Gut Dysbiosis Induced by Cardiac Pressure Overload Promotes T Cell Activation and Adverse Cardiac Remodeling Through Alterations in the Aryl Hydrocarbon Receptor Expression

Abstract

Heart failure (HF), a leading cause of morbidity and mortality worldwide, has been recently associated with gut microbiota alterations (gut dysbiosis) and T cell mediated inflammation in humans, and in experimental models of HF. The gut is a major reservoir of T cells, which are in close proximity with the gut microbiota. Gut bacterial populations process nutrients and produce metabolites that signal through cellular receptors, to maintain homeostasis or induce inflammation at distal organs. The aryl hydrocarbon receptor (AhR) is one of such receptors that recognize ligands that include gut derived tryptophan metabolites to modulate immune responses in the gut and systemically. We hypothesized that cardiac pressure overload induces gut dysbiosis and contributes to adverse cardiac remodeling through T cell activation and via AhR signaling in the gut and in the heart. We performed 16S rRNA sequencing in feces from mice undergoing Sham or transverse aortic constriction (TAC) surgery to test whether cardiac pressure overload induced gut dysbiosis, and in T cell deficient (Tcra−/−) mice to evaluate the contribution of T cells in gut dysbiosis induced by TAC. In addition, we studied the role of gut microbes in T cell activation, cardiac remodeling, and AhR expression, in mice that were orally treated with an antibiotic cocktail (ABX) to deplete the microbiota, and in ABX‐treated mice that spontaneously reconstituted the microbiota upon ABX removal during the 4 weeks of TAC (TAC‐REC). TAC resulted in increased abundance of phylum Bacteroidetes, and in a decrease in genus Lactobacillus, a tryptophan derivative producer, as compared to Sham. These microbiota alterations were not observed in Tcra−/− TAC mice, which were protected from adverse cardiac remodeling and exhibited a closer gut microbiota profile to WT Sham than to WT TAC mice in principal component analysis. However, TAC did not induce leaky gut, determined by LPS levels in serum, or T cell activation in the lamina propria, but increased T cell activation in the mediastinal lymph nodes (mLNs) that drain the heart, and drastically resulted in decreased AhR expression in the gut and in the heart. Strikingly, depletion of the gut microbiota in the onset of TAC (TAC‐ABX) resulted in a reduction in the number of activated T cells in the mLNs and heart infiltrated T cells, lack of cardiac fibrosis and systolic dysfunction, and an induction of AhR expression in the gut and the heart as compared to TAC mice that had not been depleted of the microbiota. Moreover, gut microbiota reconstitution in TAC‐REC mice resulted in decreased expression of AhR in the gut and in the heart as compared to ABX treated mice, and showed similar expression levels of AhR and systolic dysfunction as TAC mice. Our data demonstrate a role of gut microbes in T cell activation and adverse cardiac remodeling induced by cardiac pressure overload that likely involves decreased AhR signaling in the gut and in the heart.Support or Funding InformationThese studies were supported by NIH HL 123658 and the American Heart Association grant 19POST34430075/2019