Abstract
Emerging evidence has linked the gut microbiota dysbiosis to transplant rejection while memory T-cells pose a threat to long-term transplant survival. However, it's unclear if the gut microbiome alters the formation and function of alloreactive memory T-cells. Here we studied the effects of berberine, a narrow-spectrum antibiotic that is barely absorbed when orally administered, on the gut microbiota, memory T-cells, and allograft survival. In this study, C57BL/6 mice transplanted with islets or a heart from BALB/c mice were treated orally with berberine. Allograft survival was observed, while spleen, and lymph node T-cells from recipient mice were analyzed using a flow cytometer. High-throughput sequencing and qPCR were performed to analyze the gut microbiota. CD8+ T-cells from recipients were cultured with the bacteria to determine potential T-cell memory cross-reactivity to a specific pathogen. We found that berberine suppressed islet allograft rejection, reduced effector CD8+CD44highCD62Llow and central memory CD8+CD44highCD62Lhigh T-cells (TCM), altered the gut microbiota composition and specifically lowered Bacillus cereus abundance. Further, berberine promoted long-term islet allograft survival induced by conventional costimulatory blockade and induced cardiac allograft tolerance as well. Re-colonization of B. cereus upregulated CD8+ TCM cells and reversed long-term islet allograft survival induced by berberine plus the conventional costimulatory blockade. Finally, alloantigen-experienced memory CD8+ T-cells from transplanted recipients rapidly responded to B. cereus in vitro. Thus, berberine prolonged allograft survival by repressing CD8+ TCM through regulating the gut microbiota. We have provided the first evidence that donor-specific memory T-cell generation is linked to a specific microbe and uncovered a novel mechanism underlying the therapeutic effects of berberine. This study may be implicated for suppressing human transplant rejection since berberine is already used in clinic to treat intestinal infections.
Highlights
The gut microbiota is involved in host physiological processes, including vitamin synthesis, metabolism and immune defense [1, 2], and plays an important role in many diseases, including multiple sclerosis [3] and autoimmune arthritis [4]
We found that berberine promoted long-term islet allograft survival and cardiac allograft tolerance induced by brief costimulatory blockade via shrinking alloreactive CD8+ central memory T cell (TCM) pool through altering the gut microbiota
To investigate the effects of berberine on allograft survival, C57BL/6 mice were transplanted with islets from BALB/c mice and treated with berberine (Ber) or broad-spectrum antibiotics (ABX)
Summary
The gut microbiota is involved in host physiological processes, including vitamin synthesis, metabolism and immune defense [1, 2], and plays an important role in many diseases, including multiple sclerosis [3] and autoimmune arthritis [4]. It was shown that microbiota dysbiosis was obviously associated with postoperative complications, such as infection and graft rejection [16,17,18]. Pretreatment of recipient mice with broadspectrum antibiotics (ABX) prolonged survival of minor antigen-mismatched skin transplants [19] while differences in gut microbes in mice derived from different vendors resulted in a different graft outcome [20]. Acute infection could temporarily interrupt tolerance [21] while antibiotic pretreatment attenuated hepatic transplant injury [22]. It remains not fully understood how microbiota regulates immunity, recent advances in the field showed that a shortchain fatty acid, butyrate, regulated energy metabolism and inflammation [23, 24]. The gut microbiota could be a therapeutic target for preventing transplant rejection
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