Goblet Cells

The primary function of goblet cells is the production of polymeric gel-forming mucins (and other mucus proteins) to form an external barrier that protects the mucosal surfaces of the body. In the intestine, a characteristic feature of these goblet cells is the production of Mucin 2 (MUC2) that underpins the structural integrity of the mucus barrier. Intestinal epithelial goblet cells increase in density from the duodenum to the distal colon, where they comprise up to 50% of the total colonic epithelium. The small intestine has a thin, permeable mucus layer, whereas in the colon there are two highly organised layers, where the inner mucus is impenetrable to bacteria of the microbiome (Johansson et al., 2011).

The importance of goblet cell production of MUC2 has been highlighted in murine models of Muc2 deletion or mutation. These different models resulted in major intestinal inflammation, leading to the development of symptoms resembling human ulcerative colitis (Heazlewood et al., 2008) and tumours (Velcich et al., 2002) as well as loss of protection against infection (Hasnain et al., 2010).

Goblet cells are named for their cup-like shape, in which the wider upper half (theca) is densely packed with granules containing fully formed MUC2 polymers, stored and ready for rapid secretion to form mucus. These cells are specialised to synthesise and intracellularly assemble the enormous mucin polymers. Following translation, MUC2 undergoes a complex biosynthetic process including extensive post-translational modification of the MUC2 polypeptide with O-glycan chains (in the Golgi) and disulfide-mediated polymer assembly (polypeptide dimers form in the ER and are multimerized in the Golgi). O-glycans make up around 80% of the total molecular mass of mature MUC2, and this is crucial for maintaining mucus hydration, as well as regulating the gut microbiota.

Alongside MUC2, goblet cells secrete several highly abundant proteins, including Trefoil factor 3 (TFF3), Calcium-activated chloride channel regulator (CLCA1) and IgG Fc-binding protein (FCGBP). These proteins are likely involved in the structural integrity and physical barrier properties of intestinal mucus; however their exact functions are still an active area of investigation (Nyström et al., 2019, Ehrencrona et al., 2025).

Goblet cells also produce and secrete antimicrobial products that act as a chemical barrier. These include resistin-like molecule β (RELMβ) and zymogen granule protein (ZG16) that bind specifically to intestinal parasites and microbes, trapping them within the mucus barrier and preventing their contact with the intestinal epithelium (Bergström et al., 2016, Artis et al., 2004)

One of the major challenges in mucus research is the limited availability of experimental in vitro models that can mimic the human intestinal complex mucus network. Cell lines containing goblet-like cells such as LS174T cells and HT29-MTX cells are often used, but they differ in mucin production and morphology in comparison to primary goblet cells. Intestinal organoid systems are improving upon this; however true replication of mucus organisation and secretion is still lacking. Thus, many observations that fuel our understanding of goblet cells and the mucus they produce stem from the use of animal models, including rodents and pigs.

Whilst goblet cells were traditionally thought to only be secretory cells, more recent work has highlighted their ability and role in endocytosis. Goblet cells take up small antigens from the intestinal lumen and present them to dendritic cells in the lamina propria through goblet cell associated passages (GAPs) (McDole et al., 2012). This process is thought to promote immune tolerance towards commensal bacteria to prevent excessive inflammation.

The future of goblet cell research relies on the use of emerging technologies. Single-cell transcriptomics has revealed that, within the intestine, there are subsets of goblet cells, that may have unique functions and respond differently to challenge (Birchenough et al., 2016, Nyström et al., 2021). As well as this, a new appreciation for how goblet cells respond in the context of microbial cues and metabolites will further drive novel discoveries on goblet cell function.

Text authored by Isobelle Blair & David J Thornton

Manchester Cell Matrix Centre and Lydia Becker Institute of Immunology and Inflammation | School of Biological Sciences | Faculty of Biology, Medicine and Health | Manchester Academic Health Science Centre | The University of Manchester

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