Rhythmicity of Intestinal IgA Responses Confers Oscillatory Commensal Microbiota Mutualism

Abstract

Mutualistic interactions with the commensal microbiota are enforced through a range of immune responses that confer metabolic benefits for the host and ensure tissue health and homeostasis. Immunoglobulin (Ig)A responses directly determine the composition of commensal species that colonize the intestinal tract but require significant metabolic resources to fuel antibody production by tissue-resident plasma cells. Here we demonstrate IgA responses are subject to diurnal regulation by dietary-derived metabolic cues and a cell-intrinsic circadian clock. Rhythmicity in IgA secretion conferred oscillatory patterns on the commensal microbial community and its associated metabolic activity, resulting in changes to metabolite availability over the course of the circadian day. Our findings suggest circadian networks comprising intestinal IgA, the diet and the microbiota align to ensure metabolic health.

Circadian rhythms in the gut microbiota shape sex differences in host gene expression and metabolism

“…Individual variability in environmental and lifestyle exposures, including jet lag, shift work, antibiotic exposure, and altered feeding times or consumption of highly processed diets, are associated with disruption to diurnal rhythms in gut microbiota (Altaha et al, 2022; Dantas Machado et al, 2022; Leone et al, 2015; Thaiss et al, 2014; Zarrinpar et al, 2014, 2018). In turn, microbial circadian misalignment is reported to increase the risk for obesity, poor glycemic control, metabolic dysfunction, inflammation, and overall heightened susceptibility to disease (Brooks and Hooper, 2020; Choi et al, 2021; Frazier and Chang, 2020; Penny et al, 2022; Zheng et al, 2020). Although circadian disruption is often associated with sex-specific health outcomes, most studies on circadian rhythms, the microbiome, and health outcomes use only male mice or collapse both sexes into one experimental condition (Walton et al, 2022).…”

Consequences of collagen induced inflammatory arthritis on circadian regulation of the gut microbiome

“…Of all genes assigned to this pathway (43 genes) 8 exhibited significant down regulation (Figure 2C,D). Given that secretion of IgA exhibits 24 h oscillations, 21 we went on to determine if these transcriptional changes in the colon resulted in a change in rhythmic IgA production. Assays were performed on fecal samples collected from a separate cohort of animals over a 24 h period (Figure 2E).…”

“…Loss of rhythms within the microbiota in the setting of CIA may impact disease progression and the development of co‐morbidities. As an example, we know that loss in diurnal oscillations of the microbiota alters host metabolic homeostasis 21 …”

“…As an example, we know that loss in diurnal oscillations of the microbiota alters host metabolic homeostasis. 21 We further focused on investigating changes in rhythms within Lactobacilli in the setting of arthritis. These Firmicutes have been linked to the development of arthritis 49 and dietary supplementation with certain species has a protective effect in animal models of arthritis.…”

“…20 Mechanisms driving daily oscillations in the microbiome are not fully understood, but these rhythms are clearly influenced by dietary composition 14 and host behavioral rhythmicity, including timing of food intake, 13,14 also by the host circadian clock acting through neural and humoral outputs. 13,16 We have identified rhythmic secretion of immunoglobulin A (IgA) as an important mechanism driving oscillations in the abundance of a number of commensal bacteria 21 and more recently a critical role for the intestinal epithelial cell (IEC) clock in driving the rhythmic microbiome has been demonstrated. 22 The circadian clock regulates a huge range of physiological processes via temporal control of cellular function.…”