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.