Bacteroides acidifaciens produces microbial DPP4 (BaDPP4) that degrades cardioprotective peptides in plasma to exacerbate cardiac ischemia/reperfusion injury via a gut-heart axis, and pharmacological inhibition of BaDPP4 with daurisoline mitigates cardiac dysfunction.
Key Findings
Results
Gut microbiota mediates cardiac damage following ischemia/reperfusion injury through selective enrichment of Bacteroides acidifaciens.
Murine I/R models and fecal microbiota transplantation (FMT) were used to demonstrate the gut microbiota's causal role in myocardial I/R injury.
I/R-induced intestinal hypoxia and elevated luminal lactate levels selectively enrich B. acidifaciens in the gut.
FMT experiments established that this microbiota-mediated mechanism contributes causally to myocardial damage.
Results
Bacteroides acidifaciens produces a microbial dipeptidyl peptidase 4 (BaDPP4) that degrades cardioprotective peptides in the plasma.
BaDPP4 is a microbial isozyme of host DPP4 produced by B. acidifaciens.
BaDPP4 degrades cardioprotective peptides including glucagon-like peptide-1 (GLP-1) in the plasma.
Degradation of GLP-1 and similar peptides by BaDPP4 amplifies myocardial injury following I/R.
Results
I/R-induced intestinal hypoxia and elevated luminal lactate drive B. acidifaciens enrichment, defining a hypoxia-lactate-BaDPP4 axis.
Intestinal hypoxia following cardiac I/R promotes a specific luminal environment conducive to B. acidifaciens growth.
Elevated luminal lactate levels following I/R are identified as a key factor in selectively enriching B. acidifaciens.
This hypoxia-lactate-BaDPP4 axis is described as a mechanistic pathway linking gut changes to cardiac damage.
Results
Pharmacological inhibition of BaDPP4 with daurisoline, identified as a microbial DPP4-specific inhibitor, mitigates cardiac dysfunction in I/R models.
Daurisoline was identified as a pharmacological inhibitor specific to the microbial DPP4 (BaDPP4) rather than host DPP4.
Treatment with daurisoline mitigated cardiac dysfunction in murine I/R models.
The specificity for microbial DPP4 distinguishes daurisoline as a microbiota-targeted therapeutic approach.
Results
In acute myocardial infarction patients with I/R injury, B. acidifaciens abundance and BaDPP4 levels correlate with clinical markers of cardiac damage.
The study included acute myocardial infarction (AMI) patients with I/R injury in a clinical correlation analysis.
Both B. acidifaciens abundance and BaDPP4 levels were measured and correlated with clinical markers of cardiac damage.
These clinical correlations support translational relevance of the microbial mechanism identified in murine models.
Results
The findings reveal a gut-heart axis whereby microbial-derived DPP4 exacerbates cardiac I/R injury.
The gut-heart axis operates through B. acidifaciens-derived BaDPP4 entering the systemic circulation and degrading plasma cardioprotective peptides.
This represents a previously unrecognized gut microbiota-mediated mechanism contributing to myocardial I/R injury.
The microbial isozyme BaDPP4 is distinct from host DPP4, enabling microbiota-specific therapeutic targeting.
What This Means
This research suggests that the bacteria living in our gut play an unexpected role in worsening heart damage after a heart attack. Specifically, when the heart suffers from ischemia/reperfusion injury — the damage that occurs when blood flow is restored to a previously blocked heart — this also temporarily reduces oxygen delivery to the intestines. This low-oxygen gut environment, combined with increased lactic acid in the gut, causes a specific bacterium called Bacteroides acidifaciens to multiply. This bacterium produces an enzyme called BaDPP4 that enters the bloodstream and breaks down protective molecules like GLP-1 that would normally help shield the heart from damage, ultimately making the heart injury worse.
The researchers demonstrated this mechanism in mouse models using fecal transplant experiments, and then found supporting evidence in human patients with acute heart attacks — specifically showing that higher levels of B. acidifaciens and its enzyme in patients corresponded to worse indicators of heart damage. Importantly, they identified a drug called daurisoline that can specifically block the bacterial version of this enzyme (without affecting the body's own similar enzyme), and showed it reduced heart dysfunction in mice after I/R injury.
This research suggests that the gut microbiome is an active participant in the severity of cardiac injury following a heart attack, not merely a bystander. The identification of a gut bacterium and its specific enzyme as targets for intervention opens a new avenue for treatments that work through the gut-heart connection, potentially offering protective strategies that are distinct from conventional heart medications.
Zhang J, Liu C, Wang Y, Chen Y, Shang H, Zheng W, et al.. (2026). Bacteroides acidifaciens exacerbates cardiac ischemia/reperfusion injury via the microbial-host isozyme DPP4.. Cell host & microbe. https://doi.org/10.1016/j.chom.2026.03.012