Lactobacillus rhamnosus HN001 Ameliorates BEZ235-Induced Intestinal Dysbiosis and Prolongs Cardiac Transplant Survival

Cardiac allograft rejection remains a major factor limiting long-term engraftment after transplantation. A novel phosphoinositide 3-kinase (PI3K)/mTOR dual inhibitor, BEZ235, prolonged cardiac allograft survival by effectively suppressing activation of the PI3K/serine/threonine kinase (AKT)/mTOR pathway. However, long-term usage of pharmacological immunosuppressant drugs can cause intestinal microbiota dysbiosis. We established mouse models of allogeneic heterotopic heart transplantation with different treatments. Fecal samples were collected and subjected to 16S rRNA sequencing and targeted fecal metabolomic analysis. Graft samples were taken for immune cell detection by flow cytometry. Inflammatory cytokines in serum were quantified by enzyme-linked immunosorbent assay (ELISA). Compared to single-target approaches (IC-87114 and rapamycin), BEZ235 more efficiently prolongs cardiac transplant survival. Interestingly, BEZ235 reduces the diversity and abundance of the intestinal microbiota community. We demonstrated that Lactobacillus rhamnosus HN001 rescues the intestinal microbiota imbalance induced by BEZ235. 

IMPORTANCE Our data confirmed that the combination of BEZ235 and Lactobacillus rhamnosus HN001 significantly prolongs cardiac transplant survival. A main metabolic product of Lactobacillus rhamnosus HN001, propionic acid (PA), enriches regulatory T (Treg) cells and serves as a potent immunomodulatory supplement to BEZ235. Our study provides a novel and efficient therapeutic strategy for transplant recipients.

 

Comments:

The given information highlights a study conducted on cardiac allograft rejection and the use of a novel dual inhibitor called BEZ235 to prolong cardiac transplant survival. The study also examines the impact of long-term pharmacological immunosuppression on the intestinal microbiota and proposes a potential solution using Lactobacillus rhamnosus HN001 and its metabolic product, propionic acid (PA), to restore microbiota balance and enhance the immunomodulatory effects of BEZ235.

The researchers established mouse models of allogeneic heterotopic heart transplantation and compared the effects of different treatments. They collected fecal samples from the mice and performed 16S rRNA sequencing and targeted fecal metabolomic analysis to assess the impact on the intestinal microbiota. Graft samples were taken to detect immune cells using flow cytometry, and inflammatory cytokines in the serum were measured using enzyme-linked immunosorbent assay (ELISA).

The results showed that BEZ235 effectively suppressed the activation of the PI3K/AKT/mTOR pathway and prolonged cardiac transplant survival more efficiently than single-target approaches using IC-87114 and rapamycin. However, the use of BEZ235 led to a reduction in the diversity and abundance of the intestinal microbiota community, indicating microbiota dysbiosis.

To address this issue, the researchers investigated the potential of Lactobacillus rhamnosus HN001 in rescuing the intestinal microbiota imbalance induced by BEZ235. They found that this specific strain of Lactobacillus rhamnosus HN001 restored the balance of the intestinal microbiota. Additionally, propionic acid (PA), a metabolic product of Lactobacillus rhamnosus HN001, was identified as a potent immunomodulatory supplement to BEZ235. It enriched regulatory T (Treg) cells, which play a crucial role in immune tolerance.

Overall, the study suggests that the combination of BEZ235 and Lactobacillus rhamnosus HN001, along with its metabolic product propionic acid (PA), significantly prolongs cardiac transplant survival. This combination offers a promising therapeutic strategy for transplant recipients by effectively suppressing the PI3K/AKT/mTOR pathway, restoring intestinal microbiota balance, and enhancing immunomodulatory effects.