Protein Glycosylation as a Diagnostic and Prognostic Marker of Chronic Inflammatory Gastrointestinal and Liver Diseases
2019; Elsevier BV; Volume: 158; Issue: 1 Linguagem: Inglês
10.1053/j.gastro.2019.08.060
ISSN1528-0012
AutoresXavier Verhelst, Ana M. Dias, Jean‐Frédéric Colombel, Séverine Vermeire, Hans Van Vlierberghe, Nico Callewaert, Salomé S. Pinho,
Tópico(s)Helicobacter pylori-related gastroenterology studies
ResumoGlycans are sequences of carbohydrates that are added to proteins or lipids to modulate their structure and function. Glycans modify proteins required for regulation of immune cells, and alterations have been associated with inflammatory conditions. For example, specific glycans regulate T-cell activation, structures, and functions of immunoglobulins; interactions between microbes and immune and epithelial cells; and malignant transformation in the intestine and liver. We review the effects of protein glycosylation in regulation of gastrointestinal and liver functions, and how alterations in glycosylation serve as diagnostic or prognostic factors, or as targets for therapy. Glycans are sequences of carbohydrates that are added to proteins or lipids to modulate their structure and function. Glycans modify proteins required for regulation of immune cells, and alterations have been associated with inflammatory conditions. For example, specific glycans regulate T-cell activation, structures, and functions of immunoglobulins; interactions between microbes and immune and epithelial cells; and malignant transformation in the intestine and liver. We review the effects of protein glycosylation in regulation of gastrointestinal and liver functions, and how alterations in glycosylation serve as diagnostic or prognostic factors, or as targets for therapy. Protein glycosylation is a post-translational modification that provides proteins with structural diversity required for their interactions with other proteins and cells. The diversity of the glycome (repertoire of glycans structures in an organism) reflects their multiple functions in cells, and glycans act as an interface between the cell surface and the environment.1Marth J.D. Grewal P.K. 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Lago P. et al.Dysregulation of T cell receptor N-glycosylation: a molecular mechanism involved in ulcerative colitis.Hum Mol Genet. 2014; 23: 2416-2427Crossref PubMed Scopus (19) Google Scholar liver fibrosis20Vanderschaeghe D. Laroy W. Sablon E. et al.GlycoFibroTest is a highly performant liver fibrosis biomarker derived from DNA sequencer-based serum protein glycomics.Mol Cell Proteomics. 2009; 8: 986-994Crossref PubMed Scopus (80) Google Scholar and cirrhosis,21Callewaert N. Van Vlierberghe H. Van Hecke A. et al.Noninvasive diagnosis of liver cirrhosis using DNA sequencer-based total serum protein glycomics.Nat Med. 2004; 10: 429-434Crossref PubMed Scopus (345) Google Scholar nonalcoholic fatty liver disease (NAFLD),22Blomme B. Francque S. 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Vacante M. et al.Hepatocellular carcinoma markers in the omics era: the glycomic analysis.Hepatobiliary Surg Nutr. 2014; 3: 407-409PubMed Google Scholar There are many challenges to diagnosis of IBDs and liver diseases, and to predicting responses to treatment or outcomes of patients. Despite recent advances in IBD therapy, a high proportion of patients are refractory to treatment, and half of patients with ulcerative colitis (UC) do not achieve sustained remission.27Grigorian A. Araujo L. Naidu N.N. et al.N-acetylglucosamine inhibits T-helper 1 (Th1)/T-helper 17 (Th17) cell responses and treats experimental autoimmune encephalomyelitis.J Biol Chem. 2011; 286: 40133-40141Crossref PubMed Scopus (0) Google Scholar For example, despite the fact that corticosteroids are effective in controlling acute flares of IBD, 20%–30% of patients have only a partial response and 16% do not respond to corticosteroids.28Faubion Jr., W.A. Loftus Jr., E.V. Harmsen W.S. et al.The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study.Gastroenterology. 2001; 121: 255-260Abstract Full Text Full Text PDF PubMed Google Scholar It is a challenge to select the best treatment for patients due to the lack of reliable biomarkers of response or adverse events. Biomarkers are also urgently needed to differentiate patients with liver steatosis from those with nonalcoholic steatohepatitis (NASH). Changes in protein glycosylation might be used as diagnostic and prognostic markers, as well as targets of therapy for chronic inflammatory gastrointestinal diseases. We review how alterations in protein glycosylation affect development of chronic inflammatory gastrointestinal and liver diseases and the application of glycomic analysis to their diagnosis and prediction of patients' response to therapy and outcome. Glycans regulate T-cell development, activation, signaling, differentiation, and proliferation, as well as thymocyte selection.8Demetriou M. Granovsky M. Quaggin S. et al.Negative regulation of T-cell activation and autoimmunity by Mgat5 N-glycosylation.Nature. 2001; 409: 733-739Crossref PubMed Scopus (650) Google Scholar,27Grigorian A. Araujo L. Naidu N.N. et al.N-acetylglucosamine inhibits T-helper 1 (Th1)/T-helper 17 (Th17) cell responses and treats experimental autoimmune encephalomyelitis.J Biol Chem. 2011; 286: 40133-40141Crossref PubMed Scopus (0) Google Scholar,29Zhou R.W. Mkhikian H. Grigorian A. et al.N-glycosylation bidirectionally extends the boundaries of thymocyte positive selection by decoupling Lck from Ca(2)(+) signaling.Nat Immunol. 2014; 15: 1038-1045Crossref PubMed Google Scholar, 30Dias A.M. Correia A. Pereira M.S. et al.Metabolic control of T cell immune response through glycans in inflammatory bowel disease.Proc Natl Acad Sci U S A. 2018; 115: E4651-E4660Crossref PubMed Scopus (10) Google Scholar, 31Araujo L. Khim P. Mkhikian H. et al.Glycolysis and glutaminolysis cooperatively control T cell function by limiting metabolite supply to N-glycosylation.Elife. 2017; : 6Google Scholar Alterations in these processes can lead to autoimmune diseases and cancer.5Pereira M.S. Alves I. Vicente M. et al.Glycans as key checkpoints of T cell activity and function.Front Immunol. 2018; 9: 2754Crossref PubMed Scopus (1) Google Scholar,32Dias A.M. Pereira M.S. Padrao N.A. et al.Glycans as critical regulators of gut immunity in homeostasis and disease.Cell Immunol. 2018; 333: 9-18Crossref PubMed Scopus (3) Google Scholar It is not clear whether alterations in cell glycosylation profiles occur as an early event (inducing) or late event (accelerating) in intestinal inflammation. Intestinal T cells from patients with IBD have glycome profiles that differ from those individuals without IBD, characterized by decreased levels of branched N-glycans19Dias A.M. Dourado J. Lago P. et al.Dysregulation of T cell receptor N-glycosylation: a molecular mechanism involved in ulcerative colitis.Hum Mol Genet. 2014; 23: 2416-2427Crossref PubMed Scopus (19) Google Scholar,30Dias A.M. Correia A. Pereira M.S. et al.Metabolic control of T cell immune response through glycans in inflammatory bowel disease.Proc Natl Acad Sci U S A. 2018; 115: E4651-E4660Crossref PubMed Scopus (10) Google Scholar and increased levels of core fucosylation (the addition of a fucose residue to the core structure of N-linked glycans with an α1,6 linkage).33Fujii H. Shinzaki S. Iijima H. et al.Core fucosylation on T cells, required for activation of T-cell receptor signaling and induction of colitis in mice, is increased in patients with inflammatory bowel disease.Gastroenterology. 2016; 150: 1620-1632Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar These changes increase T-cell–mediated intestinal immune response. T cells from inflamed colonic mucosa of patients with active UC have reduced expression of the α-1,6-mannosylglycoprotein 6-β-N-acetylglucosaminyltransferase gene (MGAT5) or overexpression of the fucosyltransferase 8 gene (FUT8),30Dias A.M. Correia A. Pereira M.S. et al.Metabolic control of T cell immune response through glycans in inflammatory bowel disease.Proc Natl Acad Sci U S A. 2018; 115: E4651-E4660Crossref PubMed Scopus (10) Google Scholar,33Fujii H. Shinzaki S. Iijima H. et al.Core fucosylation on T cells, required for activation of T-cell receptor signaling and induction of colitis in mice, is increased in patients with inflammatory bowel disease.Gastroenterology. 2016; 150: 1620-1632Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar compared with cells from patients without UC. T cells from patients with IBD have a glycome profile that has been associated with a decreased threshold for activation and increased signaling and inflammatory response30Dias A.M. Correia A. Pereira M.S. et al.Metabolic control of T cell immune response through glycans in inflammatory bowel disease.Proc Natl Acad Sci U S A. 2018; 115: E4651-E4660Crossref PubMed Scopus (10) Google Scholar,33Fujii H. Shinzaki S. Iijima H. et al.Core fucosylation on T cells, required for activation of T-cell receptor signaling and induction of colitis in mice, is increased in patients with inflammatory bowel disease.Gastroenterology. 2016; 150: 1620-1632Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar (Figure 1). However, it is not clear whether changes in the glycoprofile of T cells are a cause or a consequence of intestinal inflammation. The cytokines interleukin (IL) 2 and IL7 alter expression of Golgi branching enzymes that control N-glycosylation in T cells.11Grigorian A. Mkhikian H. Demetriou M. Interleukin-2, interleukin-7, T cell-mediated autoimmunity, and N-glycosylation.Ann N Y Acad Sci. 2012; 1253: 49-57Crossref PubMed Scopus (0) Google Scholar An inflammatory environment would consequently influence N-glycosylation in T cells to affect their function. Studies of patients with immune-mediated diseases, such as multiple sclerosis, have found that variants in genes, including IL17RA, IL2RA, MGAT1, and CTLA-4, along with environmental factors, such as sunlight or vitamin D3 and metabolism, dysregulate Golgi N-glycosylation to promote autoimmunity.34Mkhikian H. Grigorian A. Li C.F. et al.Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis.Nat Commun. 2011; 2: 334Crossref PubMed Scopus (83) Google Scholar This finding indicates that N-glycosylation contributes, as an early event, to pathogenesis of inflammatory diseases. During colitis induction with dextran sodium sulfate (DSS), mice with the disruption of MGAT5 gene develop more severe colitis, with earlier onset, than mice without disruption of this gene, with increased responses of T-helper (Th)1 and Th17 cells.30Dias A.M. Correia A. Pereira M.S. et al.Metabolic control of T cell immune response through glycans in inflammatory bowel disease.Proc Natl Acad Sci U S A. 2018; 115: E4651-E4660Crossref PubMed Scopus (10) Google Scholar Alternatively, FUT8 knockout mice develop a less-severe colitis than mice that express wild-type FUT8, producing lower levels of Th1 and Th2 cytokines.33Fujii H. Shinzaki S. Iijima H. et al.Core fucosylation on T cells, required for activation of T-cell receptor signaling and induction of colitis in mice, is increased in patients with inflammatory bowel disease.Gastroenterology. 2016; 150: 1620-1632Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Mice that express human fucosyltransferase 2 (FUT2) from a transgene have defects in T-cell development and develop spontaneous colitis.35Brown S.J. Miller A.M. Cowan P.J. et al.Altered immune system glycosylation causes colitis in alpha1,2-fucosyltransferase transgenic mice.Inflamm Bowel Dis. 2004; 10: 546-556Crossref PubMed Scopus (0) Google Scholar Alterations in N-glycosylation therefore dysregulate the T-cell response and contribute to development of colitis. Researchers have studied mice without uridine diphosphate–N-acetylglucosamine (GlcNAc): βGal β-1,3-N-acetylglucosaminyltransferase 6 (core 3 β1,3-N-acetylglucosaminyltransferase), an enzyme involved in synthesis of core 3–derived O-glycans, and mice without core 1 synthase, glycoprotein-N-acetylgalactosamine 3-β-galactosyltransferase 1 (also called T-synthase). Core 3 β1,3-N-acetylglucosaminyltransferase–deficient mice have colon-specific reductions in mucin 2, increased permeability of the intestinal barrier, and are highly susceptible to dextran sodium sulfate–induced colitis, developing severe forms of the disease.36An G. Wei B. Xia B. et al.Increased susceptibility to colitis and colorectal tumors in mice lacking core 3-derived O-glycans.J Exp Med. 2007; 204: 1417-1429Crossref PubMed Scopus (193) Google Scholar Mice with intestinal epithelial cell-specific deficiency of core 1-derived O-glycans developed spontaneous colitis. Their colonic mucosa becomes infiltrated by tumor necrosis factor–producing myeloid cells, in the absence of lymphocytes.37Fu J. Wei B. Wen T. et al.Loss of intestinal core 1-derived O-glycans causes spontaneous colitis in mice.J Clin Invest. 2011; 121: 1657-1666Crossref PubMed Scopus (183) Google Scholar The promoter region of the MGAT3 gene has CpG methylation in CD3+ T cells from colon tissues of patients with IBD compared with healthy individuals.38Klasic M. Markulin D. Vojta A. et al.Promoter methylation of the MGAT3 and BACH2 genes correlates with the composition of the immunoglobulin G glycome in inflammatory bowel disease.Clin Epigenet. 2018; 10: 75Crossref PubMed Scopus (2) Google Scholar Genetic and epigenetic facts can therefore dysregulate the glycosylation pathway, resulting in altered glycan structures that control T-cell functions and might contribute to IBD pathogenesis. Glycans cover, essentially, all cell surfaces, forming a dense and complex coat of sugar-chains termed glycocalyx. This glycocalyx mediates interactions between intestinal cells and the microbiota. Little is known about the contributions of glycans to the composition and function of the intestinal microbiota, and how alterations affect intestinal homeostasis and the mucosa immune response. Exposure of intestinal microbes to glycans, either from diet or intestinal cells, affects their composition and function. Intestinal microbes use glycans from dietary plants, animal-derived cartilage and tissue, and human cells as sources of nutrients and energy.39Koropatkin N.M. Cameron E.A. Martens E.C. How glycan metabolism shapes the human gut microbiota.Nat Rev Microbiol. 2012; 10 (323–235)Crossref PubMed Scopus (488) Google Scholar Variations in the glycocalyx or fluctuations in the abundance of dietary glycans might lead to dysbiosis and contribute to development of IBD, colon cancer,40Hibberd A.A. Lyra A. Ouwehand A.C. et al.Intestinal microbiota is altered in patients with colon cancer and modified by probiotic intervention.BMJ Open Gastroenterol. 2017; 4: e000145Crossref PubMed Scopus (53) Google Scholar NAFLD,41Henao-Mejia J. Elinav E. Jin C. et al.Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity.Nature. 2012; 482: 179-185Crossref PubMed Scopus (1198) Google Scholar alcoholic liver disease,42Llopis M. Cassard A.M. 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How glycan metabolism shapes the human gut microbiota.Nat Rev Microbiol. 2012; 10 (323–235)Crossref PubMed Scopus (488) Google Scholar Individuals lacking a functional copy of FUT2 are known as nonsecretors and have alterations in their intestinal microbiome and increased susceptibility to infection and inflammatory disease, such as Crohn's disease.44Rausch P. Rehman A. Kunzel S. et al.Colonic mucosa-associated microbiota is influenced by an interaction of Crohn disease and FUT2 (Secretor) genotype.Proc Natl Acad Sci U S A. 2011; 108: 19030-19035Crossref PubMed Scopus (192) Google Scholar The FUT2 genotype of nursing mothers associated with decreased risk for diarrheal diseases in their infants, and milk rich in α1,2-linked fucosyl moieties was proposed to promote the growth of beneficial microbiota species like Bifidobacteria longum subsp Infantis.45Lewis Z.T. Totten S.M. 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Mice with loss of core 1–derived O-glycans from intestinal epithelial cells have alterations to the composition of their gut microbiota, with an inverse shift in the abundance of the phyla Bacteroidetes and Firmicutes.47Sommer F. Adam N. Johansson M.E. et al.Altered mucus glycosylation in core 1 O-glycan-deficient mice affects microbiota composition and intestinal architecture.PLoS One. 2014; 9: e85254Crossref PubMed Scopus (59) Google Scholar On the other hand, commensal bacteria, such as Bacteroides spp can induce epithelial fucosylation,48Goto Y. Obata T. Kunisawa J. et al.Innate lymphoid cells regulate intestinal epithelial cell glycosylation.Science. 2014; 345: 1254009Crossref PubMed Scopus (239) Google Scholar indicating the symbiosis between intestinal cells and microbes.49Bry L. Falk P.G. 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Changes in intestinal fungi have also been associated with intestinal inflammation and IBD.52Ungaro F. Massimino L. Furfaro F. et al.Metagenomic analysis of intestinal mucosa revealed a specific eukaryotic gut virome signature in early-diagnosed inflammatory bowel disease.Gut Microbes. 2018; : 1-10Google Scholar,53Liguori G. Lamas B. Richard M.L. et al.Fungal dysbiosis in mucosa-associated microbiota of Crohn's disease patients.J Crohns Colitis. 2016; 10: 296-305Crossref PubMed Google Scholar It will be interesting to explore their relationships with glycans in the intestine. Cancer cells undergo changes in glycosylation patterns18Pinho S.S. Reis C.A. Glycosylation in cancer: mechanisms and clinical implications.Nat Rev Cancer. 2015; 15: 540-555Crossref PubMed Scopus (752) Google Scholar that contribute to development and progression of colorectal cancer (CRC). Changes such as the carbohydrate antigen CA 19-9 (sialyl Lewisa) or those expressed on carcinoembryonic antigen are used as biomarkers in diagnosis of CRC and in monitoring its progression.25Holst S. Wuhrer M. Rombouts Y. Glycosylation characteristics of colorectal cancer.Adv Cancer Res. 2015; 126: 203-256Crossref PubMed Scopus (0) Google Scholar The most widely detected glycosylation alterations in colorectal tumors include increased levels of β1,6-branching N-glycans; (poly-)N-acetyllactosamine extensions of N-glycans; and sialylation. Alterations in O-glycans associated with CRC include reductions in core 3 and 4 O-glycans and higher levels of core 1 glycans, (sialyl) T-antigen and (sialyl) Tn-antigen. Changes in glycosylation profile of colon cancer cells have been described and alter their activities to promote tumorigenesis and metastases. Tumor-associated glycans are recognized by glycan-binding proteins (galectins, siglecs, and selectins) on immune cells, modulating the anti-tumor immune response.24de Freitas Junior J.C. Morgado-Diaz J.A. The role of N-glycans in colorectal cancer progression: potential biomarkers and therapeutic applications.Oncotarget. 2016; 7: 19395-19413Crossref PubMed Scopus (48) Google Scholar,54Very N. Lefebvre T. El Yazidi-Belkoura I. Drug resistance related to aberrant glycosylation in colorectal cancer.Oncotarget. 2018; 9: 1380-1402Crossref PubMed Scopus (12) Google Scholar Patients with IBD are at increased risk for CRC, which accounts for 10%–15% of deaths in patients with IBD.55Castano-Milla C. Chaparro M. Gisbert J.P. Systematic review with meta-analysis: the declining risk of colorectal cancer in ulcerative colitis.Aliment Pharmacol Ther. 2014; 39: 645-659Crossref PubMed Scopus (112) Google Scholar IBD-associated CRC results from a different sequence of genetic alterations than those observed in sporadic cancers, with early p53 mutations and frequent chromosome instability and microsatellite instability. These genetic changes, together with immune dysregulation, alterations to the microbiome, and breaches in the epithelial barrier, contribute to carcinogenesis.56Ullman T.A. Itzkowitz S.H. Intestinal inflammation and cancer.Gastroenterology. 2011; 140: 1807-1816Abstract Full Text Full Text PDF PubMed Scopus (584) Google Scholar, 57Feagins L.A. Souza R.F. Spechler S.J. Carcinogenesis in IBD: potential targets for the prevention of colorectal cancer.Nat Rev Gastroenterol Hepatol. 2009; 6: 297-305Crossref PubMed Scopus (168) Google Scholar, 58Thorsteinsdottir S. Gudjonsson T. 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