Induction of intercrypt goblet cells upon bacterial infection

Abstract

Intestinal mucins play a crucial role in the mucosal barrier, serving as the bodys initial defense against microorganisms. However, how the host regulates the secretion and glycosylation of these mucins in response to bacterial invasion remains unclear. Our study demonstrates that when exposed to Streptococcus gallolyticus (SGG), a gut pathobiont, the host mucosa promptly adjusts the behavior of specialized goblet cells (GCs) located in the middle of the crypts. A subset of these cells undergoes a transformation, becoming intercrypt goblet cells (icGCs), which do not detach from the surface but instead migrate along intercrypt spaces while secreting mucins. These mucins form a dense layer covering the epithelial cell surface and filling the gaps between mucus plumes secreted from crypt openings, thereby forming a continuous protective mucus layer. Notably, the mucins produced by icGCs exhibit a distinct glycosylation pattern that makes them impermeable to bacterial pathogens. Significantly, a non-piliated SGG mutant unable to bind to mucus fail to induce icGCs, allowing its translocation through the mucosa and submucosa. Intriguingly, a closely related mucus-adherent bacterium, SGM, which is considered non-pathogenic, also triggers the differentiation of GCs into icGCs. This discovery opens new avenues for treating patients with intestinal diseases characterized by mucus layer deficiencies, such as inflammatory bowel diseases and metabolic disorders. Utilizing mucus-adherent probiotics to induce icGCs represents a promising strategy for reinforcing the mucosal barrier. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/601821v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@e8e11org.highwire.dtl.DTLVardef@19116bdorg.highwire.dtl.DTLVardef@6bd839org.highwire.dtl.DTLVardef@40b8aa_HPS_FORMAT_FIGEXP M_FIG C_FIG In briefWe demonstrate here that, upon oral infection by a gut pathobiont, namely Streptococcus gallolyticus, the murine intestinal mucosa displays a novel type of goblet cells recently described as intercrypt goblet cells (icGCs). These icGCs are not shed at the surface of epithelial cells, in contrast to differentiated goblet cells, and produce a continuous protective mucus layer, with a specific pattern of glycosylation rendering it impenetrable to bacteria. No icGCs were induced in response to a non-mucus binding SGG mutant, thus allowing bacterial translocation into the mucosa and submucosa, highlighting the essential role played by icGCs in the protective mucus barrier function. Importantly, SGM, a commensal mucus-adherent bacterium recognized as safe, is also able to stimulate production of icGCs, opening avenues in the treatment of patients with a "leaky gut". HighlightsO_LIInduction of intercrypt goblet cells in murine intestinal tract upon bacterial infection C_LIO_LIicGC potentially arise from differentiated goblet cells through cellular plasticity C_LIO_LIMucus produced by icGCs is critical for host defense and mucosal barrier function C_LIO_LICommensal mucus-adherent bacteria also induce icGCs, paving the way for new probiotic treatments for strengthening the mucosal barrier of patients with inflammatory bowel diseases and metabolic disorders C_LI