Therapeutic Helminth Infection of Macaques with Idiopathic Chronic Diarrhea Alters the Inflammatory Signature and Mucosal Microbiota of the Colon

Mara Jana Broadhurst, Amir Ardeshir, Bittoo Kanwar, Julie Mirpuri, Uma Mahesh Gundra, Jacqueline M. Leung, Kirsten E. Wiens, Ivan Vujkovic-Cvijin, Charlie C. Kim, Felix Yarovinsky, Nicholas W. Lerche, Joseph M. McCune, P'ng Loke

Research output: Contribution to journalArticle

111 Citations (Scopus)

Abstract

Idiopathic chronic diarrhea (ICD) is a leading cause of morbidity amongst rhesus monkeys kept in captivity. Here, we show that exposure of affected animals to the whipworm Trichuris trichiura led to clinical improvement in fecal consistency, accompanied by weight gain, in four out of the five treated monkeys. By flow cytometry analysis of pinch biopsies collected during colonoscopies before and after treatment, we found an induction of a mucosal TH2 response following helminth treatment that was associated with a decrease in activated CD4+ Ki67+ cells. In parallel, expression profiling with oligonucleotide microarrays and real-time PCR analysis revealed reductions in TH1-type inflammatory gene expression and increased expression of genes associated with IgE signaling, mast cell activation, eosinophil recruitment, alternative activation of macrophages, and worm expulsion. By quantifying bacterial 16S rRNA in pinch biopsies using real-time PCR analysis, we found reduced bacterial attachment to the intestinal mucosa post-treatment. Finally, deep sequencing of bacterial 16S rRNA revealed changes to the composition of microbial communities attached to the intestinal mucosa following helminth treatment. Thus, the genus Streptophyta of the phylum Cyanobacteria was vastly increased in abundance in three out of five ICD monkeys relative to healthy controls, but was reduced to control levels post-treatment; by contrast, the phylum Tenericutes was expanded post-treatment. These findings suggest that helminth treatment in primates can ameliorate colitis by restoring mucosal barrier functions and reducing overall bacterial attachment, and also by altering the communities of attached bacteria. These results also define ICD in monkeys as a tractable preclinical model for ulcerative colitis in which these effects can be further investigated.

Original languageEnglish (US)
Article numbere1003000
JournalPLoS Pathogens
Volume8
Issue number11
DOIs
StatePublished - Nov 2012

Fingerprint

Helminths
Microbiota
Macaca
Haplorhini
Diarrhea
Colon
Intestinal Mucosa
Streptophyta
Real-Time Polymerase Chain Reaction
Tenericutes
Infection
Trichuris
Biopsy
Gene Expression
High-Throughput Nucleotide Sequencing
Macrophage Activation
Cyanobacteria
Colitis
Colonoscopy
Oligonucleotide Array Sequence Analysis

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Therapeutic Helminth Infection of Macaques with Idiopathic Chronic Diarrhea Alters the Inflammatory Signature and Mucosal Microbiota of the Colon. / Broadhurst, Mara Jana; Ardeshir, Amir; Kanwar, Bittoo; Mirpuri, Julie; Gundra, Uma Mahesh; Leung, Jacqueline M.; Wiens, Kirsten E.; Vujkovic-Cvijin, Ivan; Kim, Charlie C.; Yarovinsky, Felix; Lerche, Nicholas W.; McCune, Joseph M.; Loke, P'ng.

In: PLoS Pathogens, Vol. 8, No. 11, e1003000, 11.2012.

Research output: Contribution to journalArticle

Broadhurst, MJ, Ardeshir, A, Kanwar, B, Mirpuri, J, Gundra, UM, Leung, JM, Wiens, KE, Vujkovic-Cvijin, I, Kim, CC, Yarovinsky, F, Lerche, NW, McCune, JM & Loke, P 2012, 'Therapeutic Helminth Infection of Macaques with Idiopathic Chronic Diarrhea Alters the Inflammatory Signature and Mucosal Microbiota of the Colon', PLoS Pathogens, vol. 8, no. 11, e1003000. https://doi.org/10.1371/journal.ppat.1003000
Broadhurst, Mara Jana ; Ardeshir, Amir ; Kanwar, Bittoo ; Mirpuri, Julie ; Gundra, Uma Mahesh ; Leung, Jacqueline M. ; Wiens, Kirsten E. ; Vujkovic-Cvijin, Ivan ; Kim, Charlie C. ; Yarovinsky, Felix ; Lerche, Nicholas W. ; McCune, Joseph M. ; Loke, P'ng. / Therapeutic Helminth Infection of Macaques with Idiopathic Chronic Diarrhea Alters the Inflammatory Signature and Mucosal Microbiota of the Colon. In: PLoS Pathogens. 2012 ; Vol. 8, No. 11.
@article{c8da76bbb28d43df9368b3739cb5c317,
title = "Therapeutic Helminth Infection of Macaques with Idiopathic Chronic Diarrhea Alters the Inflammatory Signature and Mucosal Microbiota of the Colon",
abstract = "Idiopathic chronic diarrhea (ICD) is a leading cause of morbidity amongst rhesus monkeys kept in captivity. Here, we show that exposure of affected animals to the whipworm Trichuris trichiura led to clinical improvement in fecal consistency, accompanied by weight gain, in four out of the five treated monkeys. By flow cytometry analysis of pinch biopsies collected during colonoscopies before and after treatment, we found an induction of a mucosal TH2 response following helminth treatment that was associated with a decrease in activated CD4+ Ki67+ cells. In parallel, expression profiling with oligonucleotide microarrays and real-time PCR analysis revealed reductions in TH1-type inflammatory gene expression and increased expression of genes associated with IgE signaling, mast cell activation, eosinophil recruitment, alternative activation of macrophages, and worm expulsion. By quantifying bacterial 16S rRNA in pinch biopsies using real-time PCR analysis, we found reduced bacterial attachment to the intestinal mucosa post-treatment. Finally, deep sequencing of bacterial 16S rRNA revealed changes to the composition of microbial communities attached to the intestinal mucosa following helminth treatment. Thus, the genus Streptophyta of the phylum Cyanobacteria was vastly increased in abundance in three out of five ICD monkeys relative to healthy controls, but was reduced to control levels post-treatment; by contrast, the phylum Tenericutes was expanded post-treatment. These findings suggest that helminth treatment in primates can ameliorate colitis by restoring mucosal barrier functions and reducing overall bacterial attachment, and also by altering the communities of attached bacteria. These results also define ICD in monkeys as a tractable preclinical model for ulcerative colitis in which these effects can be further investigated.",
author = "Broadhurst, {Mara Jana} and Amir Ardeshir and Bittoo Kanwar and Julie Mirpuri and Gundra, {Uma Mahesh} and Leung, {Jacqueline M.} and Wiens, {Kirsten E.} and Ivan Vujkovic-Cvijin and Kim, {Charlie C.} and Felix Yarovinsky and Lerche, {Nicholas W.} and McCune, {Joseph M.} and P'ng Loke",
year = "2012",
month = "11",
doi = "10.1371/journal.ppat.1003000",
language = "English (US)",
volume = "8",
journal = "PLoS Pathogens",
issn = "1553-7366",
publisher = "Public Library of Science",
number = "11",

}

TY - JOUR

T1 - Therapeutic Helminth Infection of Macaques with Idiopathic Chronic Diarrhea Alters the Inflammatory Signature and Mucosal Microbiota of the Colon

AU - Broadhurst, Mara Jana

AU - Ardeshir, Amir

AU - Kanwar, Bittoo

AU - Mirpuri, Julie

AU - Gundra, Uma Mahesh

AU - Leung, Jacqueline M.

AU - Wiens, Kirsten E.

AU - Vujkovic-Cvijin, Ivan

AU - Kim, Charlie C.

AU - Yarovinsky, Felix

AU - Lerche, Nicholas W.

AU - McCune, Joseph M.

AU - Loke, P'ng

PY - 2012/11

Y1 - 2012/11

N2 - Idiopathic chronic diarrhea (ICD) is a leading cause of morbidity amongst rhesus monkeys kept in captivity. Here, we show that exposure of affected animals to the whipworm Trichuris trichiura led to clinical improvement in fecal consistency, accompanied by weight gain, in four out of the five treated monkeys. By flow cytometry analysis of pinch biopsies collected during colonoscopies before and after treatment, we found an induction of a mucosal TH2 response following helminth treatment that was associated with a decrease in activated CD4+ Ki67+ cells. In parallel, expression profiling with oligonucleotide microarrays and real-time PCR analysis revealed reductions in TH1-type inflammatory gene expression and increased expression of genes associated with IgE signaling, mast cell activation, eosinophil recruitment, alternative activation of macrophages, and worm expulsion. By quantifying bacterial 16S rRNA in pinch biopsies using real-time PCR analysis, we found reduced bacterial attachment to the intestinal mucosa post-treatment. Finally, deep sequencing of bacterial 16S rRNA revealed changes to the composition of microbial communities attached to the intestinal mucosa following helminth treatment. Thus, the genus Streptophyta of the phylum Cyanobacteria was vastly increased in abundance in three out of five ICD monkeys relative to healthy controls, but was reduced to control levels post-treatment; by contrast, the phylum Tenericutes was expanded post-treatment. These findings suggest that helminth treatment in primates can ameliorate colitis by restoring mucosal barrier functions and reducing overall bacterial attachment, and also by altering the communities of attached bacteria. These results also define ICD in monkeys as a tractable preclinical model for ulcerative colitis in which these effects can be further investigated.

AB - Idiopathic chronic diarrhea (ICD) is a leading cause of morbidity amongst rhesus monkeys kept in captivity. Here, we show that exposure of affected animals to the whipworm Trichuris trichiura led to clinical improvement in fecal consistency, accompanied by weight gain, in four out of the five treated monkeys. By flow cytometry analysis of pinch biopsies collected during colonoscopies before and after treatment, we found an induction of a mucosal TH2 response following helminth treatment that was associated with a decrease in activated CD4+ Ki67+ cells. In parallel, expression profiling with oligonucleotide microarrays and real-time PCR analysis revealed reductions in TH1-type inflammatory gene expression and increased expression of genes associated with IgE signaling, mast cell activation, eosinophil recruitment, alternative activation of macrophages, and worm expulsion. By quantifying bacterial 16S rRNA in pinch biopsies using real-time PCR analysis, we found reduced bacterial attachment to the intestinal mucosa post-treatment. Finally, deep sequencing of bacterial 16S rRNA revealed changes to the composition of microbial communities attached to the intestinal mucosa following helminth treatment. Thus, the genus Streptophyta of the phylum Cyanobacteria was vastly increased in abundance in three out of five ICD monkeys relative to healthy controls, but was reduced to control levels post-treatment; by contrast, the phylum Tenericutes was expanded post-treatment. These findings suggest that helminth treatment in primates can ameliorate colitis by restoring mucosal barrier functions and reducing overall bacterial attachment, and also by altering the communities of attached bacteria. These results also define ICD in monkeys as a tractable preclinical model for ulcerative colitis in which these effects can be further investigated.

UR - http://www.scopus.com/inward/record.url?scp=84870843366&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84870843366&partnerID=8YFLogxK

U2 - 10.1371/journal.ppat.1003000

DO - 10.1371/journal.ppat.1003000

M3 - Article

VL - 8

JO - PLoS Pathogens

JF - PLoS Pathogens

SN - 1553-7366

IS - 11

M1 - e1003000

ER -