image: Goblet cells (GCs) play a multifaceted role in the mucosal immune system, including (A) Mucin secretion: GCs constantly produce mucins forming a protective gel layer on the surface of the intestine. This mucus barrier acts as a first line of defence, trapping pathogens and preventing them from reaching the underlying tissues. Under normal circumstances, the thickness of this gel remains upheld through continuous mucin secretion. Nevertheless, when the gut faces challenges such as microbial intrusion or harsh stimuli, GCs undergo stimulation to accelerate mucin release. Both, physiological or pathological stimuli, result in a marked increase in intracellular calcium ions (Ca2+)-triggered stimulated mucus secretion. Various factors like neuropeptides, cytokines and lipids further influence the stimulated mucin release. On acetylcholine (ACh) exposure, the activation of muscarinic ACh receptor 1 (mAChR1) also triggers the mobilisation of Ca2+ from intracellular reserves contributing to mucus secretion and effectively displacing pathogens from the gut lining. (B) Other secretory functions: The release of chemokines and cytokines initiates and strengthens Th2 responses facilitating tissue repair and attracting effector cells that perform functions crucial to innate immunity extending beyond mere barrier maintenance. GCs also discharge antimicrobial peptides (AMPs) including resistin-like molecule ß, regenerating islet-derived 3 proteins and trefoil factor which effectively eliminate commensal bacteria and pathogens that breach the mucus layer. (C) GC-associated antigen passages (GAPs): Activation of mAChR4 by ACh initiates a process termed fluid-phase bulk endocytosis culminating in the formation of GAPs in the small intestine. Endocytic vesicles containing luminal fluid-phase cargo are transported through the cell for degradation, membrane recycling and transcytosis. This allows the cargo to be acquired by lamina propria dendritic cells (LP-DCs). The main LP-DCs subset subadjacent to GAPs is the CD103+CX3CR1− subset and possesses preferential tolerogenic properties. Created with BioRender.com. E.R., endoplasmic reticulum; IEC, intestinal epithelial cells.
Credit: By Fernanda Raya Tonetti, Alvaro Eguileor, Cristina Llorente.
In a recent study, researchers at the University of California, San Diego, have provided new insights into the central role of goblet cells—specialized cells that line the gut—in maintaining a healthy and balanced immune environment within the gastrointestinal (GI) tract. Led by Dr Fernanda Raya Tonetti, with Dr. Cristina Llorente directing the project and making significant contributions, the study underscores the critical roles of these cells, which act not only as a physical barrier but also as a sophisticated communication link between the gut lining and the immune system.
Goblet cells secrete mucus, forming a protective layer that prevents harmful pathogens from reaching the inner gut tissues. However, Dr Llorente points out that these cells serve far beyond mucus production: "Goblet cells are dynamic guardians of gut immunity, engaging in multiple protective actions that include not only pathogen defense but also immune system modulation to ensure a balanced response."
The researchers discuss the role of goblet cells in creating specialized structures known as Goblet Cell-Associated Passages (GAPs), which act as channels through which immune cells can access the contents of the gut lumen. This unique function enables the education of the immune system by sampling benign dietary substances and regular microbiota while monitoring for harmful invaders, maintaining gut tolerance, and preventing unnecessary immunogenic responses.
The study also reveals a critical relationship between goblet cells and the gut microbiome—the community of trillions of microbes in the GI tract. This relationship is mutually supportive: beneficial gut bacteria promote healthy goblet cell function, while goblet cells produce the necessary environment for a balanced microbiome. However, disruptions to this balance, such as from infections or dietary changes, can impair goblet cell function, potentially contributing to various GI diseases, including colorectal cancer, inflammatory bowel disease, cystic fibrosis, and liver diseases.
Dr Tonetti states, "This interplay between goblet cells and the gut microbiome is essential to sustaining both a strong immune defense and tolerance."
The findings open promising avenues for therapies that target goblet cell functions and could help develop treatments for GI diseases affecting millions globally. By harnessing goblet cells’ unique protective mechanisms, future therapies could reduce inflammation, support gut barrier integrity, and restore healthy microbiome balance. Dr. Llorente and her team believe these therapies could represent a breakthrough for conditions that are difficult to manage with current treatment options.
See the article:
Raya Tonetti F, Eguileor A, Llorente C. Goblet cells: guardians of gut immunity and their role in gastrointestinal diseases. eGastroenterology 2024;2:e100098. doi:10.1136/egastro-2024-100098
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Goblet cells: guardians of gut immunity and their role in gastrointestinal diseases