Publications by authors named "Randy Longman"

37 Publications

No durable impact of COVID-19 on intestinal disease activity in subjects with IBD.

Clin Gastroenterol Hepatol 2021 Jun 5. Epub 2021 Jun 5.

Jill Roberts Center for Inflammatory Bowel Disease, New York, New York; New York Presbyterian Hospital, Weill Cornell Medical Center, New York, New York; Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, New York; Jill Roberts Institute for Research in IBD, Weill Cornell Medicine, New York, New York. Electronic address:

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http://dx.doi.org/10.1016/j.cgh.2021.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178538PMC
June 2021

Thymic development of gut-microbiota-specific T cells.

Nature 2021 May 12. Epub 2021 May 12.

Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Humans and their microbiota have coevolved a mutually beneficial relationship in which the human host provides a hospitable environment for the microorganisms and the microbiota provides many advantages for the host, including nutritional benefits and protection from pathogen infection. Maintaining this relationship requires a careful immune balance to contain commensal microorganisms within the lumen while limiting inflammatory anti-commensal responses. Antigen-specific recognition of intestinal microorganisms by T cells has previously been described. Although the local environment shapes the differentiation of effector cells it is unclear how microbiota-specific T cells are educated in the thymus. Here we show that intestinal colonization in early life leads to the trafficking of microbial antigens from the intestine to the thymus by intestinal dendritic cells, which then induce the expansion of microbiota-specific T cells. Once in the periphery, microbiota-specific T cells have pathogenic potential or can protect against related pathogens. In this way, the developing microbiota shapes and expands the thymic and peripheral T cell repertoire, allowing for enhanced recognition of intestinal microorganisms and pathogens.
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http://dx.doi.org/10.1038/s41586-021-03531-1DOI Listing
May 2021

Decoding the matrix: multiomics reveals host-microbe biomarker for inflammatory bowel disease.

J Clin Invest 2021 May;131(9)

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the intestine associated with genetic susceptibility and alterations in the intestinal microbiome. Multiomics data developed and analyzed over the last several decades have yielded an unprecedented amount of genetic and microbial data. But how do we pinpoint mechanistic insight into the host-microbe relationship that will ultimately enable better care for patients with IBD? In this issue of the JCI, Grasberger et al. undertook a major decoding effort to decipher this multiomic data matrix. The authors analyzed anonymized data from more than 2800 individuals to discover a link between heterozygous carriers of deleterious DUOX2 variants and high levels of plasma IL-17C. These findings provide an example of how harnessing big data can drive mechanistic discovery to define disease biomarkers that have the potential to improve clinical care in IBD.
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http://dx.doi.org/10.1172/JCI148902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087194PMC
May 2021

Dual Biologic or Small Molecule Therapy for Treatment of Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

Clin Gastroenterol Hepatol 2021 Mar 31. Epub 2021 Mar 31.

Jill Roberts Center for Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medical College, New York, New York. Electronic address:

Background And Aims: We conducted a systematic review and meta-analysis to summarize emerging data on the safety and effectiveness of dual biologic therapy in combination or with tofacitinib in patients with refractory inflammatory bowel disease (IBD).

Methods: Through a systematic search of multiple electronic databases through November 9, 2020, we identified cohort studies or case series (>10 patients) reporting the safety and effectiveness of simultaneous use of biologic agents in combination or with tofacitinib in patients with IBD. Rates of adverse events, clinical remission, and endoscopic remission were synthesized using pooled data, and we identified factors associated with successful dual therapy.

Results: We identified 30 studies reporting 288 trials of dual biologic or small molecule therapy in 279 patients (76% Crohn's disease; median duration of treatment 24 weeks (IQR-IQR 1332)). The main indications for dual therapy included medically refractory IBD (81%) and concurrent extra-intestinal manifestations or rheumatologic disease (12%). The most common combinations of dual therapy included tumor necrosis factor-α antagonists & anti-integrins (48%), ustekinumab & anti-integrins (19%); 61% of patients had previously failed at least one of the two therapies used in combination. Over a median follow-up of 32 weeks (IQR-IQR 24-52), pooled rates of adverse and serious adverse events were 31% (95% CI, 13%-54%) and 6.5% (95% CI, 2.1%-13.1%); pooled rates of clinical and endoscopic remission were 59% (95% CI, 42%-74%), and 34% (95% CI, 23%-46%), respectively. 12% (95% CI, 4%-24%) of patients required surgery. Rates of success were higher in patients on dual therapy due to EIM. Heterogeneity was not significant for endoscopic response (P = .88, I = 0%), endoscopic remission (P = .44, I = 0%), and malignancy (P = .87, I = 0%). However, significant heterogeneity existed for other outcomes.

Conclusions: Dual biologic or small molecule therapy may be a possible option in highly selected, refractory IBD patients at specialized centers. Higher quality combination of therapies with a significant improvement in the quality of data is required prior to more widespread use.
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http://dx.doi.org/10.1016/j.cgh.2021.03.034DOI Listing
March 2021

Adherent-invasive E. coli metabolism of propanediol in Crohn's disease regulates phagocytes to drive intestinal inflammation.

Cell Host Microbe 2021 04 3;29(4):607-619.e8. Epub 2021 Feb 3.

Jill Roberts Institute for IBD Research, Weill Cornell Medicine, New York, NY 10021, USA; Jill Roberts Center for IBD, Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA. Electronic address:

Adherent-invasive E. coli (AIEC) are enriched in the intestinal microbiota of patients with Crohn's disease (CD) and promote intestinal inflammation. Yet, how AIEC metabolism of nutrients impacts intestinal homeostasis is poorly defined. Here, we show that AIEC encoding the large subunit of propanediol dehydratase (PduC), which facilitates the utilization of fucose fermentation product 1,2-propanediol, are increased in the microbiome of CD patients and drive AIEC-induced intestinal T cell inflammation. In murine models, CXCR1 mononuclear phagocytes (MNP) are required for PduC-dependent induction of T helper 17 (Th17) cells and interleukin-1β (IL-1β) production that leads to AIEC-induced inflammatory colitis. Activation of this inflammatory cascade requires the catalytic activity of PduC to generate propionate, which synergizes with lipopolysaccharide (LPS) to induce IL-1β by MNPs. Disrupting fucose availability limits AIEC-induced propionate production and intestinal inflammation. These findings identify MNPs as metabolic sensors linking AIEC metabolism with intestinal inflammation and identify microbial metabolism as a potential therapeutic target in Crohn's disease treatment.
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http://dx.doi.org/10.1016/j.chom.2021.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049981PMC
April 2021

Utility of magnetic resonance imaging in Crohn's associated sacroiliitis: A cross-sectional study.

Int J Rheum Dis 2021 Apr 2;24(4):582-590. Epub 2021 Feb 2.

Division of Rheumatology, Department of Medicine, Hospital for Special Surgery, and Weill Cornell Medicine, New York, NY, USA.

Objective: Prevalence of sacroiliitis in Crohn's disease (CD) is variable depending on defining criteria. This study utilized standardized sacroiliac joint (SIJ) magnetic resonance imaging (MRI) to identify sacroiliitis in CD patients and its association with clinical and serological markers.

Methods: Consecutive adult subjects with CD prospectively enrolled from an inflammatory bowel disease clinic underwent SIJ MRI. Data collected included CD duration, history of joint/back pain, human leukocyte antigen-B27 status, Bath Ankylosing Spondylitis Metrology Index (BASMI), Bath Ankylosing Spondylitis Disease Activity Index, Harvey Bradshaw Index (HBI) for activity of CD, Ankylosing Spondylitis Disease Activity Score, and various serologic markers of inflammation. Three blinded readers reviewed MRIs for active and structural lesions according to the Spondyloarthritis Research Consortium of Canada modules.

Results: Thirty-three CD patients were enrolled: 76% female, 80% White, median age 36.4 years (interquartile range 27.2-49.0), moderate CD activity (mean HBI 8.8 ± SD 4.5). Nineteen subjects (58%) reported any back pain, 13 of whom had inflammatory back pain. Four subjects (12%) showed sacroiliitis using global approach and 6 (18%) met Assessment of SpondyloArthritis international Society MRI criteria of sacroiliitis. Older age (mean 51.2 ± SD 12.5 vs. 37.2 ± 14; P = .04), history of dactylitis (50.0% vs. 3.4%, P = .03) and worse BASMI (4.1 ± 0.7 vs. 2.4 ± 0.8, P ≤ .001) were associated with MRI sacroiliitis; no serologic measure was associated.

Conclusion: There were 12%-18% of CD patients who had MRI evidence of sacroiliitis, which was not associated with back pain, CD activity or serologic measures. This data suggests that MRI is a useful modality to identify subclinical sacroiliitis in CD patients.
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http://dx.doi.org/10.1111/1756-185X.14081DOI Listing
April 2021

A Diamond in the Rough: IgA-Seq Signatures Stratify New Onset IBD.

Cell Host Microbe 2021 01;29(1):10-12

Division of Gastroenterology and Hepatology, Department of Medicine, Jill Roberts Institute for Research in IBD, Jill Roberts Center for IBD, Weill Cornell Medicine, New York, NY, USA. Electronic address:

Intestinal immunoglobulin (Ig)A binds to distinct commensals and pathobionts, but do these IgA-coated bacterial communities define clinical characteristics of inflammatory disease? In this issue of Cell Host & Microbe, Shapiro et al. comprehensively analyze IgA-coated bacteria in new onset inflammatory bowel disease (IBD), revealing their potential in guiding precision therapy and diagnostic stratification.
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http://dx.doi.org/10.1016/j.chom.2020.12.014DOI Listing
January 2021

Baseline Disease Activity and Steroid Therapy Stratify Risk of COVID-19 in Patients With Inflammatory Bowel Disease.

Gastroenterology 2020 Oct 29;159(4):1541-1544.e2. Epub 2020 May 29.

Jill Roberts Center for Inflammatory Bowel Disease, New York Presbyterian Hospital, Weill Cornell Medical Center, New York, New York; Division of Gastroenterology and Hepatology, New York Presbyterian Hospital, Weill Cornell Medical Center, New York, New York; Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, New York.

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http://dx.doi.org/10.1053/j.gastro.2020.05.066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256492PMC
October 2020

Defining the phenotype, pathogenesis and treatment of Crohn's disease associated spondyloarthritis.

J Gastroenterol 2020 Jul 4;55(7):667-678. Epub 2020 May 4.

Jill Roberts Center for Inflammatory Bowel Disease, Weill Cornell Medicine, 413 E 69th Street, 7th Floor, New York, NY, 10021, USA.

Peripheral and axial spondyloarthritis are the most common extra-intestinal manifestations reported in patients with Crohn's disease. Despite the frequency of Crohn's disease associated spondyloarthritis, clinical diagnostic tools are variably applied in these cohorts and further characterization with validated spondyloarthritis disease activity indexes are needed. In addition, the pathogenesis of Crohn's disease associated spondyloarthritis is not well understood. Evidence of shared genetic, cellular, and microbial mechanisms underlying both Crohn's disease and spondyloarthritis highlight the potential for a distinct clinicopathologic entity. Existing treatment paradigms for Crohn's disease associated spondyloarthritis focus on symptom control and management of luminal inflammation. A better understanding of the underlying pathogenic mechanisms in Crohn's disease associated spondyloarthritis and the link between the gut microbiome and systemic immunity will help pave the way for more targeted and effective therapies. This review highlights recent work that has provided a framework for clinical characterization and pathogenesis of Crohn's disease associated spondyloarthritis and helps identify critical gaps that will help shape treatment paradigms.
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http://dx.doi.org/10.1007/s00535-020-01692-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297835PMC
July 2020

Author Correction: Bile acid metabolites control T17 and T cell differentiation.

Nature 2020 03;579(7798):E7

Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41586-020-2030-5DOI Listing
March 2020

Bile acid metabolites control T17 and T cell differentiation.

Nature 2019 12 27;576(7785):143-148. Epub 2019 Nov 27.

Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.

Bile acids are abundant in the mammalian gut, where they undergo bacteria-mediated transformation to generate a large pool of bioactive molecules. Although bile acids are known to affect host metabolism, cancer progression and innate immunity, it is unknown whether they affect adaptive immune cells such as T helper cells that express IL-17a (T17 cells) or regulatory T cells (T cells). Here we screen a library of bile acid metabolites and identify two distinct derivatives of lithocholic acid (LCA), 3-oxoLCA and isoalloLCA, as T cell regulators in mice. 3-OxoLCA inhibited the differentiation of T17 cells by directly binding to the key transcription factor retinoid-related orphan receptor-γt (RORγt) and isoalloLCA increased the differentiation of T cells through the production of mitochondrial reactive oxygen species (mitoROS), which led to increased expression of FOXP3. The isoalloLCA-mediated enhancement of T cell differentiation required an intronic Foxp3 enhancer, the conserved noncoding sequence (CNS) 3; this represents a mode of action distinct from that of previously identified metabolites that increase T cell differentiation, which require CNS1. The administration of 3-oxoLCA and isoalloLCA to mice reduced T17 cell differentiation and increased T cell differentiation, respectively, in the intestinal lamina propria. Our data suggest mechanisms through which bile acid metabolites control host immune responses, by directly modulating the balance of T17 and T cells.
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http://dx.doi.org/10.1038/s41586-019-1785-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949019PMC
December 2019

Innate lymphoid cells link gut microbes with mucosal T cell immunity.

Gut Microbes 2020 26;11(2):231-236. Epub 2019 Jul 26.

Jill Roberts Institute for Research in IBD, Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, USA.

Despite continuous exposure to trillions of microbes, the intestinal immune system protects the mucosa by balancing barrier protection, tolerance, and immunity. As both sentinel and effector, the mucosal innate immune system plays a central role in coordinating these responses. By integrating signals from the intestinal microbiota, mononuclear phagocytes (MNPs) serve as a critical link in regulating effector functions of group 3 innate lymphoid cells (ILC3s). Our recent work identified the role for MNP production of the IBD-linked protein TNF-like ligand 1A (TL1A) in modulating microbial regulation of ILC3 barrier immunity. These findings highlight a broader role for ILC3s in local control of T cell immunity and their potential role in the pathogenesis and treatment of inflammatory disease.
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http://dx.doi.org/10.1080/19490976.2019.1638725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053954PMC
September 2020

The balance of power: innate lymphoid cells in tissue inflammation and repair.

J Clin Invest 2019 06 10;129(7):2640-2650. Epub 2019 Jun 10.

Over the last ten years, immunologists have recognized the central importance of an emerging group of innate lymphoid cells (ILCs) in health and disease. Characterization of these cells has provided a molecular definition of ILCs and their tissue-specific functions. Although the lineage-defining transcription factors, cytokine production, and nomenclature parallel those of T helper cells, ILCs do not require adaptive immune programming. Both environmental and host-derived signals shape the function of these evolutionarily ancient cells, which provide pathogen protection and promote tissue restoration. As such, ILCs function as a double-edged sword, balancing the inflammatory and reparative responses that arise during injury and disease. This Review highlights our recent understanding of tissue-resident ILCs and the signals that regulate their contribution to inflammation and tissue repair in health and disease.
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http://dx.doi.org/10.1172/JCI124617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597213PMC
June 2019

Expansion of Bacteriophages Is Linked to Aggravated Intestinal Inflammation and Colitis.

Cell Host Microbe 2019 02;25(2):285-299.e8

Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA. Electronic address:

Bacteriophages are the most abundant members of the microbiota and have the potential to shape gut bacterial communities. Changes to bacteriophage composition are associated with disease, but how phages impact mammalian health remains unclear. We noted an induction of host immunity when experimentally treating bacterially driven cancer, leading us to test whether bacteriophages alter immune responses. Treating germ-free mice with bacteriophages leads to immune cell expansion in the gut. Lactobacillus, Escherichia, and Bacteroides bacteriophages and phage DNA stimulated IFN-γ via the nucleotide-sensing receptor TLR9. The resultant immune responses were both phage and bacteria specific. Additionally, increasing bacteriophage levels exacerbated colitis via TLR9 and IFN-γ. Similarly, ulcerative colitis (UC) patients responsive to fecal microbiota transplantation (FMT) have reduced phages compared to non-responders, and mucosal IFN-γ positively correlates with bacteriophage levels. Bacteriophages from active UC patients induced more IFN-γ compared to healthy individuals. Collectively, these results indicate that bacteriophages can alter mucosal immunity to impact mammalian health.
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http://dx.doi.org/10.1016/j.chom.2019.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885004PMC
February 2019

Microbiota-Induced TNF-like Ligand 1A Drives Group 3 Innate Lymphoid Cell-Mediated Barrier Protection and Intestinal T Cell Activation during Colitis.

Immunity 2018 12 11;49(6):1077-1089.e5. Epub 2018 Dec 11.

Jill Roberts Institute for Research in IBD, Weill Cornell Medicine, New York, NY, 10021, USA; Jill Roberts Center for IBD, Weill Cornell Medicine, New York, NY, 10021, USA. Electronic address:

Inflammatory bowel disease (IBD) results from a dysregulated interaction between the microbiota and a genetically susceptible host. Genetic studies have linked TNFSF15 polymorphisms and its protein TNF-like ligand 1A (TL1A) with IBD, but the functional role of TL1A is not known. Here, we found that adherent IBD-associated microbiota induced TL1A release from CX3CR1 mononuclear phagocytes (MNPs). Using cell-specific genetic deletion models, we identified an essential role for CX3CR1MNP-derived TL1A in driving group 3 innate lymphoid cell (ILC3) production of interleukin-22 and mucosal healing during acute colitis. In contrast to this protective role in acute colitis, TL1A-dependent expression of co-stimulatory molecule OX40L in MHCII ILC3s during colitis led to co-stimulation of antigen-specific T cells that was required for chronic T cell colitis. These results identify a role for ILC3s in activating intestinal T cells and reveal a central role for TL1A in promoting ILC3 barrier immunity during colitis.
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http://dx.doi.org/10.1016/j.immuni.2018.10.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301104PMC
December 2018

Critical Role for the Microbiota in CXCR1 Intestinal Mononuclear Phagocyte Regulation of Intestinal T Cell Responses.

Immunity 2018 07 3;49(1):151-163.e5. Epub 2018 Jul 3.

Alkek Center for Metagenomics and Microbiome Research and the Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA; Biology of Inflammation Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

The intestinal barrier is vulnerable to damage by microbiota-induced inflammation that is normally restrained through mechanisms promoting homeostasis. Such disruptions contribute to autoimmune and inflammatory diseases including inflammatory bowel disease. We identified a regulatory loop whereby, in the presence of the normal microbiota, intestinal antigen-presenting cells (APCs) expressing the chemokine receptor CXCR1 reduced expansion of intestinal microbe-specific T helper 1 (Th1) cells and promoted generation of regulatory T cells responsive to food antigens and the microbiota itself. We identified that disruption of the microbiota resulted in CXCR1 APC-dependent inflammatory Th1 cell responses with increased pathology after pathogen infection. Colonization with microbes that can adhere to the epithelium was able to compensate for intestinal microbiota loss, indicating that although microbial interactions with the epithelium can be pathogenic, they can also activate homeostatic regulatory mechanisms. Our results identify a cellular mechanism by which the microbiota limits intestinal inflammation and promotes tissue homeostasis.
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http://dx.doi.org/10.1016/j.immuni.2018.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051886PMC
July 2018

Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring.

Nature 2017 09 13;549(7673):528-532. Epub 2017 Sep 13.

Division of Infectious Diseases and Immunology and Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.

Maternal immune activation (MIA) contributes to behavioural abnormalities associated with neurodevelopmental disorders in both primate and rodent offspring. In humans, epidemiological studies suggest that exposure of fetuses to maternal inflammation increases the likelihood of developing autism spectrum disorder. In pregnant mice, interleukin-17a (IL-17a) produced by T helper 17 (T17) cells (CD4 T helper effector cells involved in multiple inflammatory conditions) induces behavioural and cortical abnormalities in the offspring exposed to MIA. However, it is unclear whether other maternal factors are required to promote MIA-associated phenotypes. Moreover, the underlying mechanisms by which MIA leads to T cell activation with increased IL-17a in the maternal circulation are not well understood. Here we show that MIA phenotypes in offspring require maternal intestinal bacteria that promote T17 cell differentiation. Pregnant mice that had been colonized with mouse commensal segmented filamentous bacteria or human commensal bacteria that induce intestinal T17 cells were more likely to produce offspring with MIA-associated abnormalities. We also show that small intestine dendritic cells from pregnant, but not from non-pregnant, females secrete IL-1β, IL-23 and IL-6 and stimulate T cells to produce IL-17a upon exposure to MIA. Overall, our data suggest that defined gut commensal bacteria with a propensity to induce T17 cells may increase the risk of neurodevelopmental disorders in the offspring of pregnant mothers undergoing immune system activation owing to infections or autoinflammatory syndromes.
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http://dx.doi.org/10.1038/nature23910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870873PMC
September 2017

Regulation of inflammation by microbiota interactions with the host.

Nat Immunol 2017 Jul;18(8):851-860

Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, New York, USA.

The study of the intestinal microbiota has begun to shift from cataloging individual members of the commensal community to understanding their contributions to the physiology of the host organism in health and disease. Here, we review the effects of the microbiome on innate and adaptive immunological players from epithelial cells and antigen-presenting cells to innate lymphoid cells and regulatory T cells. We discuss recent studies that have identified diverse microbiota-derived bioactive molecules and their effects on inflammation within the intestine and distally at sites as anatomically remote as the brain. Finally, we highlight new insights into how the microbiome influences the host response to infection, vaccination and cancer, as well as susceptibility to autoimmune and neurodegenerative disorders.
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http://dx.doi.org/10.1038/ni.3780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800875PMC
July 2017

Single Delivery of High-Diversity Fecal Microbiota Preparation by Colonoscopy Is Safe and Effective in Increasing Microbial Diversity in Active Ulcerative Colitis.

Inflamm Bowel Dis 2017 06;23(6):903-911

*Jill Roberts Center for IBD, Weill Cornell Medicine, New York, New York; †Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, New York; ‡Jill Roberts Institute for Research in IBD, Weill Cornell Medicine, New York, New York; §Department of Medicine, NYU School of Medicine, New York, New York; ‖Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas; ¶Finch Therapeutics, Somerville, Massachusetts; and **OpenBiome, Medford, Massachusetts.

Background: Recent trials suggest fecal microbiota transplantation (FMT) with repeated enemas and high-diversity FMT donors is a promising treatment to induce remission in ulcerative colitis.

Methods: We designed a prospective, open-label pilot study to assess the safety, clinical efficacy, and microbial engraftment of single FMT delivery by colonoscopy for active ulcerative colitis using a 2-donor fecal microbiota preparation (FMP). Safety and clinical endpoints of response, remission, and mucosal healing at week 4 were assessed. Fecal DNA and rectal biopsies were used to characterize the microbiome and mucosal CD4 T cells, respectively, before and after FMT.

Results: Of the 20 patients enrolled in this study, 7 patients (35%) achieved a clinical response by week 4. Three patients (15%) were in remission at week 4 and 2 of these patients (10%) achieved mucosal healing. Three patients (15%) required escalation of care. No serious adverse events were observed. Microbiome analysis revealed that restricted diversity of recipients pre-FMT was significantly increased by high-diversity 2-donor FMP. The microbiome of recipients post-transplant was more similar to the donor FMP than the pretransplant recipient sample in both responders and nonresponders. Notably, donor composition correlated with clinical response. Mucosal CD4 T-cell analysis revealed a reduction in both Th1 and regulatory T-cells post-FMT.

Conclusions: High-diversity, 2-donor FMP delivery by colonoscopy seems safe and effective in increasing fecal microbial diversity in patients with active ulcerative colitis. Donor composition correlated with clinical response and further characterization of immunological parameters may provide insight into factors influencing clinical outcome.
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http://dx.doi.org/10.1097/MIB.0000000000001132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159890PMC
June 2017

IgA-coated enriched in Crohn's disease spondyloarthritis promote T17-dependent inflammation.

Sci Transl Med 2017 02;9(376)

Jill Roberts Institute for Research in Inflammatory Bowel Disease (IBD), Weill Cornell Medicine, New York, NY 10021, USA.

Peripheral spondyloarthritis (SpA) is a common extraintestinal manifestation in patients with active inflammatory bowel disease (IBD) characterized by inflammatory enthesitis, dactylitis, or synovitis of nonaxial joints. However, a mechanistic understanding of the link between intestinal inflammation and SpA has yet to emerge. We evaluated and functionally characterized the fecal microbiome of IBD patients with or without peripheral SpA. Coupling the sorting of immunoglobulin A (IgA)-coated microbiota with 16 ribosomal RNA-based analysis (IgA-seq) revealed a selective enrichment in IgA-coated in patients with Crohn's disease-associated SpA (CD-SpA) compared to CD alone. isolates from CD-SpA-derived IgA-coated bacteria were similar in genotype and phenotype to an adherent-invasive (AIEC) pathotype. In comparison to non-AIEC , colonization of germ-free mice with CD-SpA isolates induced T helper 17 cell (T17) mucosal immunity, which required the virulence-associated metabolic enzyme propanediol dehydratase (). Modeling the increase in mucosal and systemic T17 immunity we observed in CD-SpA patients, colonization of interleukin-10-deficient or K/BxN mice with CD-SpA-derived lead to more severe colitis or inflammatory arthritis, respectively. Collectively, these data reveal the power of IgA-seq to identify immunoreactive resident pathosymbionts that link mucosal and systemic T17-dependent inflammation and offer microbial and immunophenotype stratification of CD-SpA that may guide medical and biologic therapy.
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http://dx.doi.org/10.1126/scitranslmed.aaf9655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159892PMC
February 2017

Crohn's Disease: Evolution, Epigenetics, and the Emerging Role of Microbiome-Targeted Therapies.

Curr Gastroenterol Rep 2016 Mar;18(3):13

Jill Roberts Center for Inflammatory Bowel Disease, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY, 1315 York Avenue, Mezzanine Level, New York, NY, 10065, USA.

Crohn's disease (CD) is a chronic, systemic, immune-mediated inflammation of the gastrointestinal tract. Originally described in 1932 as non-caseating granulomatous inflammation limited to the terminal ileum, it is now recognized as an expanding group of heterogeneous diseases defined by intestinal location, extent, behavior, and systemic extraintestinal manifestations. Joint diseases, including inflammatory spondyloarthritis and ankylosing spondylitis, are the most common extraintestinal manifestations of CD and share more genetic susceptibility loci than any other inflammatory bowel disease (IBD) trait. The high frequency and overlap with genes associated with infectious diseases, specifically Mendelian susceptibility to mycobacterial diseases (MSMD), suggest that CD may represent an evolutionary adaptation to environmental microbes. Elucidating the diversity of the enteric microbiota and the protean mucosal immune responses in individuals may personalize microbiome-targeted therapies and molecular classifications of CD. This review will focus on CD's natural history and therapies in the context of epigenetics, immunogenetics, and the microbiome.
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http://dx.doi.org/10.1007/s11894-016-0487-zDOI Listing
March 2016

Vedolizumab and Infliximab Combination Therapy in the Treatment of Crohn's Disease.

Am J Gastroenterol 2015 Dec;110(12):1737-8

Division of Gastroenterology and Hepatology, Weill Cornell Medical College-New York Presbyterian Hospital, New York, New York, USA.

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http://dx.doi.org/10.1038/ajg.2015.355DOI Listing
December 2015

Comprehensive models of human primary and metastatic colorectal tumors in immunodeficient and immunocompetent mice by chemokine targeting.

Nat Biotechnol 2015 Jun 25;33(6):656-60. Epub 2015 May 25.

Department of Medicine, Weill Cornell Medical College, New York, New York, USA.

Current orthotopic xenograft models of human colorectal cancer (CRC) require surgery and do not robustly form metastases in the liver, the most common site clinically. CCR9 traffics lymphocytes to intestine and colorectum. We engineered use of the chemokine receptor CCR9 in CRC cell lines and patient-derived cells to create primary gastrointestinal (GI) tumors in immunodeficient mice by tail-vein injection rather than surgery. The tumors metastasize inducibly and robustly to the liver. Metastases have higher DKK4 and NOTCH signaling levels and are more chemoresistant than paired subcutaneous xenografts. Using this approach, we generated 17 chemokine-targeted mouse models (CTMMs) that recapitulate the majority of common human somatic CRC mutations. We also show that primary tumors can be modeled in immunocompetent mice by microinjecting CCR9-expressing cancer cell lines into early-stage mouse blastocysts, which induces central immune tolerance. We expect that CTMMs will facilitate investigation of the biology of CRC metastasis and drug screening.
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http://dx.doi.org/10.1038/nbt.3239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532544PMC
June 2015

The functional impact of the intestinal microbiome on mucosal immunity and systemic autoimmunity.

Curr Opin Rheumatol 2015 Jul;27(4):381-7

Department of Medicine, Jill Roberts Institute for IBD Research, Weill Cornell Medical College, New York, New York, USA.

Purpose Of Review: This review will highlight recent advances functionally linking the gut microbiome with mucosal and systemic immune cell activation underlying autoimmunity.

Recent Findings: Dynamic interactions between the gut microbiome and environmental cues (including diet and medicines) shape the effector potential of the microbial organ. Key bacteria and viruses have emerged that, in defined microenvironments, play a critical role in regulating effector lymphocyte functions. The coordinated interactions between these different microbial kingdoms - including bacteria, helminths, and viruses (termed transkingdom interactions) - play a key role in shaping immunity. Emerging strategies to identify immunologically relevant microbes with the potential to regulate immune cell functions both at mucosal sites and systemically will likely define diagnostic and therapeutic targets.

Summary: The microbiome constitutes a critical microbial organ with coordinated interactions that shape host immunity.
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http://dx.doi.org/10.1097/BOR.0000000000000190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929006PMC
July 2015

CX₃CR1⁺ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22.

J Exp Med 2014 Jul 14;211(8):1571-83. Epub 2014 Jul 14.

The Kimmel Center for Biology and Medicine of the Skirball Institute and Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016The Kimmel Center for Biology and Medicine of the Skirball Institute and Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016

Interleukin (IL)-22-producing group 3 innate lymphoid cells (ILC3) promote mucosal healing and maintain barrier integrity, but how microbial signals are integrated to regulate mucosal protection offered by these cells remains unclear. Here, we show that in vivo depletion of CX₃CR1⁺ mononuclear phagocytes (MNPs) resulted in more severe colitis and death after infection with Citrobacter rodentium. This phenotype was rescued by exogenous IL-22, which was endogenously produced by ILC3 in close spatial proximity to CX₃CR1⁺ MNPs that were dependent on MyD88 signaling. CX₃CR1⁺MNPs from both mouse and human tissue produced more IL-23 and IL-1β than conventional CD103(+) dendritic cells (cDCs) and were more efficient than cDCs in supporting IL-22 production in ILC3 in vitro and in vivo. Further, colonic ILC3 from patients with mild to moderate ulcerative colitis or Crohn's disease had increased IL-22 production. IBD-associated SNP gene set analysis revealed enrichment for genes selectively expressed in human intestinal MNPs. The product of one of these, TL1A, potently enhanced IL-23- and IL-1β-induced production of IL-22 and GM-CSF by ILC3. Collectively, these results reveal a critical role for CX₃CR1⁺ mononuclear phagocytes in integrating microbial signals to regulate colonic ILC3 function in IBD.
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http://dx.doi.org/10.1084/jem.20140678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113938PMC
July 2014

Microbiota: host interactions in mucosal homeostasis and systemic autoimmunity.

Cold Spring Harb Symp Quant Biol 2013 9;78:193-201. Epub 2014 Jun 9.

The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016 Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016

The vertebrate intestinal tract is colonized by hundreds of species of bacteria that must be compartmentalized and tolerated to prevent invasive growth and harmful inflammatory responses. Signaling initiated by commensal bacteria shapes antigen-specific mucosal and systemic adaptive immunity. A distinct type of effector CD4(+) T cells, Th17 cells, have a key role in coordinating the inflammatory immune responses that afford protection to pathogens at the mucosal interface. Balancing this powerful inflammatory response, regulatory T cells limit collateral damage and provide antigen-specific tolerance to both food and microbial antigens. Here, we discuss the implications for how the microbiota as a whole contributes to compartmentalization from the host and how individual constituents of the microbiota influence the functions and repertoire of effector T cells and organ-specific autoimmune disease.
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http://dx.doi.org/10.1101/sqb.2013.78.020081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367195PMC
March 2015

Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis.

Elife 2013 Nov 5;2:e01202. Epub 2013 Nov 5.

Department of Medicine, New York University School of Medicine and Hospital for Joint Diseases, New York, United States.

Rheumatoid arthritis (RA) is a prevalent systemic autoimmune disease, caused by a combination of genetic and environmental factors. Animal models suggest a role for intestinal bacteria in supporting the systemic immune response required for joint inflammation. Here we performed 16S sequencing on 114 stool samples from rheumatoid arthritis patients and controls, and shotgun sequencing on a subset of 44 such samples. We identified the presence of Prevotella copri as strongly correlated with disease in new-onset untreated rheumatoid arthritis (NORA) patients. Increases in Prevotella abundance correlated with a reduction in Bacteroides and a loss of reportedly beneficial microbes in NORA subjects. We also identified unique Prevotella genes that correlated with disease. Further, colonization of mice revealed the ability of P. copri to dominate the intestinal microbiota and resulted in an increased sensitivity to chemically induced colitis. This work identifies a potential role for P. copri in the pathogenesis of RA. DOI: http://dx.doi.org/10.7554/eLife.01202.001.
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http://dx.doi.org/10.7554/eLife.01202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816614PMC
November 2013

Microbial manipulation as primary therapy for Crohn's disease.

World J Gastroenterol 2013 Mar;19(10):1513-6

Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.

While antimicrobials are clinically effective in preventing post-operative recurrence, the role for antibiotics in primary therapy for Crohn's disease (CD) remains unclear. The recent multicenter phase 2 trial by Prantera et al received wide attention because it demonstrated an increase in the week 12 remission rate in patients with moderately active CD treated with rifaximin and renewed interest in microbial manipulation as primary therapy for CD. In this commentary, we discuss aspects of durability, immune cell polarization, and safety of microbial manipulation as primary therapy for CD.
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http://dx.doi.org/10.3748/wjg.v19.i10.1513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3602467PMC
March 2013

Microbiota restricts trafficking of bacteria to mesenteric lymph nodes by CX(3)CR1(hi) cells.

Nature 2013 Feb 13;494(7435):116-20. Epub 2013 Jan 13.

Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.

The intestinal microbiota has a critical role in immune system and metabolic homeostasis, but it must be tolerated by the host to avoid inflammatory responses that can damage the epithelial barrier separating the host from the luminal contents. Breakdown of this regulation and the resulting inappropriate immune response to commensals are thought to lead to the development of inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. We proposed that the intestinal immune system is instructed by the microbiota to limit responses to luminal antigens. Here we demonstrate in mice that, at steady state, the microbiota inhibits the transport of both commensal and pathogenic bacteria from the lumen to a key immune inductive site, the mesenteric lymph nodes (MLNs). However, in the absence of Myd88 or under conditions of antibiotic-induced dysbiosis, non-invasive bacteria were trafficked to the MLNs in a CCR7-dependent manner, and induced both T-cell responses and IgA production. Trafficking was carried out by CX(3)CR1(hi) mononuclear phagocytes, an intestinal-cell population previously reported to be non-migratory. These findings define a central role for commensals in regulating the migration to the MLNs of CX(3)CR1(hi) mononuclear phagocytes endowed with the ability to capture luminal bacteria, thereby compartmentalizing the intestinal immune response to avoid inflammation.
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http://dx.doi.org/10.1038/nature11809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711636PMC
February 2013

A rare intestinal infection with systemic effects.

Gastroenterol Hepatol (N Y) 2012 Jan;8(1):60-3

Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, New York, USA.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3277202PMC
January 2012