Impact of YAQ001 on the gut microbiome, permeability and markers of systemic inflammation in patients with cirrhosis

Abstract Background and aims YAQ001 is a novel, highly engineered, non-absorbable, gut-restricted, multiporous, carbon bead adsorbent. Pre-clinical studies and a clinical trial confirmed its therapeutic potential and safety in patients with cirrhosis. The aims of this sub study were to evaluate the effect of YAQ001 on the gut microbiome and its association with biomarkers of gut permeability and systemic inflammation. Methods In total, 28-patients with cirrhosis were randomized (double-blind) to receive YAQ001 (4g once daily) or Placebo. Gut microbiome and biomarkers of inflammation and gut permeability were assessed at baseline, after 4 and 12-weeks. Changes in biomarkers and relationship with microbiome composition and gene profiling were assessed. The effect of YAQ001 on Klebsiella pneumoniae bacterial biofilms was also assessed using an in vitro gut epithelial model. Results Alpha and beta diversity at different time points were unaltered. YAQ001 increased the abundance of bacteria associated with improved gut health such as Adlercreutzia equolifaciens (p<0.05), a bacterium commonly depleted in liver disease, and decreased the abundance of bacteria associated with infections and poor outcomes such as Klebsiella pneumonia and Streptococcus mutans (p<0.05 each). YAQ001 impacted positively on virulence factors such as siderophores, fimbriae structures and lipopolysaccharides that are associated with inflammation and invasion (p<0.05 each). Antibiotic resistance genes, decreased significantly in the YAQ001 group. These changes were associated with reduction in markers of gut permeability and systemic inflammation with no significant effect on bile acid metabolism. YAQ001 prevented Klebsiella pneumoniae biofilms in vitro . Conclusions The results show that YAQ001 impacts positively on the composition of the microbiome, significantly reduces its virulence, antibiotic resistance genes and biofilm formation, which is associated with modulation of gut permeability and systemic inflammation. Impact and implications YAQ001 exerts its therapeutic effect by favorably modulating the gut ecosystem in cirrhosis. It selectively increases beneficial gut bacteria while suppressing pathogenic taxa linked to adverse outcomes. Beyond composition, YAQ001 reduces microbial virulence by limiting the production of invasive toxins and lowers the abundance of antibiotic-resistance genes. In vitro models also demonstrated its efficacy in inhibiting biofilm formation by key pathogens. In summary, this multifaceted modulation of the microbiome led to tangible clinical improvements, notably enhanced gut barrier function and reduced systemic inflammation. The data support further development of YAQ001 as a novel microbiome therapeutic. Highlights In patients with cirrhosis, YAQ001 specifically enhanced beneficial gut bacteria while suppressing pathogenic bacteria linked to adverse clinical outcomes. YAQ001 significantly reduced the genetic expression of critical virulence factors, including siderophores, fimbriae, and lipopolysaccharides, thereby diminishing the potential for microbial invasion and inflammation. YAQ001 administration led to a significant decrease in the abundance of antibiotic resistance genes within the gut microbiome, potentially restoring therapeutic efficacy of antibiotics. In vitro studies demonstrated that YAQ001 effectively prevents the formation of Klebsiella pneumoniae biofilms, a key mechanism of bacterial persistence and chronic infection. The beneficial microbial shifts were directly associated with clinically relevant improvements in biomarkers of gut permeability and systemic inflammation.