Lypd8 inhibits attachment of pathogenic bacteria to colonic epithelia

Okumura, Ryu; Kodama, Takao; Hsu, Chiao-Ching; Sahlgren, Benjamin Heller; Hamano, Shota; Kurakawa, Takashi; Iida, Tetsuya; Takeda, Kiyoshi

doi:10.1038/s41385-019-0219-4

Cited by 22 publications

(20 citation statements)

References 31 publications

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“…Shared down-regulated genes include CD177 and LYPD8 (Figure 3B), both of which are in the same family of proteins containing the LY6/PLAUR domain. The latter encodes a protein that protects the gut from microbial invasion and is critical for maintaining barrier integrity and preventing intestinal inflammation (Hsu et al, 2017; Okumura et al, 2020; Okumura et al, 2016). LYPD8 is expressed 5-fold greater in CEACAM7 + colonocytes compared to CA1 + late colonocytes, but it is significantly down-regulated in CD in both cell types (Figure 3E).…”

Section: Resultsmentioning

confidence: 99%

“…Although AQP8 has previously been shown to be suppressed in IBD (Ricanek et al, 2015), our study demonstrates for the first time that this effect is very likely driven by one specific colonocyte subtype. Furthermore, the significant reduction in CD of LYPD8 , which encodes an important anti-microbial factor (Hsu et al, 2017; Okumura et al, 2020; Okumura et al, 2016), in both CEACAM7 + colonocytes and CA1 + late colonocytes, is a possible indication of the beginning stages of impaired colonocyte contribution to barrier function. We also show that LYPD8 is reduced in expression in EECs from CD patients, which has not been demonstrated previously.…”

Section: Discussionmentioning

confidence: 99%

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Single-cell analysis of colonic epithelium reveals unexpected shifts in cellular composition and molecular phenotype in treatment-naïve adult Crohn’s disease

Kanke

Kennedy

Connelly

et al. 2021

Preprint

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The intestinal epithelial barrier is comprised of a monolayer of specialized intestinal epithelial cells (IECs) that are critical in maintaining gut mucosal homeostasis. Dysfunction within various IEC fractions can increase intestinal permeability, resulting in a chronic and debilitating condition known as Crohn’s disease (CD). Defining the molecular changes in each IEC type in CD will contribute to an improved understanding of the pathogenic processes and the identification of potential therapeutic targets. Here we performed, for the first time at single-cell resolution, a direct comparison of the colonic epithelial cellular and molecular landscape between treatment-naïve adult CD and non-IBD control patients. Our analysis revealed that in CD patients there is a significant skew in the colonic epithelial cellular distribution away from canonical LGR5+ stem cells, located at the crypt-bottom, and toward one specific subtype of mature colonocytes, located at the crypt-top. Further analysis revealed unique changes to gene expression programs in every major cell type, including a previously undescribed suppression in CD of most enteroendocrine driver genes as well as L-cell markers including GCG. We also dissect a previously poorly understood SPIB+ cell cluster, revealing at least four sub-clusters that exhibit unique features. One of these SPIB+ sub-clusters expresses crypt-top colonocyte markers and is significantly up-regulated in CD, whereas another sub-cluster strongly expresses and stains positive for lysozyme (albeit no other canonical Paneth cell marker), which surprisingly is greatly reduced in expression in CD. Finally, through integration with data from genome-wide association studies, we show that genes implicated in CD risk exhibit heretofore unknown cell-type specific patterns of aberrant expression in CD, providing unprecedented insight into the potential biological functions of these genes.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Single-cell analysis of colonic epithelium reveals unexpected shifts in cellular composition and molecular phenotype in treatment-naïve adult Crohn’s disease

Kanke

Kennedy

Connelly

et al. 2021

Preprint

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“…Lypd8 strongly causes early-phase defense against C. rodentium , which can induce colitis by triggering attachment and effacement (A/E) lesions on colonic epithelia. Mechanistically, Lypd8 inhibits C. rodentium attachment to intestinal epithelial cells by binding to intimin, thereby protecting against enteric bacterial pathogens 108 . sIgA secreted as a dimer by colonocytes and integrated into the mucus layer exerts a critical function in trapping luminal bacteria to prevent unrestricted access of the microbiota to the epithelial surface 109 .…”

Section: The Mucus Barrier Regulates Bacterial Colonizationmentioning

confidence: 99%

Slimy partners: the mucus barrier and gut microbiome in ulcerative colitis

et al. 2021

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Ulcerative colitis (UC) is a chronic recurrent intestinal inflammatory disease characterized by high incidence and young onset age. Recently, there have been some interesting findings in the pathogenesis of UC. The mucus barrier, which is composed of a mucin complex rich in O-glycosylation, not only provides nutrients and habitat for intestinal microbes but also orchestrates the taming of germs. In turn, the gut microbiota modulates the production and secretion of mucins and stratification of the mucus layers. Active bidirectional communication between the microbiota and its ‘slimy’ partner, the mucus barrier, seems to be a continually performed concerto, maintaining homeostasis of the gut ecological microenvironment. Any abnormalities may induce a disorder in the gut community, thereby causing inflammatory damage. Our review mainly focuses on the complicated communication between the mucus barrier and gut microbiome to explore a promising new avenue for UC therapy.

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“…ZG16 is a highly abundant protein in the colon that intertwines with the mucin polymeric network and contributes to space separation by binding to Gram-positive bacteria (131). Lypd8, a highly glycosylated glycosylphosphatidylinositol-anchored protein, binds flagellated bacteria and was recently shown to inhibit the attachment of Citrobacter rodentium to epithelial cells through competitive binding of bacterial intimin, thereby interrupting its interaction with the translocated intimin receptor (Tir) in the host (108,132). Lypd8 thus specializes in inhibiting the colonization of intestinal pathogens.…”

Section: Antimicrobial Activity Of Hdpsmentioning

confidence: 99%