Featured Publications
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2024
Cristian-Hernandez Rocha, Williams Turpin, Krzysztof Borowski, Joanne M. Stempak, Ksenija Sabic, Kyle Gettler, Christopher Tastad, Colleen Chasteau, Ujunwa Korie, Mary Hanna, Abdul Khan, Emebet Mengesha, Alain Bitton, Marc B. Schwartz, Arthur Barrie, Lisa W. Datta, Mark Lazarev, Steven R. Brant, John D. Rioux , Dermot P.B. McGovern, Richard H. Duerr, L. Phil Schumm, Judy H. Cho, Mark S. Silverberg
Clin Gastroenterol Hepatol. 2024 Jul 3:S1542-3565(24)00592-5.
volume
14, Article number: 2256 (2023)
Abstract
Background and aims: Investigating the tissue-associated microbiota after surgically induced remission may help to understand the mechanisms initiating intestinal inflammation in Crohn's disease.
Methods: Crohn's disease patients undergoing ileocolic resection were prospectively recruited in six academic centers. Biopsy samples from the neoterminal ileum, colon and rectosigmoid were obtained from colonoscopies performed after surgery. Microbial DNA was extracted for 16S rRNA gene sequencing. Microbial diversity and taxonomic differential relative abundance were analyzed. A random forest model was applied to analyze the performance of clinical and microbial features to predict recurrence. A Rutgeerts score ≥i2 was deemed as endoscopic recurrence.
Results: A total of 349 postoperative colonoscopies and 944 biopsy samples from 262 Crohn's disease patients were analyzed. Ileal inflammation accounted for most of the explained variance of the ileal and colonic mucosa-associated microbiota. Samples obtained from 97 patients who were in surgically induced remission at first postoperative colonoscopy who went on to develop endoscopic recurrence at second colonoscopy showed lower diversity and microbial deviations when compared to patients who remained in endoscopic remission. Depletion of genus Anaerostipes and increase of several genera from class Gammaproteobacteria at the three biopsy sites increase the risk of further recurrence. Gut microbiome was able to predict future recurrence better than clinical features.
Conclusion: Ileal and colonic mucosa-associated microbiome deviations precede development of new onset ileal inflammation after surgically induced remission and show good predictive performance for future recurrence. These findings suggest that targeted microbial modulation is a plausible modality to prevent postoperative Crohn's disease recurrence.
Cristian Hernández-Rocha, Margaret Walshe, Sondra Birch, Ksenija Sabic, Ujunwa Korie, Colleen Chasteau, Vessela M Miladinova, William B Sabol, Emebet Mengesha, Mary Hanna, Valeriya Pozdnyakova, Lisa Datta, Rita Kohen, Raquel Milgrom, Joanne M Stempak, Alain Bitton, Steven R Brant, John D Rioux, Dermot P B McGovern, Richard H Duerr, Judy H Cho, Phil L Schumm, Mark S Silverberg, Mark Lazarev
Journal of Crohn's and Colitis, Volume 18, Issue 4, April 2024, Pages 615–627
volume
14, Article number: 2256 (2023)
Abstract
Background and Aims: Multiple factors are suggested to place Crohn’s disease patients at risk of recurrence after ileocolic resection with conflicting associations. We aimed to identify clinical predictors of recurrence at first [early] and further [late] postoperative colonoscopy.
Methods: Crohn’s disease patients undergoing ileocolic resection were prospectively recruited at six North American centres. Clinical data were collected and endoscopic recurrence was defined as Rutgeerts score ≥i2. A multivariable model was fitted to analyse variables independently associated with recurrence.
Results: A total of 365 patients undergoing 674 postoperative colonoscopies were included with a median age of 32 years, 189 [51.8%] were male, and 37 [10.1%] were non-Whites. Postoperatively, 133 [36.4%] used anti-tumour necrosis factor [anti-TNF] and 30 [8.2%] were smokers. At first colonoscopy, 109 [29.9%] had recurrence. Male gender (odds ratio [OR] = 1.95, 95% confidence interval [CI] 1.12–3.40), non-White ethnicity [OR = 2.48, 95% CI 1.09–5.63], longer interval between surgery and colonoscopy [OR = 1.09, 95% CI 1.002–1.18], and postoperative smoking [OR = 2.78, 95% CI 1.16–6.67] were associated with recurrence, while prophylactic anti-TNF reduced the risk [OR = 0.28, 95% CI 0.14–0.55]. Postoperative anti-TNF prophylaxis had a protective effect on anti-TNF experienced patients but not on anti-TNF naïve patients. Among patients without recurrence at first colonoscopy, Rutgeerts score i1 was associated with subsequent recurrence [OR = 4.43, 95% CI 1.73–11.35].
Conclusions: We identified independent clinical predictors of early and late Crohn’s disease postoperative endoscopic recurrence. Clinical factors traditionally used for risk stratification failed to predict recurrence and need to be revised.
2023
Yiming Wu, Kyle Gettler, Meltem Ece Kars, Mamta Giri, Dalin Li, Cigdem Sevim Bayrak, Peng Zhang, Aayushee Jain, Patrick Maffucci, Ksenija Sabic, Tielman Van Vleck, Girish Nadkarni, Lee A. Denson, Harry Ostrer, Adam P. Levine, Elena R. Schiff, Anthony W. Segal, Subra Kugathasan, Peter D. Stenson, David N. Cooper, L. Philip Schumm, Scott Snapper, Mark J. Daly, Talin Haritunians, Richard H. Duerr, Mark S. Silverberg, John D. Rioux, Steven R. Brant, Dermot P. B. McGovern, Judy H. Cho & Yuval Itan
Nature Communications volume 14, Article number: 2256 (2023)
volume
14, Article number: 2256 (2023)
Abstract
Inflammatory bowel disease (IBD) is a group of chronic digestive tract inflammatory conditions whose genetic etiology is still poorly understood. The incidence of IBD is particularly high among Ashkenazi Jews. Here, we identify 8 novel and plausible IBD-causing genes from the exomes of 4453 genetically identified Ashkenazi Jewish IBD cases (1734) and controls (2719). Various biological pathway analyses are performed, along with bulk and single-cell RNA sequencing, to demonstrate the likely physiological relatedness of the novel genes to IBD. Importantly, we demonstrate that the rare and high impact genetic architecture of Ashkenazi Jewish adult IBD displays significant overlap with very early onset-IBD genetics. Moreover, by performing biobank phenome-wide analyses, we find that IBD genes have pleiotropic effects that involve other immune responses. Finally, we show that polygenic risk score analyses based on genome-wide high impact variants have high power to predict IBD susceptibility.
Romain, Ferru-Clément PhD, Gabrielle Boucher, MSc, Anik Forest, MSc, Bertrand Bouchard, MSc, Alain Bitton, MD, Sylvie Lesage, PhD, Phil Schumm, PhD, Mark Lazarev, MD, Steve Brant, MD, Richard H. Duerr, MD, Dermot P.B. McGovern, MD PhD, Mark Silverberg, MD PhD, Judy H. Cho, MD, NIDDK IBD Genetics Consortium, iGenoMed Consortium, Ashwin Ananthakrishnan, MD, Ramnik J. Xavier, MD, John D. Rioux, PhD, and Christine Des Rosiers, PhD
Inflammatory Bowel Diseases, 2023, 29, 1024–1037
Abstract
Background
There is an unmet medical need for biomarkers that capture host and environmental contributions in inflammatory bowel diseases (IBDs). This study aimed at testing the potential of circulating lipids as disease classifiers given their major roles in inflammation.
Methods
We applied a previously validated comprehensive high-resolution liquid chromatography-mass spectrometry–based untargeted lipidomic workflow covering 25 lipid subclasses to serum samples from 100 Crohn’s disease (CD) patients and 100 matched control subjects. Findings were replicated and expanded in another 200 CD patients and 200 control subjects. Key metabolites were tested for associations with disease behavior and location, and classification models were built and validated. Their association with disease activity was tested using an independent cohort of 42 CD patients.
Results
We identified >70 metabolites with strong association (P < 1 × 10-4, q < 5 × 10-4) to CD. Highly performing classification models (area under the curve > 0.84-0.97) could be built with as few as 5 to 9 different metabolites, representing 6 major correlated lipid clusters. These classifiers included a phosphatidylethanolamine ether (O-16:0/20:4), a sphingomyelin (d18:1/21:0) and a cholesterol ester (14:1), a very long-chain dicarboxylic acid [28:1(OH)] and sitosterol sulfate. These classifiers and correlated lipids indicate a dysregulated metabolism in host cells, notably in peroxisomes, as well as dysbiosis, oxidative stress, compromised inflammation resolution, or intestinal membrane integrity. A subset of these were associated with disease behavior or location.
Conclusions
Untargeted lipidomic analyses uncovered perturbations in the circulating human CD lipidome, likely resulting from multiple pathogenic mechanisms. Models using as few as 5 biomarkers had strong disease classifier characteristics, supporting their potential use in diagnosis or prognosis.
2022
Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility
Aleksejs Sazonovs, Christine R. Stevens, Guhan R. Venkataraman, Kai Yuan, Brandon Avila, Maria T. Abreu, Tariq Ahmad, Matthieu Allez, Ashwin N. Ananthakrishnan, Gil Atzmon, Aris Baras, Jeffrey C. Barrett, Nir Barzilai, Laurent Beaugerie, Ashley Beecham, Charles N. Bernstein, Alain Bitton, Bernd Bokemeyer, Andrew Chan, Daniel Chung, Isabelle Cleynen, Jacques Cosnes, David J. Cutler, Allan Daly, Belgium IBD Consortium, Cedars-Sinai IBD,
International IBD Genetics Consortium, NIDDK IBD Genetics Consortium, NIHR IBD BioResource, Regeneron Genetics Center, SHARE Consortium, SPARC IBD Network, UK IBD Genetics Consortium, …Mark J. Daly
Nature Genetics volume 54, pages1275–1283 (2022)
Abstract
Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn’s disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.
Hajera Amatullah, Isabella Fraschilla, Sreehaas Digumarthi, Julie Huang, Fatemeh Adiliaghdam, Gracia Bonilla, Lai Ping Wong, Marie-Eve Rivard, Claudine Beauchamp, Virginie Mercier, Philippe Goyette, Ruslan I Sadreyev, Robert M Anthony, John D Rioux, Kate L Jeffrey
Cell Volume 185, Issue 17, 18 August 2022, Pages 3232-3247.e18
Abstract
How mis-regulated chromatin directly impacts human immune disorders is poorly understood. Speckled Protein 140 (SP140) is an immune-restricted PHD and bromodomain-containing epigenetic “reader,” and SP140 loss-of-function mutations associate with Crohn’s disease (CD), multiple sclerosis (MS), and chronic lymphocytic leukemia (CLL). However, the relevance of these mutations and mechanisms underlying SP140-driven pathogenicity remains unexplored. Using a global proteomic strategy, we identified SP140 as a repressor of topoisomerases (TOPs) that maintains heterochromatin and macrophage fate. In humans and mice, SP140 loss resulted in unleashed TOP activity, de-repression of developmentally silenced genes, and ultimately defective microbe-inducible macrophage transcriptional programs and bacterial killing that drive intestinal pathology. Pharmacological inhibition of TOP1/2 rescued these defects. Furthermore, exacerbated colitis was restored with TOP1/2 inhibitors in Sp140−/− mice, but not wild-type mice, in vivo. Collectively, we identify SP140 as a TOP repressor and reveal repurposing of TOP inhibition to reverse immune diseases driven by SP140 loss.
Margaret Walshe, Shadi Nayeri, Jiayi Ji, Cristian Hernandez-Rocha, Ksenija Sabic, Liangyuan Hu, Mamta Giri, Shikha Nayar, Steven Brant, Dermot P B McGovern, John D Rioux, Richard H Duerr, Judy H Cho, Phil L Schumm, Mark Lazarev, Mark S Silverberg
Journal of Crohn's and Colitis, Volume 16, Issue 6, June 2022, Pages 900–910
Abstract
Background and aims: Crohn's disease [CD] recurrence following ileocolic resection [ICR] is common. We sought to identify blood-based biomarkers associated with CD recurrence. Methods: CD patients undergoing ICR were recruited across six centres. Serum samples were obtained at post-operative colonoscopy. A multiplex immunoassay was used to analyse 92 inflammation-related proteins [Olink Proteomics]. Bayesian analysis was used to identify proteins associated with increasing Rutgeerts score. Identified proteins were used in receiver operating characteristic [ROC] analysis to examine the ability to identify CD recurrence [Rutgeerts score ≥i2]. Existing single cell data were interrogated to further elucidate the role of the identified proteins. Results: Data from 276 colonoscopies in 213 patients were available. Median time from surgery to first and second colonoscopy was 7 (interquartile range [IQR] 6-9) and 19 [IQR 16-23] months, respectively. Disease recurrence was evident at 60 [30%] first and 36 [49%] second colonoscopies. Of 14 proteins significantly associated with Rutgeerts score, the strongest signal was seen for CXCL9 and MMP1. Among patients on anti-tumour necrosis factor drugs, CXCL9 and CXCL11 were most strongly associated with Rutgeerts score. Both are CXCR3 ligands. Incorporation of identified proteins into ROC analysis improved the ability to identify disease recurrence as compared to C-reactive protein alone: area under the curve [AUC] 0.75 (95% confidence interval [CI]: 0.66-0.82] vs 0.64 [95% CI 0.56-0.72], p = 0.012. Single cell transcriptomic data provide evidence that innate immune cells are the primary source of the identified proteins. Conclusions: CXCR3 ligands are associated with CD recurrence following ICR. Incorporation of novel blood-based candidate biomarkers may aid in identification of CD recurrence.
2021
Hari K Somineni, Sini Nagpal, Suresh Venkateswaran, David J Cutler, David T Okou, Talin Haritunians, Claire L Simpson, Ferdouse Begum, Lisa W Datta, Antonio J Quiros, Jenifer Seminerio, Emebet Mengesha, Jonathan S Alexander, Robert N Baldassano, Sharon Dudley-Brown, Raymond K Cross, Themistocles Dassopoulos, Lee A Denson, Tanvi A Dhere, Heba Iskandar, Gerald W Dryden, Jason K Hou, Sunny Z Hussain, Jeffrey S Hyams, Kim L Isaacs, Howard Kader, Michael D Kappelman, Jeffry Katz, Richard Kellermayer, John F Kuemmerle, Mark Lazarev, Ellen Li, Peter Mannon, Dedrick E Moulton, Rodney D Newberry, Ashish S Patel, Joel Pekow, Shehzad A Saeed, John F Valentine, Ming-Hsi Wang, Jacob L McCauley, Maria T Abreu, Traci Jester, Zarela Molle-Rios, Sirish Palle, Ellen J Scherl, John Kwon, John D Rioux, Richard H Duerr, Mark S Silverberg, Michael E Zwick, Christine Stevens, Mark J Daly , Judy H Cho, Greg Gibson, Dermot P B McGovern, Steven R Brant, Subra Kugathasan
AJHG, Volume 108, Issue 3, 4 March 2021, Pages 431-445
Abstract
Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca2+-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.
Shikha Nayar, Joshua K. Morrison, Mamta Giri, Kyle Gettler, Ling-shiang Chuang, Laura A. Walker, Huaibin M. Ko, Ephraim Kenigsberg, Subra Kugathasan, Miriam Merad, Jaime Chu & Judy H. Cho
Nature, volume 593, pages275–281 (2021)
Abstract
Crohn’s disease is a chronic inflammatory intestinal disease that is frequently accompanied by aberrant healing and stricturing complications. Crosstalk between activated myeloid and stromal cells is critical in the pathogenicity of Crohn’s disease1,2, and increases in intravasating monocytes are correlated with a lack of response to anti-TNF treatment3. The risk alleles with the highest effect on Crohn’s disease are loss-of-function mutations in NOD24,5, which increase the risk of stricturing6. However, the mechanisms that underlie pathogenicity driven by NOD2 mutations and the pathways that might rescue a lack of response to anti-TNF treatment remain largely uncharacterized. Here we use direct ex vivo analyses of patients who carry risk alleles of NOD2 to show that loss of NOD2 leads to dysregulated homeostasis of activated fibroblasts and macrophages. CD14+ peripheral blood mononuclear cells from carriers of NOD2 risk alleles produce cells that express high levels of collagen, and elevation of conserved signatures is observed in nod2-deficient zebrafish models of intestinal injury. The enrichment of STAT3 regulation and gp130 ligands in activated fibroblasts and macrophages suggested that gp130 blockade might rescue the activated program in NOD2-deficient cells. We show that post-treatment induction of the STAT3 pathway is correlated with a lack of response to anti-TNF treatment in patients, and demonstrate in vivo in zebrafish the amelioration of the activated myeloid–stromal niche using the specific gp130 inhibitor bazedoxifene. Our results provide insights into NOD2-driven fibrosis in Crohn’s disease, and suggest that gp130 blockade may benefit some patients with Crohn’s disease—potentially as a complement to anti-TNF therapy.
Gabrielle Boucher, MSc, Alexandre Paradis, MSc, Geneviève Chabot-Roy, MSc, Lise Coderre, PhD, Erin E Hillhouse, PhD, Alain Bitton, MD, Christine Des Rosiers, PhD, Megan K Levings, PhD, L Philip Schumm, MA, Mark Lazarev, MD,
Steve R Brant, MD, Richard Duerr, MD, Dermot McGovern, MD, PhD, Mark S Silverberg, MD, PhD, Judy Cho, MD, Sylvie Lesage, PhD, John D Rioux, PhD, iGenoMed Consortium, NIDDK IBD Genetics Consortium
Inflammatory Bowel Diseases, Volume 28, Issue 1, January 2022, Pages 9–20
Abstract
Background
Crohn’s disease (CD) can affect any segment of the digestive tract but is most often localized in the ileal, ileocolonic, and colorectal regions of the intestines. It is believed that the chronic inflammation in CD is a result of an imbalance between the epithelial barrier, the immune system, and the intestinal microbiota. The aim of the study was to identify circulating markers associated with CD and/or disease location in CD patients.
Methods
We tested 49 cytokines, chemokines, and growth factors in serum samples from 300 patients with CD and 300 controls. After quality control, analyte levels were tested for association with CD and disease location.
Results
We identified 13 analytes that were higher in CD patients relative to healthy controls and that remained significant after conservative Bonferroni correction (P < 0.0015). In particular, CXCL9, CXCL1, and interleukin IL-6 had the greatest effect and were highly significant (P < 5 × 10–7). We also identified 9 analytes that were associated with disease location, with VEGF, IL-12p70, and IL-6 being elevated in patients with colorectal disease (P < 3 × 10–4).
Conclusions
Multiple serum analytes are elevated in CD. These implicate the involvement of multiple cell types from the immune, epithelial, and endothelial systems, suggesting that circulating analytes reflect the inflammatory processes that are ongoing within the gut. Moreover, the identification of distinct profiles according to disease location supports the existence of a biological difference between ileal and colonic CD, consistent with previous genetic and clinical observations.
2020
Eva Gonçalves Serra, Tobias Schwerd, Loukas Moutsianas, Athena Cavounidis, Laura Fachal, Sumeet Pandey, Jochen Kammermeier, Nicholas M. Croft, Carsten Posovszky, Astor Rodrigues, Richard K. Russell, Farah Barakat, Marcus K. H. Auth, Robert Heuschkel, Matthias Zilbauer, Krzysztof Fyderek, Christian Braegger, Simon P. Travis, Jack Satsangi, Miles Parkes, Nikhil Thapar, Helen Ferry, Julie C. Matte, Kimberly C. Gilmour, Andrzej Wedrychowicz, Peter Sullivan, Carmel Moore, Jennifer Sambrook, Willem Ouwehand, David Roberts, John Danesh, Toni A. Baeumler, Tudor A. Fulga, Eli M. Carrami, Ahmed Ahmed, Rachel Wilson, Jeffrey C. Barrett, Abdul Elkadri, Anne M. Griffiths, COLORS in IBD group investigators, Oxford IBD cohort study investigators, INTERVAL Study, Swiss IBD cohort investigators, UK IBD Genetics Consortium, NIDDK IBD Genetics Consortium, Scott B. Snapper, Neil Shah, Aleixo M. Muise, David C. Wilson, Holm H. Uhlig & Carl A. Anderson
Nature Communications, volume 11, Article number: 995 (2020)
Abstract
Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P < 4 × 10−10), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10−10). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis.
Connie W.Y. Ha, Anthony Martin, Gregory D. Sepich-Poore, Baochen Shi, Yizhou Wang , Kenneth Gouin, Gregory Humphrey, Karenina Sanders, Yasiru Ratnayake, Kelvin S.L. Chan, Gustaf Hendrick, J.R. Caldera, Christian Arias, Jacob E. Moskowitz, Shannan J. Ho Sui, Shaohong Yang, David Underhill, Matthew J. Brady, Simon Knott, Kelly Kaihara, Michael J. Steinbaugh, Huiying Li, Dermot P.B. McGovern, Rob Knight, Phillip Fleshner, Suzanne Devkota
Cell, Volume 183, Issue 3, 29 October 2020, Pages 666-683.e17
Abstract
A mysterious feature of Crohn's disease (CD) is the extra-intestinal manifestation of "creeping fat" (CrF), defined as expansion of mesenteric adipose tissue around the inflamed and fibrotic intestine. In the current study, we explore whether microbial translocation in CD serves as a central cue for CrF development. We discovered a subset of mucosal-associated gut bacteria that consistently translocated and remained viable in CrF in CD ileal surgical resections, and identified Clostridium innocuum as a signature of this consortium with strain variation between mucosal and adipose isolates, suggesting preference for lipid-rich environments. Single-cell RNA sequencing characterized CrF as both pro-fibrotic and pro-adipogenic with a rich milieu of activated immune cells responding to microbial stimuli, which we confirm in gnotobiotic mice colonized with C. innocuum. Ex vivo validation of expression patterns suggests C. innocuum stimulates tissue remodeling via M2 macrophages, leading to an adipose tissue barrier that serves to prevent systemic dissemination of bacteria.
Kyle Gettler, Rachel Levantovsky, Arden Moscati, Mamta Giri, Yiming Wu, Nai-Yun Hsu, Ling-Shiang Chuang, Aleksejs Sazonovs, Suresh Venkateswaran, Ujunwa Korie, Colleen Chasteau, UK IBD Genetics Consortium, National Institute of Diabetes, Digestive and Kidney Diseases Inflammatory Bowel Disease Genetics Consortium, Richard H. Duerr, Mark S. Silverberg, Scott B. Snapper, Mark J. Daly, Dermot P. McGovern, Steven R. Brant, John D. Rioux, Subra Kugathasan, Carl A. Anderson, Yuval Itan, Judy H. Cho
Gastroenterology, Volume 160, Issue 5, April 2021, Pages 1546-1557
Abstract
Background and Aims
Polygenic risk scores (PRS) may soon be used to predict inflammatory bowel disease (IBD) risk in prevention efforts. We leveraged exome-sequence and single nucleotide polymorphism (SNP) array data from 29,358 individuals in the multiethnic, randomly ascertained health system-based BioMe biobank to define effects of common and rare IBD variants on disease prediction and pathophysiology.
Methods
PRS were calculated from European, African American, and Ashkenazi Jewish (AJ) reference case-control studies, and a meta-GWAS run using all three association datasets. PRS were then combined using regression to assess which combination of scores best predicted IBD status in European, AJ, Hispanic, and African American cohorts in BioMe. Additionally, rare variants were assessed in genes associated with very early-onset IBD (VEO-IBD), by estimating genetic penetrance in each BioMe population.
Results
Combining risk scores based on association data from distinct ancestral populations improved IBD prediction for every population in BioMe and significantly improved prediction among European ancestry UK Biobank individuals. Lower predictive power for non-Europeans was observed, reflecting in part substantially lower African IBD case-control reference sizes. We replicated associations for two VEO-IBD genes, ADAM17 and LRBA, with high dominant model penetrance in BioMe. Autosomal recessive LRBA risk alleles are associated with severe, early-onset autoimmunity; we show that heterozygous carriage of an African-predominant LRBA protein-altering allele is associated with significantly decreased LRBA and CTLA-4 expression with T-cell activation.
Conclusions
Greater genetic diversity in African populations improves prediction across populations, and generalizes some VEO-IBD genes. Increasing African American IBD case-collections should be prioritized to reduce health disparities and enhance pathophysiological insight.
2019
Jason Lloyd-Price, Cesar Arze, Ashwin N. Ananthakrishnan, Melanie Schirmer, Julian Avila-Pacheco, Tiffany W. Poon, Elizabeth Andrews, Nadim J. Ajami, Kevin S. Bonham, Colin J. Brislawn, David Casero, Holly Courtney, Antonio Gonzalez, Thomas G. Graeber, A. Brantley Hall, Kathleen Lake, Carol J. Landers, Himel Mallick, Damian R. Plichta, Mahadev Prasad, Gholamali Rahnavard, Jenny Sauk, Dmitry Shungin, Yoshiki Vázquez-Baeza, Richard A. White III, IBDMDB Investigators, Jonathan Braun, Lee A. Denson, Janet K. Jansson, Rob Knight, Subra Kugathasan, Dermot P. B. McGovern, Joseph F. Petrosino, Thaddeus S. Stappenbeck, Harland S. Winter, Clary B. Clish, Eric A. Franzosa, Hera Vlamakis, Ramnik J. Xavier & Curtis Huttenhower
Nature, volume 569, pages655–662 (2019)
Abstract
Inflammatory bowel diseases, which include Crohn’s disease and ulcerative colitis, affect several million individuals worldwide. Crohn’s disease and ulcerative colitis are complex diseases that are heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Individual contributing factors have been the focus of extensive research. As part of the Integrative Human Microbiome Project (HMP2 or iHMP), we followed 132 subjects for one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each; in total 2,965 stool, biopsy, and blood specimens). Here we present the results, which provide a comprehensive view of functional dysbiosis in the gut microbiome during inflammatory bowel disease activity. We demonstrate a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (for example, among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and levels of antibodies in host serum. Periods of disease activity were also marked by increases in temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to this dysregulation. The study’s infrastructure resources, results, and data, which are available through the Inflammatory Bowel Disease Multi’omics Database (http://ibdmdb.org), provide the most comprehensive description to date of host and microbial activities in inflammatory bowel diseases.
Jerome C Martin, Christie Chang, Gilles Boschetti, Ryan Ungaro, Mamta Giri, John A Grout, Kyle Gettler, Ling-Shiang Chuang, Shikha Nayar, Alexander J Greenstein, Marla Dubinsky, Laura Walker, Andrew Leader, Jay S Fine, Charles E Whitehurst, M Lamine Mbow, Subra Kugathasan, Lee A Denson, Jeffrey S Hyams, Joshua R Friedman, Prerak T Desai, Huaibin M Ko, Ilaria Laface, Guray Akturk, Eric E Schadt, Helene Salmon, Sacha Gnjatic, Adeeb H Rahman, Miriam Merad, Judy H Cho, Ephraim Kenigsberg
Cell, 2019 Sep 5;178(6):1493-1508.e20
Abstract
Clinical benefits of cytokine blockade in ileal Crohn's disease (iCD) are limited to a subset of patients. Here, we applied single-cell technologies to iCD lesions to address whether cellular heterogeneity contributes to treatment resistance. We found that a subset of patients expressed a unique cellular module in inflamed tissues that consisted of IgG plasma cells, inflammatory mononuclear phagocytes, activated T cells, and stromal cells, which we named the GIMATS module. Analysis of ligand-receptor interaction pairs identified a distinct network connectivity that likely drives the GIMATS module. Strikingly, the GIMATS module was also present in a subset of patients in four independent iCD cohorts (n = 441), and its presence at diagnosis correlated with failure to achieve durable corticosteroid-free remission upon anti-TNF therapy. These results emphasize the limitations of current diagnostic assays and the potential for single-cell mapping tools to identify novel biomarkers of treatment response and tailored therapeutic opportunities.
2018
Ken Y Hui, Heriberto Fernandez-Hernandez, Jianzhong Hu, Adam Schaffner, Nathan Pankratz, Nai-Yun Hsu, Ling-Shiang Chuang, Shai Carmi, Nicole Villaverde, Xianting Li, Manual Rivas, Adam P Levine, Xiuliang Bao, Philippe R Labrias, Talin Haritunians, Darren Ruane, Kyle Gettler, Ernie Chen, Dalin Li, Elena R Schiff, Nikolas Pontikos, Nir Barzilai, Steven R Brant, Susan Bressman, Adam S Cheifetz, Lorraine N Clark, Mark J Daly, Robert J Desnick, Richard H Duerr, Seymour Katz, Todd Lencz, Richard H Myers, Harry Ostrer, Laurie Ozelius, Haydeh Payami, Yakov Peter, John D Rioux, Anthony W Segal, William K Scott, Mark S Silverberg, Jeffery M Vance, Iban Ubarretxena-Belandia, Tatiana Foroud, Gil Atzmon, Itsik Pe'er, Yiannis Ioannou, Dermot P B McGovern, Zhenyu Yue, Eric E Schadt, Judy H Cho, Inga Peter
Science Translational Medicine, 2018 Jan 10;10(423):eaai7795.
Abstract
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 nonsynonymous mutations, we performed exome sequencing of Ashkenazi Jewish patients with CD, followed by array-based genotyping and association analysis in 2066 CD cases and 3633 healthy controls. We detected association signals in the LRRK2 gene that conferred risk for CD (N2081D variant, P = 9.5 × 10-10) or protection from CD (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 shared 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 was associated with increased kinase activity, whereas neither N551K nor R1398H variants on the protective haplotype altered kinase activity. We also confirmed that R1398H, but not N551K, increased guanosine triphosphate binding and hydrolyzing enzyme (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.