Paneth cell defects in Crohn’s disease patients promote dysbiosis

Liu, Ta‐Chiang; Gurram, Bhaskar; Baldridge, Megan T.; Head, Richard D.; Lam, Vy; Luo, Chengwei; Cao, Yumei; Simpson, Pippa; Hayward, Michael A.; Holtz, Mary L.; Bousounis, Pavlos; Noe, Joshua D.; Lerner, Diana; Cabrera, José; Biank, Vincent; Stephens, Michael C.; Huttenhower, Curtis; McGovern, Dermot P.; Xavier, Ramnik J.; Stappenbeck, Thaddeus S.; Salzman, Nita H.

doi:10.1172/jci.insight.86907

Cited by 96 publications

(120 citation statements)

References 66 publications

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“…The staining for defensin-5 was specific for Paneth cells and the results were highly correlative to that obtained by lysozyme immunofluorescence (R 2 = 0.6451; P < 0.0001) (Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.91917DS1). There was a similar range of intracellular staining patterns to those previously observed in multiple North American CD cohorts (19,20) (Figure 2A). The average percentage of normal Paneth cells was similar between Japanese and North American CD subjects (82.13 ± 1.06 vs. 81.9 ± 0.55; P = 0.87) ( Figure 2B).…”

Section: Resultssupporting

confidence: 83%

“…This in turn correlates with the development of dysbiosis and inflammation (20). Together, these studies suggest that, at least in a subset of CD patients, Paneth cells are the origin of intestinal inflammation (10).…”

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

confidence: 79%

“…Furthermore, we have also demonstrated that abnormal Paneth cell phenotype is associated with mucosal dysbiosis and aggressive disease course (19,20). Thus, Paneth cell phenotype is a biologically and clinically relevant biomarker that can stratify CD patients.…”

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

confidence: 80%

“…The overall work flow for the determination of genetic associations of Paneth cell defect in Japanese CD patients is outlined in Figure 1. We first determined the percentage of normal Paneth cells in resection specimens of adult Japanese CD subjects using a previously reported method of immunofluorescence localization for defensin-5 (20). The staining for defensin-5 was specific for Paneth cells and the results were highly correlative to that obtained by lysozyme immunofluorescence (R 2 = 0.6451; P < 0.0001) (Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.91917DS1).…”

Section: Resultsmentioning

confidence: 99%

“…We have previously shown that Paneth cell phenotypes are associated with CD susceptibility alleles, pathological hallmarks, unique transcriptomic and mucosal microbiome changes, and outcome in patients undergoing surgery in North American CD (19,20). However, it was unclear whether similar associations would be present in CD patients from different genetic/ethnic backgrounds, particularly as the incidence of CD in other ethnic groups has continued to rise (50,51).…”

Section: Discussionmentioning

confidence: 99%

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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: Resultssupporting

confidence: 83%

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

confidence: 79%

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

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

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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Fecal Microbial Transplant Capsules Are Safe in Hepatic Encephalopathy: A Phase 1, Randomized, Placebo‐Controlled Trial

et al. 2019

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Hepatic encephalopathy (HE) can cause major morbidity despite standard of care (SOC; rifaximin/lactulose). Fecal microbial transplant (FMT) enemas postantibiotics are safe, but the effect of FMT without antibiotics using the capsular route requires investigation. The aim of this work was to determine the safety, tolerability, and impact on mucosal/stool microbiota and brain function in HE after capsular FMT in a randomized, single-blind, placebocontrolled clinical trial in Virginia. Patients with cirrhosis with recurrent HE with MELD (Model for End-Stage Liver Disease) <17 on SOC were randomized 1:1 into receiving 15 FMT capsules versus placebo from a single donor enriched in Lachnospiraceae and Ruminococcaceae. Endoscopies with duodenal and sigmoid biopsies, stool analysis, cognition, serum lipopolysaccharide-binding protein (LBP), and duodenal antimicrobial peptide (AMP) expression at baseline were used. Clinical follow-up with SOC maintenance was performed until 5 months. FMTassigned patients underwent repeat endoscopies 4 weeks postenrollment. Twenty subjects on lactulose/rifaximin were randomized 1:1. MELD score was similar at baseline (9.6 vs. 10.2) and study end (10.2 vs. 10.5). Six patients in the placebo group required hospitalizations compared to 1 in FMT, which was deemed unrelated to FMT. Infection/ HE episodes were similar between groups. Baseline microbial diversity was similar in all tissues between groups. Post-FMT, duodenal mucosal diversity (P = 0.01) increased with higher Ruminococcaceae and Bifidobacteriaceae and lower Streptococcaceae and Veillonellaceae. Reduction in Veillonellaceae were noted post-FMT in sigmoid (P = 0.04) and stool (P = 0.05). Duodenal E-cadherin (P = 0.03) and defensin alpha 5 (P = 0.03) increased whereas interleukin-6 (P = 0.02) and serum LBP (P = 0.009) reduced post-FMT. EncephalApp performance improved post-FMT only (P = 0.02). Conclusion: In this phase 1 study, oral FMT capsules are safe and well tolerated in patients with cirrhosis and recurrent HE. FMT was associated with improved duodenal mucosal diversity, dysbiosis, and AMP expression, reduced LBP, and improved EncephalApp performance. Further studies are needed to prove efficacy.

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Gut Microbial Signature of Hepatocellular Cancer in Men With Cirrhosis

et al. 2021

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The gut microbiome is altered in cirrhosis. Recent evidence has suggested a key role for the gut microbiota in the progression of cirrhosis and the development of hepatocellular carcinoma (HCC). We studied the differences in the microbial composition in patients with cirrhosis with prior and future HCC in the context of other complications (eg, infections, hepatic encephalopathy). The following 2 cohorts were recruited prospectively: the prior HCC cohort, in which outpatients with HCC within 2 years were age-matched, sex-matched, and Model for End-Stage Liver Disease (MELD) score-matched with those without HCC; and the future HCC cohort, in which patients were followed for 2 years and divided into future HCC versus no HCC after age, sex, and MELD-score matching and other complications were also recorded. Microbiota composition and predicted function were analyzed with ribosomal RNA sequencing and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PiCRUST)and compared between (1) prior HCC versus none and (2) future HCC versus none, and in the future cohort, comparisons were also made between those patients who developed (1) HCC only versus without complications, (2) HCC only versus non-HCC complications only, and (3) HCC + other complications versus non-HCC complications only. A total of 142 men (76 total in the prior cohort [38 with/38 without HCC] and 66 total in the future cohort [33 with/33 without future HCC]) were included. The groups had similar etiology, lactulose/rifaximin/proton pump inhibitor use, diabetes mellitus, and non-HCC complications. Microbial diversity was similar between prior HCC/not or future HCC/ not. On DESeq2 higher Clostridium sensu stricto and Anaerotruncus were significantly associated with protection from HCC, whereas the reverse was seen with Raoultella and Haemophilus regardless of prior/future HCC comparisons. Functions focused on urea cycle, bioenergetics, tryptophan, and toluene metabolism were different between the groups. Rothia was specific for other complications. Despite age, sex, and MELD-score matching and accounting for other complications, gut microbiota composition and the predicted function are different in men with cirrhosis with and without prior HCC and can be extended toward future HCC development.

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Paneth cell defects in Crohn’s disease patients promote dysbiosis

Cited by 96 publications

References 66 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

Fecal Microbial Transplant Capsules Are Safe in Hepatic Encephalopathy: A Phase 1, Randomized, Placebo‐Controlled Trial

Gut Microbial Signature of Hepatocellular Cancer in Men With Cirrhosis

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