Abstract
The intestinal tract faces numerous challenges that require several layers of defence. The tight epithelium forms a physical barrier that is further protected by a mucus layer, which provides various site-specific protective functions. Mucus is produced by goblet cells, and as a result of single-cell RNA sequencing identifying novel goblet cell subpopulations, our understanding of their various contributions to intestinal homeostasis has improved. Goblet cells not only produce mucus but also are intimately linked to the immune system. Mucus and goblet cell development is tightly regulated during early life and synchronized with microbial colonization. Dysregulation of the developing mucus systems and goblet cells has been associated with infectious and inflammatory conditions and predisposition to chronic disease later in life. Dysfunctional mucus and altered goblet cell profiles are associated with inflammatory conditions in which some mucus system impairments precede inflammation, indicating a role in pathogenesis. In this Review, we present an overview of the current understanding of the role of goblet cells and the mucus layer in maintaining intestinal health during steady-state and how alterations to these systems contribute to inflammatory and infectious disease.
Key points
-
The intestinal epithelium is covered by mucus with properties adapted to the local environment and associated challenges.
-
Intestinal goblet cells are represented by several subsets with different expression profiles linked to their differentiation and location.
-
Goblet cells sample luminal antigens and deliver them to the immune system for induction of adaptive immune responses, a process that occurs in a time-specific and location-specific manner.
-
Loss of mucus barrier function and altered composition of goblet cell populations are linked to the development of colitis.
-
Several commensal and pathogenic bacteria and viruses specifically use goblet cells as ports of entry to the host.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Boron, W. F. & Boulpaep, E. L. Medical physiology 3rd edn (Elsevier, 2017).
Johansson, M. E., Larsson, J. M. & Hansson, G. C. The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host-microbial interactions. Proc. Natl Acad. Sci. USA 108, 4659–4665 (2011).
Lechuga, S. & Ivanov, A. I. Disruption of the epithelial barrier during intestinal inflammation: quest for new molecules and mechanisms. Biochim. Biophys. Acta Mol. Cell Res. 1864, 1183–1194 (2017).
Atuma, C., Strugula, V., Allen, A. & Holm, L. The adherent gastrointestinal mucus gel layer: thickness and physical state in vivo. Am. J. Physiol. Gastrointest. Liver Physiol. 280, G922–G929 (2001).
Ermund, A., Schutte, A., Johansson, M. E., Gustafsson, J. K. & Hansson, G. C. Studies of mucus in mouse stomach, small intestine, and colon. I. Gastrointestinal mucus layers have different properties depending on location as well as over the Peyer’s patches. Am. J. Physiol. Gastrointest. Liver Physiol. 305, G341–G347 (2013).
Mestecky, J. et al. Mucosal Immunology (Academic, 2015).
Birchenough, G. M., Nyström, E. E., Johansson, M. E. & Hansson, G. C. A sentinel goblet cell guards the colonic crypt by triggering Nlrp6-dependent Muc2 secretion. Science 352, 1535–1542 (2016).
Grondin, J. A., Kwon, Y. H., Far, P. M., Haq, S. & Khan, W. I. Mucins in intestinal mucosal defense and inflammation: learning from clinical and experimental studies. Front. Immunol. https://doi.org/10.3389/fimmu.2020.02054 (2020).
Knoop, K. A. et al. Synchronization of mothers and offspring promotes tolerance and limits allergy. JCI Insight https://doi.org/10.1172/jci.insight.137943 (2020).
Bergstrom, K. et al. Proximal colon-derived O-glycosylated mucus encapsulates and modulates the microbiota. Science 370, 467–472 (2020).
Kulkarni, D. H. et al. Goblet cell associated antigen passages support the induction and maintenance of oral tolerance. Mucosal Immunol. 13, 271–282 (2020).
Witten, J., Samad, T. & Ribbeck, K. Selective permeability of mucus barriers. Curr. Opin. Biotechnol. 52, 124–133 (2018).
Rodriguez-Pineiro, A. M. et al. Studies of mucus in mouse stomach, small intestine, and colon. II. Gastrointestinal mucus proteome reveals Muc2 and Muc5ac accompanied by a set of core proteins. Am. J. Physiol. Gastrointest. Liver Physiol. 305, G348–G356 (2013).
van der Post, S. et al. Structural weakening of the colonic mucus barrier is an early event in ulcerative colitis pathogenesis. Gut 68, 2142–2151 (2019).
Nyström, E. E. L. et al. Calcium-activated chloride channel regulator 1 (CLCA1) controls mucus expansion in colon by proteolytic activity. EBioMedicine 33, 134–143 (2018).
Ehrencrona, E. et al. The IgG Fc-binding protein FCGBP is secreted with all GDPH sequences cleaved, but maintained by inter-fragment disulfide bonds. J. Biol. Chem. https://doi.org/10.1016/j.jbc.2021.100871 (2021).
Jabbar, K. S. et al. Association between Brachyspira and irritable bowel syndrome with diarrhoea. Gut 70, 1117–1129 (2021).
Ambort, D. et al. Calcium and pH-dependent packing and release of the gel-forming MUC2 mucin. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.1120269109 (2012).
Javitt, G. et al. Assembly mechanism of mucin and von Willebrand factor polymers. Cell 183, 717–729.e6 (2020).
Recktenwald, C. V. & Hansson, G. C. The reduction-insensitive bonds of the MUC2 mucin are isopeptide bonds. J. Biol. Chem. 291, 13580–13590 (2016).
Arike, L., Hansson, G. C. & Recktenwald, C. V. Identifying transglutaminase reaction products via mass spectrometry as exemplified by the MUC2 mucin – pitfalls and traps. Anal. Biochem. 597, 113668 (2020).
Birchenough, G. M., Johansson, M. E., Gustafsson, J. K., Bergstrom, J. H. & Hansson, G. C. New developments in goblet cell mucus secretion and function. Mucosal Immunol. 8, 712–719 (2015).
Javitt, G. et al. Intestinal Gel-forming mucins polymerize by disulfide-mediated dimerization of D3 domains. J. Mol. Biol. 431, 3740–3752 (2019).
Neutra, M. R., O’Malley, L. J. & Specian, R. D. Regulation of intestinal goblet cell secretion. II. A survey of potential secretagogues. Am. J. Physiol. 242, G380–G387 (1982).
Gustafsson, J. K. et al. Carbachol-induced colonic mucus formation requires transport via NKCC1, K(+) channels and CFTR. Pflugers Arch. 467, 1403–1415 (2015).
Schutte, A. et al. Microbial-induced meprin β cleavage in MUC2 mucin and a functional CFTR channel are required to release anchored small intestinal mucus. Proc. Natl Acad. Sci. USA 111, 12396–12401 (2014).
Smithson, K. W., Millar, D. B., Jacobs, L. R. & Gray, G. M. Intestinal diffusion barrier: unstirred water layer or membrane surface mucous coat? Science 214, 1241–1244 (1981).
Lai, S. K., Wang, Y.-Y., Wirtz, D. & Hanes, J. Micro- and macrorheology of mucus. Adv. Drug Deliv. Rev. 61, 86–100 (2009).
Critchfield, A. S. et al. Cervical mucus properties stratify risk for preterm birth. PLoS ONE 8, e69528 (2013).
Krupa, L. et al. Comparing the permeability of human and porcine small intestinal mucus for particle transport studies. Sci. Rep. 10, 20290 (2020).
Witten, J. & Ribbeck, K. The particle in the spider’s web: transport through biological hydrogels. Nanoscale 9, 8080–8095 (2017).
Johansson, M. E. et al. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc. Natl Acad. Sci. USA 105, 15064–15069 (2008).
Kamphuis, J. B. J., Mercier-Bonin, M., Eutamene, H. & Theodorou, V. Mucus organisation is shaped by colonic content; a new view. Sci. Rep. 7, 8527 (2017).
Schneider, H., Pelaseyed, T., Svensson, F. & Johansson, M. E. V. Study of mucin turnover in the small intestine by in vivo labeling. Sci. Rep. 8, 5760 (2018).
Johansson, M. E. Fast renewal of the distal colonic mucus layers by the surface goblet cells as measured by in vivo labeling of mucin glycoproteins. PLoS ONE 7, e41009 (2012).
Arike, L. et al. Protein turnover in epithelial cells and mucus along the gastrointestinal tract is coordinated by the spatial location and microbiota. Cell Rep. 30, 1077–1087.e3 (2020).
Macierzanka, A., Mackie, A. R. & Krupa, L. Permeability of the small intestinal mucus for physiologically relevant studies: impact of mucus location and ex vivo treatment. Sci. Rep. 9, 17516 (2019).
Schroeder, B. O. et al. Obesity-associated microbiota contributes to mucus layer defects in genetically obese mice. J. Biol. Chem. 295, 15712–15726 (2020).
Sababi, M., Nilsson, E. & Holm, L. Mucus and alkali secretion in the rat duodenum: effects of indomethacin, Nω-nitro-L-arginine, and luminal acid. Gastroenterology 109, 1526–1534 (1995).
McQueen, S., Hutton, D., Allen, A. & Garner, A. Gastric and duodenal surface mucus gel thickness in rat: effects of prostaglandins and damaging agents. Am. J. Physiol. 245, G388–G393 (1983).
Sotres, J., Jankovskaja, S., Wannerberger, K. & Arnebrant, T. Ex-vivo force spectroscopy of intestinal mucosa reveals the mechanical properties of mucus blankets. Sci. Rep. 7, 7270 (2017).
Johansson, M. E. et al. Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis. Gut 63, 281–291 (2014).
Gustafsson, J. K. et al. Bicarbonate and functional CFTR channel are required for proper mucin secretion and link cystic fibrosis with its mucus phenotype. J. Exp. Med. 209, 1263–1272 (2012).
Allen, A. & Flemstrom, G. Gastroduodenal mucus bicarbonate barrier: protection against acid and pepsin. Am. J. Physiol. Cell Physiol. 288, C1–C19 (2005).
Bell, A. E. et al. Properties of gastric and duodenal mucus: effect of proteolysis, disulfide reduction, bile, acid, ethanol, and hypertonicity on mucus gel structure. Gastroenterology 88, 269–280 (1985).
Johansson, M. E. et al. Normalization of host intestinal mucus layers requires long-term microbial colonization. Cell Host Microbe 18, 582–592 (2015).
Schroeder, B. O. et al. Bifidobacteria or fiber protects against diet-induced microbiota-mediated colonic mucus deterioration. Cell Host Microbe 23, 27–40.e7 (2018).
Petersson, J. et al. Importance and regulation of the colonic mucus barrier in a mouse model of colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 300, G327–G333 (2011).
Mukherjee, S. & Hooper, L. V. Antimicrobial defense of the intestine. Immunity 42, 28–39 (2015).
Bevins, C. L. & Salzman, N. H. Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. Nat. Rev. Microbiol. 9, 356–368 (2011).
Macpherson, A. J. & McCoy, K. D. Stratification and compartmentalisation of immunoglobulin responses to commensal intestinal microbes. Semin. Immunol. 25, 358–363 (2013).
Meyer-Hoffert, U. et al. Secreted enteric antimicrobial activity localises to the mucus surface layer. Gut 57, 764–771 (2008).
Gustafsson, J. K. et al. An ex vivo method for studying mucus formation, properties, and thickness in human colonic biopsies and mouse small and large intestinal explants. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G430–G438 (2012).
Nava, G. M., Friedrichsen, H. J. & Stappenbeck, T. S. Spatial organization of intestinal microbiota in the mouse ascending colon. ISME J. 5, 627–638 (2011).
Hugenholtz, F. & de Vos, W. M. Mouse models for human intestinal microbiota research: a critical evaluation. Cell Mol. Life Sci. 75, 149–160 (2018).
Swidsinski, A., Loening-Baucke, V., Verstraelen, H., Osowska, S. & Doerffel, Y. Biostructure of fecal microbiota in healthy subjects and patients with chronic idiopathic diarrhea. Gastroenterology 135, 568–579 (2008).
Nyström, E. E. L. et al. An intercrypt subpopulation of goblet cells is essential for colonic mucus barrier function. Science 372, eabb1590 (2021).
Burclaff, J. et al. A proximal-to-distal survey of healthy adult human small intestine and colon epithelium by single-cell transcriptomics. Cell. Mol. Gastroenterol. Hepatol. https://doi.org/10.1016/j.jcmgh.2022.02.007 (2022).
Bergstrom, J. H. et al. Gram-positive bacteria are held at a distance in the colon mucus by the lectin-like protein ZG16. Proc. Natl Acad. Sci. USA 113, 13833–13838 (2016).
Luis, A. S. et al. A single sulfatase is required to access colonic mucin by a gut bacterium. Nature 598, 332–337 (2021).
Martens, E. C., Chiang, H. C. & Gordon, J. I. Mucosal glycan foraging enhances fitness and transmission of a saccharolytic human gut bacterial symbiont. Cell Host Microbe 4, 447–457 (2008).
Desai, M. S. et al. A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell 167, 1339–1353.e21 (2016).
Zou, J. et al. Fiber-mediated nourishment of gut microbiota protects against diet-induced obesity by restoring IL-22-mediated colonic health. Cell Host Microbe 23, 41–53.e4 (2018).
Birchenough, G. M. et al. Postnatal development of the small intestinal mucosa drives age-dependent, regio-selective susceptibility to Escherichia coli K1 infection. Sci. Rep. 7, 83 (2017).
Burger-van Paassen, N. et al. Colitis development during the suckling-weaning transition in mucin Muc2-deficient mice. Am. J. Physiol. Gastrointest. Liver Physiol. 301, G667–G678 (2011).
Fu, J. et al. Loss of intestinal core 1-derived O-glycans causes spontaneous colitis in mice. J. Clin. Invest. 121, 1657–1666 (2011).
Van der Sluis, M. et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131, 117–129 (2006).
Velcich, A. et al. Colorectal cancer in mice genetically deficient in the mucin Muc2. Science 295, 1726–1729 (2002).
Barker, N., Van de, W. M. & Clevers, H. The intestinal stem cell. Genes Dev. 22, 1856–1864 (2008).
Noah, T. K., Donahue, B. & Shroyer, N. F. Intestinal development and differentiation. Exp. Cell Res. 317, 2702–2710 (2011).
Koo, B.-K., van Es Johan, H., van den Born, M. & Clevers, H. Porcupine inhibitor suppresses paracrine Wnt-driven growth of Rnf43;Znrf3-mutant neoplasia. Proc. Natl Acad. Sci. USA 112, 7548–7550 (2015).
Lo, Y. H. et al. Transcriptional regulation by ATOH1 and its target SPDEF in the intestine. Cell. Mol. Gastroenterol. Hepatol. 3, 51–71 (2017).
Noah, T. K., Kazanjian, A., Whitsett, J. & Shroyer, N. F. SAM pointed domain ETS factor (SPDEF) regulates terminal differentiation and maturation of intestinal goblet cells. Exp. Cell Res. 316, 452–465 (2010).
Shroyer, N. F. et al. Intestine-specific ablation of mouse atonal homolog 1 (Math1) reveals a role in cellular homeostasis. Gastroenterology 132, 2478–2488 (2007).
Shroyer, N. F., Wallis, D., Venken, K. J. T., Bellen, H. J. & Zoghbi, H. Y. Gfi1 functions downstream of Math1 to control intestinal secretory cell subtype allocation and differentiation. Genes Dev. 19, 2412–2417 (2005).
Gregorieff, A. et al. The Ets-domain transcription factor Spdef promotes maturation of goblet and Paneth cells in the intestinal epithelium. Gastroenterology 137, 1333–1345 (2009).
Wang, Y. et al. Single-cell transcriptome analysis reveals differential nutrient absorption functions in human intestine. J. Exp. Med. https://doi.org/10.1084/jem.20191130 (2020).
Barker, N. Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration. Nat. Rev. Mol. Cell Biol. 15, 19–33 (2014).
Dalerba, P. et al. Single-cell dissection of transcriptional heterogeneity in human colon tumors. Nat. Biotechnol. 29, 1120–1127 (2011).
Tabula Muris, C. et al. Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature 562, 367–372 (2018).
Haber, A. L. et al. A single-cell survey of the small intestinal epithelium. Nature 551, 333–339 (2017).
Herring, C. A. et al. Unsupervised trajectory analysis of single-cell RNA-Seq and imaging data reveals alternative tuft cell origins in the gut. Cell Syst. 6, 37–51.e9 (2018).
Moor, A. E. et al. Spatial reconstruction of single enterocytes uncovers broad zonation along the intestinal villus axis. Cell 175, 1156–1167.e15 (2018).
Parikh, K. et al. Colonic epithelial cell diversity in health and inflammatory bowel disease. Nature 567, 49–55 (2019).
Smillie, C. S. et al. Intra- and inter-cellular rewiring of the human colon during ulcerative colitis. Cell 178, 714–730.e22 (2019).
Capdevila, C. et al. Cellular origins and lineage relationships of the intestinal epithelium. Am. J. Physiol. Gastrointest. Liver Physiol. 321, G413–G425 (2021).
Mills, J. C., Stanger, B. Z. & Sander, M. Nomenclature for cellular plasticity: are the terms as plastic as the cells themselves? EMBO J. 38, e103148 (2019).
Larsen, H. L. & Jensen, K. B. Reprogramming cellular identity during intestinal regeneration. Curr. Opin. Genet. Dev. 70, 40–47 (2021).
Radwan, K. A., Oliver, M. G. & Specian, R. D. Cytoarchitectural reorganization of rabbit colonic goblet cells during baseline secretion. Am. J. Anat. 189, 365–376 (1990).
Rothenberg, M. E. et al. Identification of a cKit(+) colonic crypt base secretory cell that supports Lgr5(+) stem cells in mice. Gastroenterology 142, 1195–1205.e6 (2012).
Specian, R. D. & Neutra, M. R. Mechanism of rapid mucus secretion in goblet cells stimulated by acetylcholine. J. Cell Biol. 85, 626–640 (1980).
Jaramillo, A. M. et al. Different Munc18 proteins mediate baseline and stimulated airway mucin secretion. JCI Insight https://doi.org/10.1172/jci.insight.124815 (2019).
Cornick, S., Kumar, M., Moreau, F., Gaisano, H. & Chadee, K. VAMP8-mediated MUC2 mucin exocytosis from colonic goblet cells maintains innate intestinal homeostasis. Nat. Commun. 10, 4306 (2019).
Huang, B. et al. Mucosal profiling of pediatric-onset colitis and IBD reveals common pathogenics and therapeutic pathways. Cell 179, 1160–1176.e24 (2019).
Halm, D. R. & Halm, S. T. Secretagogue response of goblet cells and columnar cells in human colonic crypts. Am. J. Physiol. Cell Physiol. 278, C212–C233 (2000).
Garcia, M. A., Yang, N. & Quinton, P. M. Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator-dependent bicarbonate secretion. J. Clin. Invest. 119, 2613–2622 (2009).
Phillips, T. E. Both crypt and villus intestinal goblet cells secrete mucin in response to cholinergic stimulation. Am. J. Physiol. 262, G327–G331 (1992).
Corfield, A. P. Mucins: a biologically relevant glycan barrier in mucosal protection. Biochim. Biophys. Acta Gen. Subj. 1850, 236–252 (2015).
Harada, N. et al. Human IgGFc binding protein (FcγBP) in colonic epithelial cells exhibits mucin-like structure. J. Biol. Chem. 272, 15232–15241 (1997).
Tsuru, A. et al. Negative feedback by IRE1β optimizes mucin production in goblet cells. Proc. Natl Acad. Sci. USA 110, 2864–2869 (2013).
Park, S. W. et al. The protein disulfide isomerase AGR2 is essential for production of intestinal mucus. Proc. Natl Acad. Sci. USA 106, 6950–6955 (2009).
Zhao, F. et al. Disruption of Paneth and goblet cell homeostasis and increased endoplasmic reticulum stress in Agr2-/- mice. Dev. Biol. 338, 268–277 (2010).
Zheng, W. et al. Evaluation of AGR2 and AGR3 as candidate genes for inflammatory bowel disease. Genes Immun. 7, 11–18 (2006).
Cloots, E. et al. Evolution and function of the epithelial cell-specific ER stress sensor IRE1β. Mucosal Immunol. 14, 1235–1246 (2021).
Heazlewood, C. K. et al. Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med. 5, e54 (2008).
McGuckin, M. A., Eri, R. D., Das, I., Lourie, R. & Florin, T. H. ER stress and the unfolded protein response in intestinal inflammation. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G820–G832 (2010).
Litvak, Y., Byndloss, M. X. & Baumler, A. J. Colonocyte metabolism shapes the gut microbiota. Science https://doi.org/10.1126/science.aat9076 (2018).
Montgomery, R. K., Mulberg, A. E. & Grand, R. J. Development of the human gastrointestinal tract: twenty years of progress. Gastroenterology 116, 702–731 (1999).
Stanford, A. H. et al. A direct comparison of mouse and human intestinal development using epithelial gene expression patterns. Pediatr. Res. 88, 66–76 (2020).
Gomes, J. R. et al. Goblet cells and intestinal alkaline phosphatase expression (IAP) during the development of the rat small intestine. Acta Histochem. 119, 71–77 (2017).
Lev, R., Siegel, H. I. & Bartman, J. Histochemical studies of developing human fetal small intestine. Histochemie 29, 103–119 (1972).
Elmentaite, R. et al. Single-cell sequencing of developing human gut reveals transcriptional links to childhood Crohn’s disease. Dev. Cell 55, 771–783.e5 (2020).
Buisine, M. P. et al. Mucin gene expression in human embryonic and fetal intestine. Gut 43, 519–524 (1998).
Chambers, J. A., Hollingsworth, M. A., Trezise, A. E. & Harris, A. Developmental expression of mucin genes MUC1 and MUC2. J. Cell Sci. 107, 413–424 (1994).
Fawkner-Corbett, D. et al. Spatiotemporal analysis of human intestinal development at single-cell resolution. Cell 184, 810–826.e23 (2021).
Gao, S. et al. Tracing the temporal-spatial transcriptome landscapes of the human fetal digestive tract using single-cell RNA-sequencing. Nat. Cell Biol. 20, 721–734 (2018).
Colony, P. C. & Specian, R. D. Endocytosis and vesicular traffic in fetal and adult colonic goblet cells. Anat. Rec. 218, 365–372 (1987).
Colony, P. C. & Neutra, M. R. Epithelial differentiation in the fetal rat colon. I. Plasma membrane phosphatase activities. Dev. Biol. 97, 349–363 (1983).
Mathan, M., Moxey, P. C. & Trier, J. S. Morphogenesis of fetal rat duodenal villi. Am. J. Anat. 146, 73–92 (1976).
Sumigray, K. D., Terwilliger, M. & Lechler, T. Morphogenesis and compartmentalization of the intestinal crypt. Dev. Cell 45, 183–197.e5 (2018).
Arévalo Sureda, E., Weström, B., Pierzynowski, S. G. & Prykhodko, O. Maturation of the intestinal epithelial barrier in neonatal rats coincides with decreased FcRn expression, replacement of vacuolated enterocytes and changed Blimp-1 expression. PLoS ONE 11, e0164775 (2016).
Skrzypek, T. et al. The contribution of vacuolated foetal-type enterocytes in the process of maturation of the small intestine in piglets. J. Anim. Feed. Sci. 27, 187–201 (2018).
Clark, S. L. Jr. The ingestion of proteins and colloidal materials by columnar absorptive cells of the small intestine in suckling rats and mice. J. Biophys. Biochem. Cytol. 5, 41–50 (1959).
Reisinger, K. W. et al. Intestinal fatty acid-binding protein: a possible marker for gut maturation. Pediatr. Res. 76, 261–268 (2014).
Israel, E. J., Simister, N., Freiberg, E., Caplan, A. & Walker, W. A. Immunoglobulin G binding sites on the human foetal intestine: a possible mechanism for the passive transfer of immunity from mother to infant. Immunology 79, 77–81 (1993).
Malmuthuge, N. & Griebel, P. J. Fetal environment and fetal intestine are sterile during the third trimester of pregnancy. Vet. Immunol. Immunopathol. 204, 59–64 (2018).
Perez-Munoz, M. E., Arrieta, M. C., Ramer-Tait, A. E. & Walter, J. A critical assessment of the “sterile womb” and “in utero colonization” hypotheses: implications for research on the pioneer infant microbiome. Microbiome 5, 48 (2017).
Urushiyama, D. et al. Microbiome profile of the amniotic fluid as a predictive biomarker of perinatal outcome. Sci. Rep. 7, 12171 (2017).
Wang, L. X. et al. Epidermal growth factor promotes intestinal secretory cell differentiation in weaning piglets via Wnt/β-catenin signalling. Animal 14, 790–798 (2020).
Bergström, A. et al. Nature of bacterial colonization influences transcription of mucin genes in mice during the first week of life. BMC Res. Notes 5, 402 (2012).
Fança-Berthon, P. et al. Intrauterine growth restriction alters postnatal colonic barrier maturation in rats. Pediatr. Res. 66, 47–52 (2009).
McDole, J. R. et al. Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature 483, 345–349 (2012).
Hansen, G. H., Rasmussen, K., Niels-Christiansen, L. L. & Danielsen, E. M. Endocytic trafficking from the small intestinal brush border probed with FM dye. Am. J. Physiol. Gastrointest. Liver Physiol. 297, G708–G715 (2009).
Knoop, K. A., McDonald, K. G., McCrate, S., McDole, J. R. & Newberry, R. D. Microbial sensing by goblet cells controls immune surveillance of luminal antigens in the colon. Mucosal Immunol. 8, 198–210 (2015).
Noah, T. K. et al. IL-13-induced intestinal secretory epithelial cell antigen passages are required for IgE-mediated food-induced anaphylaxis. J. Allergy Clin. Immunol. 144, 1058–1073.e3 (2019).
Gustafsson, J. K. et al. Intestinal goblet cells sample and deliver lumenal antigens by regulated endocytic uptake and transcytosis. eLife 10, e67292 (2021).
Knoop, K. A. et al. Antibiotics promote the sampling of luminal antigens and bacteria via colonic goblet cell associated antigen passages. Gut Microbes 8, 400–411 (2017).
Knoop, K. A. et al. Microbial antigen encounter during a preweaning interval is critical for tolerance to gut bacteria. Sci. Immunol. 2, eaao1314 (2017).
Al Nabhani, Z. et al. A weaning reaction to microbiota is required for resistance to immunopathologies in the adult. Immunity 50, 1276–1288.e5 (2019).
Shan, M. et al. Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals. Science 342, 447–453 (2013).
Barrios, B. E., Maccio-Maretto, L., Nazar, F. N. & Correa, S. G. A selective window after the food-intake period favors tolerance induction in mesenteric lymph nodes. Mucosal Immunol. 12, 108–116 (2019).
Barbosa, F. L. et al. Goblet cells contribute to ocular surface immune tolerance-implications for dry eye disease. Int. J. Mol. Sci. https://doi.org/10.3390/ijms18050978 (2017).
Ko, B. Y., Xiao, Y., Barbosa, F. L., de Paiva, C. S. & Pflugfelder, S. C. Goblet cell loss abrogates ocular surface immune tolerance. JCI Insight https://doi.org/10.1172/jci.insight.98222 (2018).
Kulkarni, D. H. et al. Goblet cell associated antigen passages are inhibited during Salmonella typhimurium infection to prevent pathogen dissemination and limit responses to dietary antigens. Mucosal Immunol. 11, 1103–1113 (2018).
Wlodarska, M. et al. NLRP6 inflammasome orchestrates the colonic host–microbial interface by regulating goblet cell mucus secretion. Cell 156, 1045–1059 (2014).
Volk, J. K. et al. The Nlrp6 inflammasome is not required for baseline colonic inner mucus layer formation or function. J. Exp. Med. 216, 2602–2618 (2019).
Grootjans, J. et al. Ischaemia-induced mucus barrier loss and bacterial penetration are rapidly counteracted by increased goblet cell secretory activity in human and rat colon. Gut 62, 250–258 (2013).
Grootjans, J., Hundscheid, I. H. & Buurman, W. A. Goblet cell compound exocytosis in the defense against bacterial invasion in the colon exposed to ischemia–reperfusion. Gut Microbes 4, 232–235 (2013).
Johansson, M. E. & Hansson, G. C. The goblet cell: a key player in ischaemia–reperfusion injury. Gut 62, 188–189 (2013).
Sovran, B. et al. Age-associated impairment of the mucus barrier function is associated with profound changes in microbiota and immunity. Sci. Rep. 9, 1437 (2019).
Hansen, A. K., Hansen, C. H., Krych, L. & Nielsen, D. S. Impact of the gut microbiota on rodent models of human disease. World J. Gastroenterol. 20, 17727–17736 (2014).
Johansson, M. E. et al. Bacteria penetrate the inner mucus layer before inflammation in the dextran sulfate colitis model. PLoS ONE 5, e12238 (2010).
Liu, J. Z. & Anderson, C. A. Genetic studies of Crohn’s disease: past, present and future. Best. Pract. Res. Clin. Gastroenterol. 28, 373–386 (2014).
Adolph, T. E. et al. Paneth cells as a site of origin for intestinal inflammation. Nature 503, 272–276 (2013).
Wehkamp, J. & Stange, E. F. An update review on the Paneth cell as key to ileal Crohn’s disease. Front. Immunol. 11, 646 (2020).
Kaser, A. et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134, 743–756 (2008).
Lassen, K. G. et al. Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense. Proc. Natl Acad. Sci. USA 111, 7741–7746 (2014).
Pullan, R. D. Colonic mucus, smoking and ulcerative colitis. Ann. R. Coll. Surg. Engl. 78, 85–91 (1996).
Pullan, R. D. et al. Thickness of adherent mucus gel on colonic mucosa in humans and its relevance to colitis. Gut 35, 353–359 (1994).
Nonnecke, E. B. et al. Human intelectin-1 (ITLN1) genetic variation and intestinal expression. Sci. Rep. 11, 12889 (2021).
Strugala, V., Dettmar, P. W. & Pearson, J. P. Thickness and continuity of the adherent colonic mucus barrier in active and quiescent ulcerative colitis and Crohn’s disease. Int. J. Clin. Pract. 62, 762–769 (2008).
Gersemann, M. et al. Differences in goblet cell differentiation between Crohn’s disease and ulcerative colitis. Differentiation 77, 84–94 (2009).
Coleman, O. I. & Haller, D. ER stress and the UPR in shaping intestinal tissue homeostasis and immunity. Front. Immunol. https://doi.org/10.3389/fimmu.2019.02825 (2019).
Tawiah, A. et al. High MUC2 mucin biosynthesis in goblet cells impedes restitution and wound healing by elevating endoplasmic reticulum stress and altered production of growth factors. Am. J. Pathol. 188, 2025–2041 (2018).
Wilson, R. et al. Identification of key pro-survival proteins in isolated colonic goblet cells of Winnie, a murine model of spontaneous colitis. Inflamm. Bowel Dis. 26, 80–92 (2020).
Wang, R. et al. Gut microbiota shape the inflammatory response in mice with an epithelial defect. Gut Microbes 13, 1887720 (2021).
Das, I. et al. Glucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteins. J. Exp. Med. 210, 1201–1216 (2013).
Larsson, J. M. et al. Altered O-glycosylation profile of MUC2 mucin occurs in active ulcerative colitis and is associated with increased inflammation. Inflamm. Bowel Dis. 17, 2299–2307 (2011).
Tytgat, K. M., van der Wal, J. W., Einerhand, A. W., Buller, H. A. & Dekker, J. Quantitative analysis of MUC2 synthesis in ulcerative colitis. Biochem. Biophys. Res. Commun. 224, 397–405 (1996).
Xiao, F. et al. Slc26a3 deficiency is associated with loss of colonic HCO secretion, absence of a firm mucus layer and barrier impairment in mice. Acta Physiol. https://doi.org/10.1111/apha.12220 (2013).
Gurney, M. A., Laubitz, D., Ghishan, F. K. & Kiela, P. R. Pathophysiology of Intestinal Na+/H+ exchange. Cell. Mol. Gastroenterol. Hepatol. 3, 27–40 (2017).
Sellon, R. K. et al. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect. Immun. 66, 5224–5231 (1998).
Rigottier-Gois, L. Dysbiosis in inflammatory bowel diseases: the oxygen hypothesis. ISME J. 7, 1256–1261 (2013).
Guo, X. Y., Liu, X. J. & Hao, J. Y. Gut microbiota in ulcerative colitis: insights on pathogenesis and treatment. J. Dig. Dis. 21, 147–159 (2020).
Jakobsson, H. E. et al. The composition of the gut microbiota shapes the colon mucus barrier. EMBO Rep. 16, 164–177 (2015).
Miyauchi, E. et al. Analysis of colonic mucosa-associated microbiota using endoscopically collected lavage. Sci. Rep. 12, 1758 (2022).
Li, H. et al. The outer mucus layer hosts a distinct intestinal microbial niche. Nat. Commun. 6, 8292 (2015).
Lavelle, A. et al. Spatial variation of the colonic microbiota in patients with ulcerative colitis and control volunteers. Gut 64, 1553–1561 (2015).
Sunderhauf, A. et al. Loss of mucosal p32/gC1qR/HABP1 triggers energy deficiency and impairs goblet cell differentiation in ulcerative colitis. Cell. Mol. Gastroenterol. Hepatol. 12, 229–250 (2021).
Kumar, M. et al. Increased intestinal permeability exacerbates sepsis through reduced hepatic SCD-1 activity and dysregulated iron recycling. Nat. Commun. 11, 483 (2020).
Ozdirik, B., Muller, T., Wree, A., Tacke, F. & Sigal, M. The role of microbiota in primary sclerosing cholangitis and related biliary malignancies. Int. J. Mol. Sci. https://doi.org/10.3390/ijms22136975 (2021).
Fenton, C. G., Taman, H., Florholmen, J., Sorbye, S. W. & Paulssen, R. H. Transcriptional signatures that define ulcerative colitis in remission. Inflamm. Bowel Dis. 27, 94–105 (2021).
Bergstrom, K. S. et al. Muc2 protects against lethal infectious colitis by disassociating pathogenic and commensal bacteria from the colonic mucosa. PLoS. Pathog. 6, e1000902 (2010).
Sharpe, C., Thornton, D. J. & Grencis, R. K. A sticky end for gastrointestinal helminths; the role of the mucus barrier. Parasite Immunol. 40, e12517 (2018).
Hasnain, S. Z., Gallagher, A. L., Grencis, R. K. & Thornton, D. J. A new role for mucins in immunity: insights from gastrointestinal nematode infection. Int. J. Biochem. Cell Biol. 45, 364–374 (2013).
Allain, T., Amat, C. B., Motta, J. P., Manko, A. & Buret, A. G. Interactions of Giardia sp. with the intestinal barrier: epithelium, mucus, and microbiota. Tissue Barriers 5, e1274354 (2017).
Furter, M., Sellin, M. E., Hansson, G. C. & Hardt, W. D. Mucus architecture and near-surface swimming affect distinct Salmonella typhimurium infection patterns along the murine intestinal tract. Cell Rep. 27, 2665–2678.e3 (2019).
van der Post, S. et al. Site-specific O-glycosylation on the MUC2 mucin protein inhibits cleavage by the Porphyromonas gingivalis secreted cysteine protease (RgpB). J. Biol. Chem. 288, 14636–14646 (2013).
Haider, K. et al. Production of mucinase and neuraminidase and binding of Shigella to intestinal mucin. J. Diarrhoeal Dis. Res. 11, 88–92 (1993).
Luo, Q. et al. Enterotoxigenic Escherichia coli secretes a highly conserved mucin-degrading metalloprotease to effectively engage intestinal epithelial cells. Infect. Immun. 82, 509–521 (2014).
Gibold, L. et al. The Vat-AIEC protease promotes crossing of the intestinal mucus layer by Crohn’s disease-associated Escherichia coli. Cell. Microbiol. 18, 617–631 (2016).
Schauer, D. B. & Falkow, S. Attaching and effacing locus of a Citrobacter freundii biotype that causes transmissible murine colonic hyperplasia. Infect. Immun. 61, 2486–2492 (1993).
Cornelis, G. R. The Yersinia deadly kiss. J. Bacteriol. 180, 5495–5504 (1998).
Levine, M. M. et al. Pathogenesis of Shigella dysenteriae 1 (Shiga) dysentery. J. Infect. Dis. 127, 261–270 (1973).
Hansen-Wester, I., Stecher, B. & Hensel, M. Type III secretion of Salmonella enterica serovar typhimurium translocated effectors and SseFG. Infect. Immun. 70, 1403–1409 (2002).
Teschler, J. K. et al. Living in the matrix: assembly and control of Vibrio cholerae biofilms. Nat. Rev. Microbiol. 13, 255–268 (2015).
Scaletsky, I. C., Silva, M. L. & Trabulsi, L. R. Distinctive patterns of adherence of enteropathogenic Escherichia coli to HeLa cells. Infect. Immun. 45, 534–536 (1984).
Nikitas, G. et al. Transcytosis of Listeria monocytogenes across the intestinal barrier upon specific targeting of goblet cell accessible E-cadherin. J. Exp. Med. 208, 2263–2277 (2011).
Van Houdt, R. & Michiels, C. W. Role of bacterial cell surface structures in Escherichia coli biofilm formation. Res. Microbiol. 156, 626–633 (2005).
Sansonetti, P. J. & Phalipon, A. M cells as ports of entry for enteroinvasive pathogens: mechanisms of interaction, consequences for the disease process. Semin. Immunol. 11, 193–203 (1999).
Fasciano, A. C. et al. Yersinia pseudotuberculosis YopE prevents uptake by M cells and instigates M cell extrusion in human ileal enteroid-derived monolayers. Gut Microbes 13, 1988390 (2021).
Clark, M. A., Jepson, M. A., Simmons, N. L. & Hirst, B. H. Preferential interaction of Salmonella typhimurium with mouse Peyer’s patch M cells. Res. Microbiol. 145, 543–552 (1994).
Wassef, J. S., Keren, D. F. & Mailloux, J. L. Role of M cells in initial antigen uptake and in ulcer formation in the rabbit intestinal loop model of shigellosis. Infect. Immun. 57, 858–863 (1989).
Grützkau, A., Hanski, C., Hahn, H. & Riecken, E. O. Involvement of M cells in the bacterial invasion of Peyer’s patches: a common mechanism shared by Yersinia enterocolitica and other enteroinvasive bacteria. Gut 31, 1011–1015 (1990).
Kim, M., Fevre, C., Lavina, M., Disson, O. & Lecuit, M. Live imaging reveals Listeria hijacking of E-cadherin recycling as it crosses the intestinal barrier. Curr. Biol. 31, 1037–1047.e4 (2021).
Linden, S. K. et al. Listeria monocytogenes internalins bind to the human intestinal mucin MUC2. Arch. Microbiol. 190, 101–104 (2008).
Hohmann, A. W., Schmidt, G. & Rowley, D. Intestinal colonization and virulence of Salmonella in mice. Infect. Immun. 22, 763–770 (1978).
Tran, E. N. H. et al. Shigella flexneri targets human colonic goblet cells by O antigen binding to sialyl-Tn and Tn antigens via glycan–glycan interactions. ACS Infect. Dis. 6, 2604–2615 (2020).
Clark, M. A., Hirst, B. H. & Jepson, M. A. M-cell surface β1 integrin expression and invasin-mediated targeting of Yersinia pseudotuberculosis to mouse Peyer’s patch M cells. Infect. Immun. 66, 1237–1243 (1998).
Knoop, K. A. et al. Maternal activation of the EGFR prevents translocation of gut-residing pathogenic Escherichia coli in a model of late-onset neonatal sepsis. Proc. Natl Acad. Sci. USA 117, 7941–7949 (2020).
Liang, K., Wei, L. & Chen, L. Exocytosis, endocytosis, and their coupling in excitable cells. Front. Mol. Neurosci. 10, 109 (2017).
Wu, L. G., Hamid, E., Shin, W. & Chiang, H. C. Exocytosis and endocytosis: modes, functions, and coupling mechanisms. Annu. Rev. Physiol. 76, 301–331 (2014).
Cortez, V. et al. Astrovirus infects actively secreting goblet cells and alters the gut mucus barrier. Nat. Commun. 11, 2097 (2020).
Ingle, H. et al. Murine astrovirus tropism for goblet cells and enterocytes facilitates an IFN-λ response in vivo and in enteroid cultures. Mucosal Immunol. 14, 751–761 (2021).
Good, C., Wells, A. I. & Coyne, C. B. Type III interferon signaling restricts enterovirus 71 infection of goblet cells. Sci. Adv. 5, eaau4255 (2019).
Holly, M. K. & Smith, J. G. Adenovirus infection of human enteroids reveals interferon sensitivity and preferential infection of goblet cells. J. Virol. https://doi.org/10.1128/JVI.00250-18 (2018).
Cortez, V. & Schultz-Cherry, S. The role of goblet cells in viral pathogenesis. FEBS J. 288, 7060–7072 (2021).
Holm, L. & Phillipson, M. Assessment of mucus thickness and production in situ. Methods Mol. Biol. 842, 217–227 (2012).
Vunjak-Novakovic, G., Ronaldson-Bouchard, K. & Radisic, M. Organs-on-a-chip models for biological research. Cell 184, 4597–4611 (2021).
Sato, T. & Clevers, H. Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. Science 340, 1190–1194 (2013).
VanDussen, K. L. et al. Development of an enhanced human gastrointestinal epithelial culture system to facilitate patient-based assays. Gut 64, 911–920 (2015).
Wang, Y., Kim, R., Sims, C. E. & Allbritton, N. L. Building a thick mucus hydrogel layer to improve the physiological relevance of in vitro primary colonic epithelial models. Cell. Mol. Gastroenterol. Hepatol. 8, 653–655.e5 (2019).
Knoop, K. A. et al. In vivo labeling of epithelial cell-associated antigen passages in the murine intestine. Lab. Anim. 49, 79–88 (2020).
Johansson, M. E. V. & Hansson, G. C. in Mucins: Methods and Protocols (eds McGuckin, M. A. & Thornton, D. J.) 229–235 (Humana, 2012).
Johansson, M. E. V. & Hansson, G. C. in Mucins: Methods and Protocols (eds McGuckin, M. A. & Thornton, D. J.) 109–121 (Humana, 2012).
Miyoshi, H. & Stappenbeck, T. S. In vitro expansion and genetic modification of gastrointestinal stem cells in spheroid culture. Nat. Protoc. 8, 2471–2482 (2013).
Sato, T. et al. Single Lgr5 stem cells build crypt–villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009).
Moriya, S. et al. Macrolide antibiotics block autophagy flux and sensitize to bortezomib via endoplasmic reticulum stress-mediated CHOP induction in myeloma cells. Int. J. Oncol. 42, 1541–1550 (2013).
van der Post, S., Birchenough, G. M. H. & Held, J. M. NOX1-dependent redox signaling potentiates colonic stem cell proliferation to adapt to the intestinal microbiota by linking EGFR and TLR activation. Cell Rep. 35, 108949 (2021).
Liu, J., Walker, N. M., Ootani, A., Strubberg, A. M. & Clarke, L. L. Defective goblet cell exocytosis contributes to murine cystic fibrosis-associated intestinal disease. J. Clin. Invest. 125, 1056–1068 (2015).
Wang, Y. et al. Long-term culture captures injury–repair cycles of colonic stem cells. Cell 179, 1144–1159.e15 (2019).
Wang, Y. et al. A microengineered collagen scaffold for generating a polarized crypt–villus architecture of human small intestinal epithelium. Biomaterials 128, 44–55 (2017).
Wang, Y. et al. Formation of human colonic crypt array by application of chemical gradients across a shaped epithelial monolayer. Cell. Mol. Gastroenterol. Hepatol. 5, 113–130 (2018).
Nikolaev, M. et al. Homeostatic mini-intestines through scaffold-guided organoid morphogenesis. Nature 585, 574–578 (2020).
Dutton, J. S., Hinman, S. S., Kim, R., Wang, Y. & Allbritton, N. L. Primary cell-derived intestinal models: recapitulating physiology. Trends Biotechnol. 37, 744–760 (2019).
Acknowledgements
The authors were supported by the Swedish Research Council (2020-01588, 2019-0113420), the Crohn’s and Colitis foundation (580014) and the Sahlgrenska University Hospital (ALFGBG-724681, ALFGBG-965686). The authors thank S. van der Post and T. Pelaseyed for their constructive feedback and comments.
Author information
Authors and Affiliations
Contributions
The authors contributed equally to all aspects of the article.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature Reviews Gastroenterology & Hepatology thanks Michael McGuckin, Sumaira Hasnain and the other, anonymous, reviewer for their contribution to the peer review of this work.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Gustafsson, J.K., Johansson, M.E.V. The role of goblet cells and mucus in intestinal homeostasis. Nat Rev Gastroenterol Hepatol 19, 785–803 (2022). https://doi.org/10.1038/s41575-022-00675-x
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41575-022-00675-x
This article is cited by
-
The role of goblet cells in Crohn’ s disease
Cell & Bioscience (2024)
-
SLE serum induces altered goblet cell differentiation and leakiness in human intestinal organoids
EMBO Molecular Medicine (2024)
-
Acute gastrointestinal permeability after traumatic brain injury in mice precedes a bloom in Akkermansia muciniphila supported by intestinal hypoxia
Scientific Reports (2024)
-
Neonatal intestinal mucus barrier changes in response to maturity, inflammation, and sodium decanoate supplementation
Scientific Reports (2024)
-
Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
Signal Transduction and Targeted Therapy (2024)
