Acute colitis chronically alters epithelial barrier and immune tolerance responses to subsequent colitis re-activation independently of shifts in microbiota composition — ASN Events
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  3. Acute colitis chronically alters epithelial barrier and immune tolerance responses to subsequent colitis re-activation independently of shifts in microbiota composition

Acute colitis chronically alters epithelial barrier and immune tolerance responses to subsequent colitis re-activation independently of shifts in microbiota composition (#66)

Hannah R Wardill 1 , Jocelyn M Choo 2 , Nicole Dmochowska 1 , Melissa Campaniello 1 , Chris Mavrangelos 1 , Joanne Bowen 1 , Geraint B Rogers 2 , Patrick A Hughes 1
  1. University of Adelaide, Adelaide, SA, Australia
  2. Microbiome Research, South Australian Health and Medical Research Institute, Adelaide, SA, Australia

Background: Inflammatory Bowel Disease (IBD) is a remitting and relapsing inflammatory disease of the lower gastrointestinal tract. We have previously shown that acute colitis chronically alters colonic sensory afferent nerves and immune responses (Hughes et. al. Gut 2009, Campaniello et. al. BBI 2017). However, little is understood regarding the chronic effects colitis has on epithelial barrier function and immune pathways involved in mucosal tolerance despite the importance of these pathways in IBD.

Methods: Mice were treated with TNBS (100uL of 130ug/ml TNBS in 30% EtOH) and killed 2 (Acute) or 28 days later (Remission). Some mice were treated with a second dose of TNBS at 28 days and killed 2 days later (Reactivated). Healthy mice were aged across the treatment range. Colonic epithelial integrity and secretory responses were compared by Ussing chamber, infiltration of innate and regulatory T cells by flow cytometry and expression of IL-10 and TGF-β by qRT-PCR. Colonic microbiota composition was determined based on 16S rRNA sequence analysis.

Results: When compared to Acute colitis, Reactivated colitis had less severe colonic shortening, changes in permeability and infiltration of monocyte / macrophages and dendritic cells, but a greater infiltration of neutrophils and TREG. Epithelial short-circuit current responses to secretagogues were impaired in Acute colitis and did not recover in Remission or Re-activated colitis. TGF-β but not IL-10 expression was increased in Reactivated compared to Acute colitis. Microbiotal composition shifted significantly between Heath and Acute mice, but normalised in Remission and did not differ between Acute and Reactivated colitis.

Conclusions: Acute colitis chronically alters epithelial barrier and immune pathways involved in immune tolerance. These changes appear to be driven by mucosal immune responses rather than compositional shifts in colonic microbiota.

 

Supported by NHMRC Australia.

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