomes and fecal microbiome in active crohn's disease. Inflamm Bowel Dis. 21, 556-563.

Swindell, W.R., Johnston, A., Xing, X., Little, A., Robichaud, P., Voorhees, J.J., Fisher, G.,Gudjonsson, J.E., 2013. Robust shifts in s100a9 expression with aging: A novel mechanism for chronic inflammation. Sci Rep. 3, 1215.

Turovskaya, O., Foell, D., Sinha, P., Vogl, T., Newlin, R., Nayak, J., Nguyen, M., Olsson, A., Nawroth, P.P., Bierhaus, A., et al., 2008. Rage, carboxylated glycans and s100a8/a9 play essential roles in colitis-associated carcinogenesis. Carcinogenesis. 29, 2035-2043.

Vaughn, B.P., Vatanen, T., Allegretti, J.R., Bai, A., Xavier, R.J., Korzenik, J., Gevers, D., Ting, A., Robson, S.C.,Moss, A.C., 2016. Increased intestinal microbial diversity following fecal microbiota transplant for active crohn's disease. Inflamm Bowel Dis. 22, 2182-2190.

von Roon, A.C., Karamountzos, L., Purkayastha, S., Reese, G.E., Darzi, A.W., Teare, J.P., Paraskeva, P.,Tekkis, P.P., 2007. Diagnostic precision of fecal calprotectin for inflammatory bowel disease and colorectal malignancy. The American journal of gastroenterology. 102, 803-813.

Wang, S., Song, R., Wang, Z., Jing, Z., Wang, S.,Ma, J., 2018. S100a8/a9 in inflammation. Front Immunol. 9, 1298.

Wang, W., Li, Y.,Guo, X., 2020. A mouse model of citrobacter rodentium oral infection and evaluation of innate and adaptive immune responses. STAR Protoc. 1, 100218.

Wang, X., Lin, S., Wang, L., Cao, Z., Zhang, M., Zhang, Y., Liu, R.,Liu, J., 2023. Versatility of bacterial outer membrane vesicles in regulating intestinal homeostasis. Sci Adv. 9, eade5079.

Willers, M., Ulas, T., Vollger, L., Vogl, T., Heinemann, A.S., Pirr, S., Pagel, J., Fehlhaber, B., Halle, O., Schoning, J., et al., 2020. S100a8 and s100a9 are important for postnatal development of gut microbiota and immune system in mice and infants. Gastroenterology. 159, 2130-2145.e5.

Xue, H., Li, T., Wang, P., Mo, X., Zhang, H., Ding, S., Ma, D., Lv, W., Zhang, J.,Han, W., 2019. Cmtm4 inhibits cell proliferation and migration via akt, erk1/2, and stat3 pathway in colorectal cancer. Acta Biochim Biophys Sin (Shanghai). 51, 915-924.

Yui, S., Nakatani, Y.,Mikami, M., 2003. Calprotectin (s100a8/s100a9), an inflammatory protein complex from neutrophils with a broad apoptosis-inducing activity. Biol Pharm Bull. 26, 753-760.

Zhang, Y., Shen, J., Cheng, W., Roy, B., Zhao, R., Chai, T., Sheng, Y., Zhang, Z., Chen, X., Liang, W., et al., 2023. Microbiota-mediated shaping of mouse spleen structure and immune function characterized by scrna-seq and stereo-seq. J Genet Genomics. 50, 688-701.

Zheng, M., Han, R., Yuan, Y., Xing, Y., Zhang, W., Sun, Z., Liu, Y., Li, J.,Mao, T., 2022. The role of akkermansia muciniphila in inflammatory bowel disease: Current knowledge and perspectives. Front Immunol. 13, 1089600.

Zhou, G., Yu, L., Fang, L., Yang, W., Yu, T., Miao, Y., Chen, M., Wu, K., Chen, F., Cong, Y., et al., 2018. Cd177(+) neutrophils as functionally activated neutrophils negatively regulate ibd. Gut. 67, 1052-1063.

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