Commensal bacteria direct selective cargo sorting to promote symbiosis

Zhang, Qin; Pan, Ying; Yan, Ruiqing; Zeng, Benhua; Wang, Haifang; Zhang, Xinwen; Li, Wenxia; Wei, Hong; Liu, Zhihua

doi:10.1038/ni.3233

Cited by 185 publications

(199 citation statements)

References 52 publications

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“…Interestingly, the only SNP within the pool of 56 selected alleles for hypothesis-driven correlation analysis that showed significant association with Paneth cell defects in Japanese CD was LRRK2 M2397T ( Figure 4C). The LRRK2 M2397T SNP (rs3761863) is a missense susceptibility allele for European ancestry CD (3,33), and Lrrk2 knockout mice have defective Paneth cells (34). In the Japanese CD cohort, we found that the numbers of the T (risk) allele LRRK2 M2397T correlated with the percentage of normal Paneth cells (R 2 = 0.247; P = 3.62 × 10 -4…”

Section: L I N I C a L M E D I C I N Ementioning

confidence: 74%

LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn’s disease patients

Liu¹,

Naito²,

Liu³

et al. 2017

JCI Insight

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IntroductionCrohn's disease (CD) and ulcerative colitis are 2 main classical types of inflammatory bowel disease (IBD) (1, 2). The etiology of IBD involves genetic susceptibility and environmental triggers. Over 200 single nucleotide polymorphisms (SNPs) have been associated with susceptibility to IBD (3-7). This complex genetic network indicates that IBD likely encompasses more than the 2 classical subtypes. Therefore, novel, rationally designed biomarkers that can lead to disease stratification and personalized treatments are needed (8). One candidate method to subtype CD is to define the morphological patterns of small intestinal Paneth cells based on the intracellular distribution of granules containing antimicrobial proteins (Paneth cell phenotypes) (7). Paneth cells are specialized secretory cells located at the bases of the crypts of Lieberkühn in the small intestine (9-11). These cells produce a wide repertoire of antimicrobial BACKGROUND. Morphological patterns of Paneth cells are a prognostic biomarker in Western Crohn's disease (CD) patients, and are associated with autophagy-associated ATG16L1 and NOD2 variants. We hypothesized that genetic determinants of Paneth cell phenotype in other ethnic CD cohorts are distinct but also involved in autophagy.

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Section: L I N I C a L M E D I C I N Ementioning

confidence: 74%

LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn’s disease patients

Liu¹,

Naito²,

Liu³

et al. 2017

JCI Insight

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“…In the gastrointestinal tract of CD patients, LRRK2 expression is restricted to lamina propria macrophages, dendritic cells and B lymphocytes and is induced by interferon-γ, which is consistent with its role in IBD (38). A recent study has found high expression of LRRK2 in Paneth cells in the ileum demonstrating that both NOD2 and LRRK2 are required for proper lysosomal sorting within Paneth cells (31). Our correlations of N2081D in LRRK2 to an earlier age of CD onset and an ileal location mirror previously reported NOD2 risk allele phenotypic correlations.…”

Section: Discussionmentioning

confidence: 99%

Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease

et al. 2018

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Crohn’s disease (CD), a form of inflammatory bowel disease, has a higher prevalence in Ashkenazi Jewish than in non-Jewish European populations. To define the role of non-synonymous mutations, we performed exome sequencing of Ashkenazi Jewish patients with CD, followed by array-based genotyping and association analysis in 2,066 CD cases and 3,633 healthy controls. We detected association signals in the LRRK2 gene that conferred CD risk (N2081D variant, P=9.5×10−10) or protection (N551K variant, tagging R1398H-associated haplotype, P=3.3×10−8). These variants affected CD age of onset, disease location, LRRK2 activity, and autophagy. Bayesian network analysis of CD patient intestinal tissue further implicated LRRK2 in CD pathogenesis. Analysis of the extended LRRK2 locus in 24,570 CD cases, patients with Parkinson’s disease (PD), and healthy controls revealed extensive pleiotropy, with similar genetic effects between CD and PD in both Ashkenazi Jewish and non-Jewish cohorts. The LRRK2 N2081D CD risk allele is located in the same kinase domain as G2019S, a mutation that is the major genetic cause of familial and sporadic PD. Like the G2019S mutation, the N2081D variant is associated with increased kinase activity, whereas neither N551K nor R1398H on the protective haplotype altered kinase activity. R1398H, but not N551K, increased GTPase activity, thereby deactivating LRRK2. The presence of shared LRRK2 alleles in CD and PD provides refined insight into disease mechanisms and may have major implications for the treatment of these two seemingly unrelated diseases.

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“…Despite such progress, the cellular and molecular mechanisms underlying the intestinal abnormalities in Nod2 −/− mice remain to be further investigated. A recent study has shown that sensing of microbes by Nod2 directs lysozyme sorting in Paneth cells (Zhang et al, 2015). In Paneth cells of germ-free mice or Nod2 −/− mice, newly synthesized lysozyme is targeted to lysosomes for degradation.…”

Section: The Cellular Processes Modulated By Commensal Bacteria In Pamentioning

confidence: 99%

“…Lysozyme, but not other AMPs, is selectively depleted from DCVs in Lrrk2 −/− Paneth cells (Zhang et al, 2015). LRRK2, originally identified as a gene most mutated in autosomal dominant familial Parkinson's disease (Paisan-Ruiz et al, 2004;Zimprich et al, 2004), encodes a major susceptibility gene for CD (Anderson et al, 2011;Barrett et al, 2008;Franke et al, 2010;Paisan-Ruiz et al, 2004;Zimprich et al, 2004).…”

Section: The Cellular Processes Modulated By Commensal Bacteria In Pamentioning

confidence: 99%

Paneth cells: the hub for sensing and regulating intestinal flora

Zhang

Liu

2016

Sci. China Life Sci.

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The complex interplay between symbiotic bacteria and host immunity plays a key role in shaping intestinal homeostasis and maintaining host health. Paneth cells, as one of the major producers of antimicrobial peptides in the intestine under steady-state conditions, play a vital role in regulating intestinal flora. Many studies on inflammatory bowel disease (IBD)-associated genes have put Paneth cells at the center of IBD pathogenesis. In this perspective, we focus on mechanistic studies of different cellular processes in Paneth cells that are regulated by various IBD-associated susceptibility genes, and we discuss the hypothesis that Paneth cells function as the central hub for sensing and regulating intestinal flora in the maintenance of intestinal homeostasis. inflammatory bowel disease, Paneth cell, commensal bacteria, intestinal homeostasisCitation:

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Commensal bacteria direct selective cargo sorting to promote symbiosis

Cited by 185 publications

References 52 publications

LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn’s disease patients

LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn’s disease patients

Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease

Paneth cells: the hub for sensing and regulating intestinal flora

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