Antibiotics induce sustained dysregulation of intestinal T cell immunity by perturbing macrophage homeostasis

Abstract

Macrophages in the healthy intestine are highly specialized and usually respond to the gut microbiota without provoking an inflammatory response. A breakdown in this tolerance leads to inflammatory bowel disease (IBD), but the mechanisms by which intestinal macrophages normally become conditioned to promote microbial tolerance are unclear. Strong epidemiological evidence linking disruption of the gut microbiota by antibiotic use early in life to IBD indicates an important role for the gut microbiota in modulating intestinal immunity. Here, we show that antibiotic use causes intestinal macrophages to become hyperresponsive to bacterial stimulation, producing excess inflammatory cytokines. Re-exposure of antibiotic-treated mice to conventional microbiota induced a long-term, macrophage-dependent increase in inflammatory T helper 1 (TH1) responses in the colon and sustained dysbiosis. The consequences of this dysregulated macrophage activity for T cell function were demonstrated by increased susceptibility to infections requiring TH17 and TH2 responses for clearance (bacterial Citrobacter rodentium and helminth Trichuris muris infections), corresponding with increased inflammation. Short-chain fatty acids (SCFAs) were depleted during antibiotic administration; supplementation of antibiotics with the SCFA butyrate restored the characteristic hyporesponsiveness of intestinal macrophages and prevented T cell dysfunction. Butyrate altered the metabolic behavior of macrophages to increase oxidative phosphorylation and also promoted alternative macrophage activation. In summary, the gut microbiota is essential to maintain macrophage-dependent intestinal immune homeostasis, mediated by SCFA-dependent pathways. Oral antibiotics disrupt this process to promote sustained T cell–mediated dysfunction and increased susceptibility to infections, highlighting important implications of repeated broad-spectrum antibiotic use.

Metabolism at the centre of the host–microbe relationship

“…Antibiotics have been shown to affect SCFA-producing bacteria causing a decrease in SCFA abundance [73,74]. In a recent study, macrophage dysfunction was noted following antibiotic-induced dysbiosis causing aberrant activation of T helper type 1 (Th1) cells, leaving mice susceptible to Th17 and Th2-type infections [75]. The authors demonstrated that SCFA were reduced following antibiotics, and that supplementing butyrate could restore macrophage hyporesponsiveness to microbial ligands and prevent Th1 over-activation [75], thus showing a wider effect of antibiotics on the host beyond microbial composition and effects on colonization resistance.…”

“…In a recent study, macrophage dysfunction was noted following antibiotic-induced dysbiosis causing aberrant activation of T helper type 1 (Th1) cells, leaving mice susceptible to Th17 and Th2-type infections [75]. The authors demonstrated that SCFA were reduced following antibiotics, and that supplementing butyrate could restore macrophage hyporesponsiveness to microbial ligands and prevent Th1 over-activation [75], thus showing a wider effect of antibiotics on the host beyond microbial composition and effects on colonization resistance. This observation is likely to also be applicable to conditions where SCFA are known to have peripheral effects and also suggest that antibiotic treatment would affect other microbial-derived metabolites.…”

Regulation of mononuclear phagocyte function by the microbiota at mucosal sites

“…57 These changes in SCFA levels corresponded with aberrant macrophage functions upon re-population of the microbiota, with excess production of pro-inflammatory cytokines leading to a long-term induction of pro-inflammatory T helper type 1 responses. 57 Critically, supplementation of antibiotics with butyrate prevented immune dysfunction and butyrate directly induced an alternative activation signature in macrophages, with an increase in the expression of genes classically associated with alternative activation (Arg1 and retnla) alongside increased expression of genes involved in oxidative phosphorylation. 57 Additionally, another novel role for butyrate in macrophage function was recently demonstrated, showing that butyrate enhanced anti-microbial peptide production from macrophages and protected against colitis-causing intestinal infections.…”

“…Butyrate is recognized by cell surface expression of G‐protein‐coupled receptors including GPR109a, which is essential for the anti‐inflammatory effects of butyrate on intestinal macrophages . More recent studies in mice demonstrate that microbial disruption by antibiotic use drastically reduces SCFA levels in the intestine, with butyrate remaining low even during re‐population of the microbiota . These changes in SCFA levels corresponded with aberrant macrophage functions upon re‐population of the microbiota, with excess production of pro‐inflammatory cytokines leading to a long‐term induction of pro‐inflammatory T helper type 1 responses .…”

“…More recent studies in mice demonstrate that microbial disruption by antibiotic use drastically reduces SCFA levels in the intestine, with butyrate remaining low even during re‐population of the microbiota . These changes in SCFA levels corresponded with aberrant macrophage functions upon re‐population of the microbiota, with excess production of pro‐inflammatory cytokines leading to a long‐term induction of pro‐inflammatory T helper type 1 responses . Critically, supplementation of antibiotics with butyrate prevented immune dysfunction and butyrate directly induced an alternative activation signature in macrophages, with an increase in the expression of genes classically associated with alternative activation ( Arg1 and retnla) alongside increased expression of genes involved in oxidative phosphorylation .…”