To the best of our knowledge, this is the first study to investigate the causal relationship between gut microbiome and FRTOT. The abundance of Bifidobacteriaceae was discovered to be a protective factor for FRTOT. Gene enrichment analysis revealed that genes harboring SNPs that associated with Bifidobacteriaceae abundance were primarily enriched in synapse and membrane related terms.
Bifidobacteriaceae is a common probiotic in the human gut that plays important roles in intestinal homeostasis and inflammation (14, 15). Previous research found that Bifidobacteriaceae improved Treg suppressive activity by activating the IL-10/IL10Ra signaling loop (16). Tregs are a subgroup of T cells that secrete inhibitory cytokines to reduce immunological response. Treg activation improves T cell suppression and lowers the likelihood of transplant rejection (17). Furthermore, CXCL2 activation has been identified as one of the primary causes of lung transplantation failure (18). Short-chain fatty acids (SCFAs) can influence CXCL2 expression, and SCFA treatment inhibits TNF-induced CXCL2 production in BALB/c mice (19). Bifidobacterium is a major genus of Bifidobacteriaceae that generates SCFAs (mainly acetate and lactic acid) during carbohydrate fermentation (14, 20, 21). As a result, by suppressing CXCL2 activation, Bifidobacterium may decrease the likelihood of transplantation failure. In general, a reduction in the abundance of gut Bifidobacterium may raise the likelihood of transplantation failure. The abundance of Bifidobacteriaceae and Bifidobacterium exhibited a negative causal effect on FRTOT in our investigation, which was consistent with this hypothesis. Because Bifidobacterium is one of the most important probiotic bacteria and has been developed into a therapeutic product, supplementing Bifidobacterium to lower the risk of transplantation failure will be possible in the near future.
The microbiome-gut-brain axis is a bidirectional connection between intestinal bacteria and the brain, and synaptic plasticity is important in this axis(22). Interestingly, we discovered that genes harboring Bifidobacteriaceae abundance associated SNPs were primarily enriched in synapse related terms. This finding suggested that polymorphisms in synapse-related genes might affect brain-to-intestine signaling, and then altering the abundance of some intestinal bacteria. Moreover, aberrant synaptic plasticity has been related to a number of brain diseases(23). As a result, some brain diseases may alter the composition of the gut microbiome via affecting synaptic signaling pathways, therefore influencing the prognosis of organ or tissue transplantation. According to recent studies, patients with Alzheimer's disease have dysbiosis of the gut microbiome, and the abundance of Bifidobacterium is down regulated when compared to healthy controls (24, 25). In the future, studies on how brain changes impact the prognosis of organ or tissue transplantation should also be concerned.
This study still has several shortcomings. First, in the MR analysis, different categories of transplantation failure were combined into one group due to data and sample size limitations. The effect of confounders would increase as different forms of organ or tissue transplant failure may be attributed to various causes. Furthermore, we were unable to use patients without failure or rejection after transplantation as controls in the MR study of FRTOT. In order to exclude the influence of Bifidobacteriaceae on the risk of transplantation, we performed a MR analysis on transplant status, and the findings revealed that Bifidobacteriaceae was not a causal factor for the occurrence of tissue and organ transplantation. This indicated that the abundance of Bifidobacteriaceae and FRTOT had a causal relationship. Second, few research have suggested an association between intestinal bacteria and transplantation failure, and our findings need to be validated by more clinical and mechanism investigations. Nonetheless, our findings add to the body of knowledge on transplantation failure.
In conclusion, using MR approach, the current study investigated the causal relationship between gut microbiota and transplantation failure and discovered that lower abundance of gut Bifidobacteriaceae may be one of the contributions of transplantation failure. Our findings contributed new ideas for further explaining the mechanism of transplantation failure, which was important for intervening and avoiding transplantation failure.