Inflammation Drives Dysbiosis and Bacterial Invasion in Murine Models of Ileal Crohn’

[kiny]

Inflammation Drives Dysbiosis and Bacterial Invasion in Murine Models of Ileal Crohn’

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http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0041594

Inflammation Drives Dysbiosis and Bacterial Invasion in Murine Models of Ileal Crohn’s Disease



Background and Aims

Understanding the interplay between genetic susceptibility, the microbiome, the environment and the immune system in Crohn’s Disease (CD) is essential for developing optimal therapeutic strategies. We sought to examine the dynamics of the relationship between inflammation, the ileal microbiome, and host genetics in murine models of ileitis.

Methods

We induced ileal inflammation of graded severity in C57BL6 mice by gavage with Toxoplasma gondii, Giardia muris, low dose indomethacin (LDI;0.1 mg/mouse), or high dose indomethacin (HDI;1 mg/mouse). The composition and spatial distribution of the mucosal microbiome was evaluated by 16S rDNA pyrosequencing and fluorescence in situ hybridization. Mucosal E. coli were enumerated by quantitative PCR, and characterized by phylogroup, genotype and pathotype.

Results

Moderate to severe ileitis induced by T. gondii (day 8) and HDI caused a consistent shift from >95% Gram + Firmicutes to >95% Gram - Proteobacteria. This was accompanied by reduced microbial diversity and mucosal invasion by adherent and invasive E. coli, mirroring the dysbiosis of ileal CD. In contrast, dysbiosis and bacterial invasion did not develop in mice with mild ileitis induced by Giardia muris. Superimposition of genetic susceptibility and T. Gondii infection revealed greatest dysbiosis and bacterial invasion in the CD-susceptible genotype, NOD2−/−, and reduced dysbiosis in ileitis-resistant CCR2−/− mice. Abrogating inflammation with the CD therapeutic anti-TNF-α-mAb tempered dysbiosis and bacterial invasion.

Conclusions

Acute ileitis induces dysbiosis and proliferation of mucosally invasive E. coli, irrespective of trigger and genotype. The identification of CCR2 as a target for therapeutic intervention, and discovery that host genotype and therapeutic blockade of inflammation impact the threshold and extent of ileal dysbiosis are of high relevance to developing effective therapies for CD.

 

[Mark in Seattle]

This is an awesome research report kiny, I've really found this enjoyable & enlightening. I really like how the authors demonstrated that only severe inflammation causes dysbiosis with the way they structured their tests, using a moderately-inflammatory invader, a maximally-inflammatory invader, along with teasing out the effects of NOD2 & CCR2, and finally the attenuating effects of anti-TNF-alpha.

I also really appreciated their measuring the complete transformation of the microbiota composition from 95% gram+ to 95% gram- in just 8 days, wow!

This has given me some good food for thought.

I see that some of these authors focus a lot on the T. Gondi parasite, and some focus on IBD in animals, such as cats and dogs.

Here's one more abstract I found by one of the authors, which comments a bit more on the relevance and utility of selecting T. Gondi as a trigger in experiments for researching IBD:

Immunol Cell Biol. 2012 Aug;90(7):668-75. doi: 10.1038/icb.2011.93. Epub 2011 Nov 8.
Insights into inflammatory bowel disease using Toxoplasma gondii as an infectious trigger.
Egan CE, Cohen SB, Denkers EY.
SourceDepartment of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.

Abstract
Oral infection of certain inbred mouse strains with the protozoan Toxoplasma gondii triggers inflammatory pathology resembling lesions seen during human inflammatory bowel disease, in particular Crohn's disease (CD). Damage triggered by the parasite is largely localized to the distal portion of the small intestine, and as such is one of only a few models for ileal inflammation. This is important because ileal involvement is a characteristic of CD in over two-thirds of patients. The disease induced by Toxoplasma is mediated by Th1 cells and the cytokines tumor necrosis factor-α and interferon-γ. Inflammation is dependent upon IL-23, also identified by genome-wide association studies as a risk factor in CD. Development of lesions is concomitant with emergence of E. coli that display enhanced adhesion to the intestinal epithelium and subepithelial translocation. Furthermore, depletion of gut flora renders mice resistant to Toxoplasma-triggered ileitis. Recent findings suggest complex CCR2-dependent interactions between lamina propria T cells and intraepithelial lymphocytes in fueling proinflammatory pathology in the intestine. The advantage of the Toxoplasma model is that disease develops rapidly (within 7-10 days of infection) and can be induced in immunodeficient mice by adoptive transfer of mucosal T cells from infected donors. We propose that Toxoplasma acts as a trigger setting into motion a series of events culminating in loss of tolerance in the intestine and emergence of pathogenic T cell effectors. The Toxoplasma trigger model is providing new leaps in our understanding of immunity in the intestine.

PMID:22064707[PubMed - in process]