The gut-kidney axis in IgAN: between genes and environment
The function of the microbiota and mucosal immunity in the development of IgAN rests central [
48], although searching for specific mucosal microorganisms promoting IgA synthesis has been inexhaustible [
23]. Advancement in the field of knowledge on the role played by gut microbiota exposure in patients susceptible to developing IgAN was proposed by genome-wide association studies (GWAS) [
49]. GWAS are methods that provide a complete analysis of the total genome in order to identify genetic regions (loci) associated at risk of developing the disease [
50]. The most important milestone in IgAN GWAS studies belongs to the Gharavi group [
49]. In this study, the authors identified a relationship between the genetic probability to develop IgAN and climatic, pathogenic load, and dietary elements; nevertheless, the strongest positive correlation was showed between the local pathogen diversity (including viruses, bacteria, protozoa, and helminths) and the score of genetic risk for IgAN. The increased prevalence of IgAN in some regions might be the effect of a defensive adaptation from gut worm mucosal invasion. On the other hand, IgAN susceptibility loci were related with the predisposition to inflammatory bowel diseases (IBD), with the proteins implicated in the protection of the gut integrity and in the control of the mucosal immune response of the gut environment. In particular, these genetic risk alleles significantly impact the age at onset of the disease. The conclusion was that the striking association between genetics and environmental elements could induce the functional changes into the gut mucosal immune system favoring the onset of the disease.
The gut-kidney axis in IgAN: a “microbiotic” view on IgAN
The intestinal microbiota and its metabolites (the metabolome) have been indicated to have a key role on immune balance [
51]. It has been assessed that the human gastrointestinal system comprises up to 10
14 bacteria with a biomass of 2 kg. These gut microbiota are in contact with MALT and are involved in maintaining the intestinal permeability and the immune system [
52]. The gut microbiota is known to be implicated in the host innate and adaptive immune system; mutually, the composition of the gut flora depends on intestinal immune system that defends against pathogens through the production of IgA. In particular, numerous studies indicate that the microbial infections stimulate the differentiation of B-cells into IgA-secreting plasma cells, through T cell–independent or T cell–dependent pathways [
53,
54]. However, the precise correlation between Gd-IgA and gut microbiota in patients with IgAN is uncertain.
It has been theorized that the release of intestinal microbiome products, such as lipopolysaccharide (LPS) and lipoteichoic acid, may activate GALT through TLR pathways. Indeed, LPS is a ligand for TLR4; lipoteichoic acid, for TLR2 [
55]. Microbiota signal via TLRs may modulate gut microbe challenge, mucosal injury, and repair [
56]. Modifications in intestinal barrier, with increased intestinal permeability documented in patients with IgAN [
57,
58], may facilitate LPS absorption and blood circulation. Bacterial LPS stimulates the activation of TLR4 in cultured peripheral B cells causing a methylation of Cosmc, leading to the defective galactosylation of IgA1 [
59]. The TLR4 and the membrane CD14 (the receptor for complexes of LPS and LPS binding protein) are the main elements implicated in cellular LPS signaling, and CD14/-159 polymorphism was found to be correlated with progressive incidents of IgAN [
60]. Coppo’s group reported that children and adults with IgAN and IgA vasculitis [
61,
62] had greater levels of TRL4 mRNA in peripheral blood lymphomononuclear cells, which was associated with the activation of mucosal immunity and clinical signs. These observations suggest that raised gut permeability to intestinal microbes’ triggers, through activation of TLR4, may modulate the immune response in IgAN.
The interaction between MALT and gut flora, in the promotion of experimental IgAN, was showed in a transgenic mouse model overexpressing BAFF [
20]. These mice with B cell hyperplasia show an increase in all Ig classes including IgA [
63]. The overexpression of BAFF in this animal model is correlated with high expression of polymeric hypogalactosylated IgA and IgA renal deposits. The development of the disease was dependent on the microbiota, leading to the theory that an overexpression of BAFF signaling modifies the normal equilibrium with the commensal flora and alters the systemic immune response.
Gesualdo et al. conducted the first human study that showed a correlation between gut dysbiosis and IgAN [
64]. In this cross-sectional study, they investigated the fecal microbiota, and the fecal and urinary metabolome of non-progressor (NP) and progressor (P) IgAN patients. Patients with progressive disease showed the lowest microbial diversity compared to NP and HC. At genera/species levels,
Ruminococcaceae,
Lachnospiraceae,
Eubacteriaceae, and
Streptococcaeae raised in the stool samples of NP and P patients result in an increase of
Firmicutes, while HC showed higher abundance of
Clostridium,
Enterococcus, and
Lactobacillus genera. Compared with HC,
Bifidobacterium species decreased in the fecal samples of NP and P, while
Sutterellaceae and
Enterobacteriaceae species showed an opposite trend. Along the same lines, Sun et al. [
65] have suggested the prospective role of intestinal microbiota as a specific biomarker and an actor in the diagnosis and pathogenesis of IgAN. Indeed, the authors demonstrated a substantial difference in the gut microbiota not only between IgAN patients and HC but also between IgAN patients and patients with membranous nephropathy (MN). The abundance of
Escherichia-Shigella, consistent with the previous study, and
Defluviitaleaceae_incertae_sedis were higher in IgAN than those in HC, while lower levels were found for
Roseburia,
Lachnospiraceae_unclassified,
Clostridium_sensu_stricto_1,
Haemophilus, and
Fusobacterium. Moreover, in IgAN patients, the level of
Megasphaera and
Bilophila was higher, whereas that of
Megamonas,
Veillonella,
Klebsiella, and
Streptococcus was lower compared with those with MN. In addition, the authors correlated the microbiota with the clinical factors. The analysis demonstrated that in IgAN patients,
Prevotella was positively correlated with the level of serum albumin, while
Klebsiella,
Citrobacter, and
Fusobacterium were negatively correlated. Moreover, a positive correlation was showed between
Bilophila and the presence of kidney crescents in the Oxford classification of IgAN.
Another step toward understanding the tight link between microbiota and IgAN is represented by one of the latest papers of Gesualdo’s group [
54]. They showed that the modification of mucosal immunity, due to a change of the gut flora, has a key role in the development of the disease. Indeed, they found that IgAN patients had increased serum levels of BAFF and that it was positively correlated with amounts of five specific microbiota metabolites (4-(1,1,3,3-tetramethylbutyl) phenol, p-tert-butyl-phenol, methyl neopentyl phthalic acid, hexadecyl ester benzoic acid, and furanone A). Phenol exerts a toxic effect against the gut lumen; indeed, it is able to reduce barrier function, and to increase gut permeability [
66], leading to mucosal hyper-responsivity. They also showed that IgAN patients have a higher level of circulating gut-homing (CCR9+ β7 integrin+) regulatory B cells, memory B cells, and IgA+ memory B cells compared with HC that predisposes to an atypical synthesis of Gd-IgA.
The close connection between microbiota and IgAN opens up a new field of therapeutic strategies in the gut microbiota manipulation, such as the use of dietary interventions, or antibiotics, prebiotics, and probiotics, or through fecal microbiota transplantation (FMT).