An imbalance in mucosal cytokine profile causes transient intestinal inflammation following an animal's first exposure to faecal bacteria and antigens

Abstract

SummaryIntestinal microflora play a critical role in the initiation and perpetuation of chronic inflammatory bowel diseases. In genetically susceptible hosts, bacterial colonization results in rapid-onset chronic intestinal inflammation. Nevertheless, the intestinal and systemic immune response to faecal bacteria and antigen exposure into a sterile intestinal lumen of a post-weaned animal with a mature immune system are not understood clearly. This study examined the effects of faecal bacteria and antigen exposure on the intestinal mucosal and systemic immune system in healthy axenic mice. Axenic wild-type mice were inoculated orally with a crude faecal slurry solution derived from conventionally raised mice and were analysed prior to and then at days 3, 7, 14 and 28 post-treatment. Ingestion of faecal slurry resulted in a transient, early onset of proinflammatory interferon (IFN)-g, tumour necrosis factor (TNF)-a and interleukin (IL)-17 response that was maximal at day 3. In contrast, the transient release of the anti-inflammatory cytokines IL-10 and IL-4 occurred later and was maximal at day 7. Both responses subsided by day 14. This early cytokine imbalance was associated with a brief rise in colonic and caecal histopathological injury score at day 7. The bacterial antigen-specific systemic response was found to follow the intestinal immune response with a maximal release of both pro-and anti-inflammatory cytokines at day 7. Thus, first exposure of healthy axenic wild-type mice to normal faecal flora and antigens results in an early proinflammatory cytokine response and transient colonic inflammation that then resolves in conjunction with a subsequent antiinflammatory cytokine profile.

Microbiota maintain colonic homeostasis by activating TLR2/MyD88/PI3K signaling in IL-10–producing regulatory B cells

“…The consortium of resident enteric bacteria provides protective signals to host immune defenses (40)(41)(42). Colonization of GF WT mice with resident fecal microbiota rapidly stimulated mucosal proinflammatory cytokine production manifested by transient release of TNF-α, IL-12p40, and IFN-γ, but not IL-17a, within 3 days, while intestinal IL-10 levels gradually increased to maximum sustained levels in 7 days (43). The finding that transient in vivo stimulation of proinflammatory cytokine gene expression was followed by downregulation to basal levels in ex-GF Il10 +/+ but not in Il10 -/mice advances the hypothesis that resident microbiota induces IL-10 production by LP immune cells that mediates mucosal homeostasis.…”

Effect of Solar Particle Event Radiation on Gastrointestinal Tract Bacterial Translocation and Immune Activation

“…The first introduction of gut microbiota to an animal raised under axenic conditions results in a transient proinflammatory response that is replaced by an anti-inflammatory response by 7 days and is associated with inflammatory mononuclear cell infiltrates into the lamina propria (38). Effects of gut microbiota and the amount of LPS in the diet also affect the acquired immune response in the gut and draining lymphoid organs (39).…”

Neonatal exposure to fecal antigens reduces intestinal inflammation

“…We have recently demonstrated that normal wildtype mice kept in an axenic environment and then exposed to the endogenous microbiota as adults mount a transitory inflammatory immune response to the bacteria and their antigens resulting in a brief intestinal inflammation. Subsequent establishment of homeostasis appears to be an important step for tolerance induction 23…”

“…We have shown previously that acquisition of the endogenous flora leads to a brief immune response to bacterial antigens that may be required for tolerance induction 22. These bacteria‐triggered immune responses can lead to transient intestinal inflammation in adult axenic mice following association with endogenous flora, due to a temporary imbalance in intestinal homeostatic cytokine release 23. Healthy wildtype mice return to a state of nonresponsiveness to bacterial antigens within 14 days; in contrast, mice with a genetic defect, such as the lack of cytokines (interleukin [IL]‐10 and IL‐2), T‐cell receptor (TCR) abnormalities (TCRα −/− ), and epithelial barrier deficiencies (mdr1a−/−) remain responsive to bacterial antigens 22, 24–28.…”