Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • ASCI Milestone Awards
    • Video Abstracts
    • Conversations with Giants in Medicine
  • Reviews
    • View all reviews ...
    • Neurodegeneration (Mar 2026)
    • Clinical innovation and scientific progress in GLP-1 medicine (Nov 2025)
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • ASCI Milestone Awards
  • Video Abstracts
  • Conversations with Giants in Medicine
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Pathobiont-triggered induction of goblet cell response drives regional susceptibility to inflammatory bowel disease
Paige N. Spencer, Monica E. Brown, Erin P. Smith, Jiawei Wang, William Kim, Luisella Spiga, Naila Tasneem, Alan J. Simmons, Taewoo Kim, Yilin Yang, Yanwen Xu, Lin Zheng, James Ro, Harsimran Kaur, Seung Woo Kang, Matthew D. Helou, Mason A. Lee, Deronisha Arceneaux, Katherine D. Mueller, Ozge S. Kuddar, Mariah H. Harned, Jing Li, Amrita Banerjee, Nicholas O. Markham, Keith T. Wilson, Lori A. Coburn, Jeremy A. Goettel, Qi Liu, M. Kay Washington, Raphael H. Valdivia, Wenhan Zhu, Ken S. Lau
Paige N. Spencer, Monica E. Brown, Erin P. Smith, Jiawei Wang, William Kim, Luisella Spiga, Naila Tasneem, Alan J. Simmons, Taewoo Kim, Yilin Yang, Yanwen Xu, Lin Zheng, James Ro, Harsimran Kaur, Seung Woo Kang, Matthew D. Helou, Mason A. Lee, Deronisha Arceneaux, Katherine D. Mueller, Ozge S. Kuddar, Mariah H. Harned, Jing Li, Amrita Banerjee, Nicholas O. Markham, Keith T. Wilson, Lori A. Coburn, Jeremy A. Goettel, Qi Liu, M. Kay Washington, Raphael H. Valdivia, Wenhan Zhu, Ken S. Lau
View: Text | PDF
Research Article Cell biology Gastroenterology Inflammation

Pathobiont-triggered induction of goblet cell response drives regional susceptibility to inflammatory bowel disease

  • Text
  • PDF
Abstract

The gastrointestinal tract varies in structure and function by region, yet the drivers of region-specific inflammatory disease remain elusive. Here, a TNF-overexpressing murine model (TnfΔARE/+) of Crohn’s disease (CD) was used to investigate how pathobionts interact with host immune susceptibilities to drive region-specific disease. We identified the pathobiont Chlamydia muridarum, an intracellular bacterium and murine counterpart to the human sexually transmitted C. trachomatis, as a necessary and sufficient trigger for disease manifestation in the proximal/ascending colon, a common site of CD. In genetically susceptible hosts, pathobiont-triggered proximal colonic inflammation is driven by goblet cell responses, including tryptophan metabolism via indoleamine 2,3-dioxygenase 1 (IDO1). Our findings translate to human disease, where we demonstrate upregulation of epithelia-derived IDO1 in actively inflamed ascending colon specimens, but not actively inflamed terminal ileum specimens, of patients with CD. Our findings mechanistically reveal how genetic and microbial factors drive the manifestation of disease in a region-specific manner and provide a unique model to study CD specific to the ascending colon.

Authors

Paige N. Spencer, Monica E. Brown, Erin P. Smith, Jiawei Wang, William Kim, Luisella Spiga, Naila Tasneem, Alan J. Simmons, Taewoo Kim, Yilin Yang, Yanwen Xu, Lin Zheng, James Ro, Harsimran Kaur, Seung Woo Kang, Matthew D. Helou, Mason A. Lee, Deronisha Arceneaux, Katherine D. Mueller, Ozge S. Kuddar, Mariah H. Harned, Jing Li, Amrita Banerjee, Nicholas O. Markham, Keith T. Wilson, Lori A. Coburn, Jeremy A. Goettel, Qi Liu, M. Kay Washington, Raphael H. Valdivia, Wenhan Zhu, Ken S. Lau

×

Figure 5

Perturbation of the IDO1 pathway reduces Chlamydia-driven PC inflammation in the TnfΔARE/+ model.

Options: View larger image (or click on image) Download as PowerPoint
Perturbation of the IDO1 pathway reduces Chlamydia-driven PC inflammatio...
(A) Representative IF images of IDO1, Chlamydia MOMP, and nuclei costaining on PC sections from age-matched (11–12 weeks) CONV TnfΔARE/+ mice treated with doxycycline or vehicle. N = 4 mice per condition. Scale bars: 100 μm. (B) Representative IF images as in A of PC sections from age-matched (16–20 weeks) SPF-B TnfΔARE/+ mice that are sham or CM001-GFP inoculated. N = 5 mice per condition. Scale bars: 200 μm. (C) Experimental paradigm for secretory cell ablation in TnfΔARE/+ mice. (D) Representative H&E-stained PC sections, with insets, from age-matched (20–27 weeks) TnfΔARE/+ mice with (N = 3) or without (N = 5) secretory cell ablation. Scale bars: 200 μm. (E) Representative IF images as in A of PC sections from age-matched TnfΔARE/+ mice in D with or without secretory cell ablation. Scale bars: 100 μm. (F) Colitis scores from histopathological scoring of colons from D. (G) Colitis subscores that contribute to overall colitis score in F. (H) Ratio of kynurenine to tryptophan, measured by liquid chromatography–mass spectrometry, in PC tissue from age-matched mice. N = 4 per condition. (I) Experimental paradigm for administration of tryptophan-deficient diet to TnfΔARE/+ mice from the CONV facility. (J) Representative H&E-stained PC sections from age-matched (11–12 weeks) CONV TnfΔARE/+ mice fed a control diet (N = 7) or a tryptophan-deficient diet (N = 5). Scale bars: 200 μm. (K and L) Histopathological scoring analysis as in F and G of colons from J. (M) Representative IF images as in A of PC sections from age-matched TnfΔARE/+ mice in J fed a control or tryptophan-deficient diet. Scale bars: 100 μm. Data are shown as the mean ± SEM in quantifications. Statistical significance was determined using an unpaired 2-tailed t test (F and K), multiple unpaired 2-tailed t tests with FDR of 1% (G and L), or an ordinary 1-way ANOVA with Šidák’s multiple-comparison test (H). *P < 0.05, **P < 0.01, ****P < 0.0001. See also Supplemental Figures 7 and 8.

Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts