Determining the functional consequences of circadian regulation of intestinal IgA plasma cell responses

Abstract

The intestinal immune system provides protection from potential pathogens and promotes beneficial interactions with the commensal microbiota. In turn, the commensal microbiota confers protection to the host from invading pathogens and plays a major role in producing diet-derived nutrients which are essential for host development and survival. Dysregulated immune responses towards commensal microbes manifest in a wide variety of inflammatory and metabolic disorders. Thus, immune regulation of the intestinal microbiota is closely linked with mammalian health and metabolism. However, the pathways governing this relationship are incompletely understood. Intestinal plasma cells produce several grams of immunoglobulin (Ig)A each day, which promotes mutualism with the commensal microbiota and intestinal homeostasis. The constitutive production of large quantities of IgA suggests that significant metabolic resources may be utilised to maintain mucosal antibody responses. To minimise metabolic cost, several biological processes are imprinted with rhythmicity over the 24-hour (circadian) day. Peak responses align with the time of greatest exposure to environmental challenge and/ or nutrient resources, to maximise the response around the time of greatest need. Whether intestinal IgA responses are imprinted with circadian rhythmicity in the steady state is not known. We hypothesised that IgA-mediated regulation of the microbiota is subject to temporal entrainment by circadian cues. We further postulated that dysregulation of rhythmicity in mucosal antibody secretion could have important consequences for host metabolism. Here, I found that intestinal plasma cell-intrinsic IgA secretion exhibits circadian rhythmicity, which was subject to entrainment by dietary-derived metabolic cues and a cell-intrinsic circadian clock. Moreover, I found that compositional and functional oscillations in the intestinal commensal microbiota, and microbial metabolites, are altered in the absence of mucosal antibodies, suggesting that IgA may in part entrain circadian rhythmicity of the microbiota and nutrient availability. Together, these data suggest a previously unappreciated circadian dialogue exists between dietary cues, IgA and the commensal microbiota. This has clinical implications for furthering our understanding of the progression of human metabolic diseases, which are recognised to associate with circadian misalignment.

Date of Award	1 Aug 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Richard Grencis (Supervisor) & Matthew Hepworth (Supervisor)