Gut dysbiosis induced by cardiac pressure overload enhances adverse cardiac remodeling in a T cell-dependent manner

Abstract

Despite the existing association of gut dysbiosis and T cell inflammation in heart failure (HF), whether and how gut microbes contribute to T cell immune responses, cardiac fibrosis and dysfunction in HF remains largely unexplored. Our objective was to investigate whether gut dysbiosis is induced by cardiac pressure overload, and its effect in T cell activation, adverse cardiac remodeling, and cardiac dysfunction. We used 16S rRNA sequencing of fecal samples and discovered that cardiac pressure overload-induced by transverse aortic constriction (TAC) results in gut dysbiosis, characterized by a reduction of tryptophan and short-chain fatty acids producing bacteria in WT mice, but not in T cell-deficient mice ( Tcra −/- ) mice. These changes did not result in T cell activation in the gut or gut barrier disruption. Strikingly, microbiota depletion in WT mice resulted in decreased heart T cell infiltration, decreased cardiac fibrosis, and protection from systolic dysfunction in response to TAC. Spontaneous reconstitution of the microbiota partially reversed these effects. We observed decreased cardiac expression of the Aryl hydrocarbon receptor (AhR) and enzymes associated with tryptophan metabolism in WT mice, but not in Tcra −/- mice, or in mice depleted of the microbiota. These findings demonstrate that cardiac pressure overload induced gut dysbiosis and T cell immune responses contribute to adverse cardiac remodeling, and identify the potential contribution of tryptophan metabolites and the AhR to protection from adverse cardiac remodeling and systolic dysfunction in HF.

Intestinal Barrier Dysfunction Exacerbates Neuroinflammation via the TLR4 Pathway in Mice With Heart Failure

“…Intestinal abnormalities caused by HF are gradually being discovered. Previous basic studies revealed that HF animal models exhibited obvious gut dysfunction and intestinal dysbacteriosis (Carrillo-Salinas et al, 2020;Seo et al, 2020). Consistently, Kummen et al (2018) also found that HF patients had decreased microbial richness and altered gut microbiota through profiling 2 independent cohorts.…”

Gut Dysbiosis and Its Associations with Gut Microbiota-Derived Metabolites in Dogs with Myxomatous Mitral Valve Disease

“…The DI was negatively correlated with two secondary BAs, DCA and LCA (P , 3.4e 213 in both cases; r = 20.62 and 20.75, respectively) (Fig. 6C and D), but positively correlated with UDCA (P = 7.8e 25 , r = 0.36) (Fig. 6E).…”

“…Alpha diversity, which describes the number (richness) or distribution (evenness) of different bacterial species in the gut, was greater in the healthy dogs than in dogs with MMVD, but no difference was found among the three MMVD groups. So far, two studies reported reduced alpha diversities in human HF patients and in a rodent model with induced HF ( 24 , 25 ), but other studies showed no change in alpha diversity between HF subjects and healthy controls in humans or dogs ( 20 – 23 ). We also observed nominal differences in beta diversity, which measures similarity of different microbial groups.…”

“…A limited number of studies have examined the roles of gut microbiota in heart failure (HF) in humans and animal models (20)(21)(22)(23)(24)(25). Emerging evidence causally links gut microbiota to atherosclerotic disease, but observations between gut bacteria and HF remain associative (26).…”

Sialomucin CD43 Plays a Deleterious Role in the Development of Experimental Heart Failure Induced by Pressure Overload by Modulating Cardiac Inflammation and Fibrosis

“…Hematoxylin and eosin (H&E) and picrosirius red staining was performed as previously described ( Ngwenyama et al, 2019 ; Carrillo-Salinas et al, 2020 ). Cardiomyocyte area was determined in H&E stained left ventricle (LV) sections by measuring the area of 10–20 myocytes per heart using ImageJ (NIH; Bethesda, MD).…”