4. Discussion
This was the first MR study aiming to clarify whether the gut microbiota was associated with the risk of MN through using the large-scale gut microbiome gene data. The results identified eight bacterial taxa that might have causal effects on the risk of MN, which provided novel insights into the pathogenesis of MN. Although our results indicated that most of the bacteria did not reveal obvious causal effect using the Bonferroni-corrected test, which does not rule out the possibility of the association between them considering that the Bonferroni-corrected test is very stringent.
In our study, only the Genus. Oscillibacter was the protective factor for MN. Previous studies indicated that Oscillibacter abundance was negatively correlated with weight and positively correlated with adiponectin levels [19]. At present, the relevant study involved in Oscillibacter on the kidney remains lacking. In addition, Class. Melainabacteria, Genus. Butyricicoccus, Genus. Catenibacterium, Genus.Ruminiclostridium5, Genus. Ruminococcaceae UCG-003, Order. Bacillales, and Order. Gastranaerophilales were all related to the increased risk of MN. Although there is currently insufficient evidence for their roles in the kidney, several studies have reported their unique function in multiple human diseases, such as neurodegenerative diseases, Wilson’s disease, allergy rhinitis, lung cancer, Graves’ disease and Graves’ orbitopathy, Parkinson’s disease, chronic insomnia, cardiometabolic diseases, cancer, etc. [20-23]. Consistent with our results, Ruminococcus gnavus was shown to participate in the immune pathogenesis of lupus nephritis with the positive correction between its abundance and the lupus activity [24]. It is also manifested that there is positive correlation between the blood urea nitrogen levels in the idiopathic nephrotic syndrome patients, and the abundance of Ruminococcaceae but reduced abundance of Ruminiclostridium [25]. Moreover, the MR study regarding causal effects between gut microbiota and IgA nephropathy indicate genus butyricicoccus was a risk factor for IgA nephropathy [16]. The exiting results of the species and abundance of gut microbe of host with different kind of disease may be different or event contrary to the results we have here. It must be noted that the results of this study are a causal relationship between gut microbe and MN, focusing on the protective effect or the risk factor the gut microbe to MN.
The protective effects of Genus Oscillibacter against MN might be explained by the ability of maintaining immune homeostasis and intestinal barrier. The short-chain fatty acids (SCFAs) such as valeric or butyric acid from Oscillibacter can facilitate the repair of the intestinal barrier and stimulate the immune response [26-28]. Oscillibacter function to clear damaged intestinal cells and upregulate the expression of tight junction proteins or mucus production to promote intestinal integrity [29]. Except the function of enhancing the intestinal mucosal barrier, gut microbiotas play a crucial role in regulating innate and adaptive immune responses by modulating gene expression and regulating immune homeostasis [30]. SCFAs such as butyrate and propionate promote the extrathymic generation of Treg cells by inhibiting histone deacetylation and further promote the differentiation of anti-inflammatory Treg which play a vital role to regulate the massive autoimmunity [31, 32]. This SCFAs can also suppress inflammatory responses in the gut by downregulating the expression of INF-γ, TLR-2 and TNF-α [33, 34]. Part of the gut microbiota is suggested the novel regulators of autoimmune diseases via the immune-gut axis [35].
Under the normal circumstances, the diversity and abundance of gut microbe are in a suitable state, which do not cause disease. The destroyed gut homeostasis after the change of gut environment or experiencing heterogeneous interference such as infection, cancer, radiotherapy, and diets may be the risk factor of MN [36-38]. For the mechanism of this causal relationship, it can be explained by the several ways: Many of the intrinsic components of gut microbe cell wall, such as lipopolysaccharides and lipoglycans, may act as antigen to induce immune responses to produce antibodies [24]. In addition, microbial dysbiosis can result in the damaged integrity of the intestinal epithelial barrier, causing the absorption of heterogeneity substance which can lead to local or systemic inflammation and injury kidney [39-41]. Furthermore, metabolites from specific microbiota will break the balance of Treg / TH17, and the lack of Treg may lead to a reduced ability to regulate the autoimmune response in the host, later will increase the risk of MN [42-44]. These metabolites also enter the blood circulation through the breakdown intestinal epithelial barrier, triggering the release of inflammatory cytokines, activating the B cell activity and production of antibodies. The deposition of autoantibodies and reactive oxygen species (ROS) induced by inflammatory cells can cause the injury of podocytes to promote the progression of MN [45]. In human body, the immune disease may occur because of the aryl hydrocarbon receptor (AHR), a nuclear receptor which has been shown to contribute to immune/inflammatory diseases [46]. Gut microbiota which can produces tryptophan-produced indole derivatives (TPIDs) could influence the development of MN by enhancing the activation of AHR signaling pathway [47].
However, with the positive impact of butyrate on immune system in the prior evidence, butyrate-producing gut microbe such as Genus Butyricicoccus and Gastranaerophilales are suggested a protective factor for MN, which is inconsistent with our findings. This may because of the Gene-gene interactions and gene-environment interactions. Of note, MN might not necessarily be associated with the dysregulation of a single bacterium [48]. Conversely, comprehensive regulation of gut microbiota could be a more beneficial approach to protect and intervene the MN in the future.
Our study was the first large-scale MR analysis aiming to evaluate the causal relationship between gut microbiota and MN at the genetic level. Additionally, a genetic prediction method was applied in this study to explore the causal association between specific gut bacterial taxa and MN, which was based on a large GWAS data. Moreover, we have adopted a variety of statistical methods in order to ensure the robustness of our results. However, this study also had several limitations. First, considering the limited number of SNPs available from GWAS, we relaxed the P threshold. Second, all GWAS data were acquired from the European participants. Hence, the MR results should be further validated in other populations. Third, despite the excellent causal inference by the MR method, the results should also be further confirmed in randomized controlled trials.
This MR analysis first confirmed a causal association between gut microbiota and MN, which reminds nephrologists that the disorder of specific gut microbiota might related to the elevated risk of MN. Further study should focus on the potential pathophysiological mechanisms on the imbalance of these specific gut microbiota taxa in MN, which would be of great significance to guide clinical prevention and treatment in MN.