Rhythmicity of Intestinal IgA Responses Confers Oscillatory Commensal Microbiota Mutualism

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.

IgA dysfunction induced by the early-lifetime disruption of gut microbiota aggravates diet–induced metabolic syndrome in mice

BackgroundLow-dose antibiotic contamination in animal food is still a severe food safety problem worldwide. Penicillin is one of the main classes of antibiotics being detected in food. Previous studies have shown that transient exposure of low-dose penicillin (LDP) during early life resulted in metabolic syndrome (MetS) in mice. However, the underlying mechanism(s) and efficient approaches to counteracting this are largely unknown.MethodsWild-type (WT) or secretory IgA (SIgA)-deficient (Pigr-/-) C57BL/6 mice were exposed to LDP or not from several days before birth to 30 d of age. Five times of FMT or probiotics (a mixture of Lactobacillus bulgaricus and L. rhamnosus GG) treatments were applied to parts of these LDP-treated mice from 12 d to 28 d of life. Bacterial composition from different regions (mucosa and lumen) of the colon and ileum were analyzed through 16S rDNA sequencing. Intestinal IgA response was analyzed. Multiple parameters related to MetS were also determined. In addition, germ-free animals and in vitro tissue culture were also used to determine the correlations between LDP, gut microbiota (GM) and intestinal IgA response.ResultsLDP disturbed the intestinal bacterial composition, especially for ileal mucosa, the main inductive and effective sites of IgA response, in 30-d-old mice. The alteration of early GM resulted in a persistent inhibition of the intestinal IgA response, leading to a constant reduction of fecal and caecal SIgA levels throughout the 25-week experiment, which is early life-dependent, as transfer of LDP-GM to 30 d germ-free mice only resulted in a transient reduction in fecal SIgA. LDP-induced reduction in SIgA led to a decrease in IgA+ bacteria and a dysbiosis in the ileal mucosal samples of 25 week wild-type but not Pigr-/- mice. Moreover, LDP also resulted in increases in ileal bacterial encroachment and adipose inflammation, along with an enhancement of diet-induced MetS in an intestinal SIgA-dependent manner. Furthermore, several times of FMT or probiotic treatments during LDP treatment are efficient to fully (for FMT) or partially (for probiotics) counteract the LDP-effect on both GM and metabolism.ConclusionsEarly-life LDP-induced enhancement of diet-induced MetS is mediated by intestinal SIgA, which could be (partially) restored by FMT or probiotics treatment.

Development of Microbiome Biomarkers for IgA: a Joint Modeling Approach

Our aim in this study is to develop predictive microbiome biomarkers for intestinal IgA levels. In this article, a operational taxonomic units(OTU)-specific (family-specific) and time-specific joint model is presented as a tool to model the association between OTU (or family) and biological response (measured by IgA level) taking into account the treatment group (Control or PAT) of the subjects. The model allows detecting OTUs (families) that are associated with the IgA; for some OTUs (families), the association is driven by the treatment while for others the association reflects the correlation between the OTUs (families) and IgA.The results of the analysis reveal that: (1) the observed diversity of S24-7 family can be used as a biomarker to classify samples according to treatment group for days 6 and 12; (2) the treatment effect induces the corrlelation between the S24-7 diversity and the IgA level at day 20; (3) The OTUs that are identified to be significantly differentially abundant (FDR level of 0.05) between the two treatment groups for days 12 and 20 are all part of the S24-7 family, although most of the differentially abundant ones at day 1 are from the Lactobacillaceae family; (4) only the Lachnospiraceae family diversity at day 6, and 20 can be used as predictive biomarker for the IgA level at day 20; (5) New.ReferenceOTU513, correlated with the IgA level at day 20, since day 12, belongs to the Lachnospiraceae family and all other OTUs among the top 10 significantly associated OTUs at day 20 are from the S24-7 family; (6) the observed alpha diversity at day 6 is significantly differentially abundant and can be used as predictive biomarker for IgA level at day 20.

Bruton’s Tyrosine Kinase Supports Gut Mucosal Immunity and Commensal Microbiome Recognition in Autoimmune Arthritis

Bruton’s tyrosine kinase (Btk) deficiency preferentially eliminates autoreactive B cells while sparing normal humoral responses, but has not been studied in mucosal immunity. Commensal microbes are essential for arthritis in K/BxN mice, used here to examine how BTK-mediated signaling interfaces with the microbiome. Btk-deficient K/BxN mice were found to have small Peyer’s Patches with reduced germinal center and IgA+ B cells. Although lamina propria IgA+ plasma cells were numerically normal, intestinal IgA was low and IgA coating of commensal bacteria was reduced. IgA-seq showed a shift in microbes that are normally IgA-coated into the uncoated fraction in Btk-deficient mice. In this altered microbial milieau, the proportion of Parabacteroides distasonis was reduced in Btk-deficient K/BxN mice. To determine whether P. distasonis contributes to arthritis, it was reintroduced into antibiotic-protected K/BxN mice, where it restored disease. This suggests that P. distasonis’ inability to thrive in Btk-deficient mice may be a factor in disease protection. Thus, BTK supports normal intestinal IgA development, with downstream effects on the microbiome that may contribute to autoimmunity.

IgA dysfunctions induced by the early-lifetime disruption of gut microbitoa result in metabolic syndrome in mice

Backgroud: Disruption of the gut microbiota (GM), mainly induced by antibiotic treatments and C-sections, is prevalent during the early lifetime, which can result in lifelong changes in the GM composition and metabolism.Results: The GM of newborn mice was influenced after being subjected to transitory treatment with low-dose penicillin (LDP), resulting in a permanent reduction of intestinal IgA. Germ-free (GF) mice transferred GM from the LDP-treated mice also showed decreased intestinal IgA levels. Similarly, antigens derived from the LDP-treated mice induced lower IgA production during in vitro incubation with small intestinal tissues. Furthermore, a lack of intestinal IgA led to the persistent dysbiosis of mucosal GM, causing metabolic syndrome (MetS) in the LDP-treated mice. The mice lacking intestinal IgA (Pigr-/-) only showed transient alteration in GM after LDP exposure while the long-period metabolism was not influenced. Moreover, gavage with GM from the LDP-free mice or probiotics (partially) restored the GM and intestinal IgA, while improving the MetS in LDP-treated mice.Conclusions: The antibiotics–induced changes of GM in early lifetime permanently dampened the IgA responses to the GM, which lead to the long-term dysbiosis of intestinal mucosal bacteria and MetS.