The role of Adiponectin in acute Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD), consisting of Crohn’s Disease and Ulcerative Colitis, are highly multifactorial, comprising a complex relationship between genetics, immunity, the microbiota and environmental influences. Although treatment options have vastly improved over the last decade, patients may still be unresponsive to treatments and thus require surgical intervention. Homeostasis within the colonic environment is of paramount importance in curtailing exaggerated immune responses. A breakdown in the balance between proliferation and apoptosis in the colonic environment, alongside excessive immune cell infiltrate has been implicated in disease progression. Conflicting studies with respect to the hormone adiponectin are published in IBD, and are yet to properly define its role in IBD pathogenesis. In the studies outlined, adiponectin knockout mice were administered dextran sulfate sodium (DSS) to induce colitis, and suffered severe disease activity compared with wild type mice. This was characterised by significant colonic epithelial cell architectural distortion, accompanied by a reduction in colonic crypt length, and a notable immune cell infiltrate. To investigate the processes underlying this pathology, further studies were undertaken at both the in vitro and in vivo level. The results reported in this thesis revealed that a disruption between proliferative and apoptotic pathways were prominent in the adiponectin knockout colitic mice, alongside the activation of signal transducer and activator of transcription factor 3 (STAT3) and nuclear factor kappa B (NFκB) signalling, compared with wild type mice. Analysis of signalling pathways in vitro suggested that the addition of adiponectin in the presence of the colitis causing agent, DSS, ameliorated disease activity with respect to the balance between proliferation, apoptosis and stress signals, mediated by the receptor AdipoR1. An interesting phenotype yet to be reported in adiponectin null colitic mice was brought to light, where excessive B cell infiltration was noted in the colon, compared with wild type mice. Moreover, adiponectin knockout mice had a highly inflammatory cytokine profile characteristic of B cell proliferation and stimulation, compared with wild type mice. To date, no studies have reported an association between adiponectin and B cell infiltration in acute IBD. The adiponectin knockout model may provide a vehicle to assess immune mediated colitis, and may thus contribute to understanding the multifaceted complexity underlying the cross talk between the immune system and the colonic environment in the development of colitis.