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Microbiota and glomerulonephritis: An immunological point of view

      Abstract

      Glomerular injury is the major cause of chronic kidney diseases (CKD) worldwide and is characterized by proteinuria. Glomerulonephritis (GN) has a wide spectrum of etiologies, the intensity of glomerular damage, histopathology, and clinical outcomes that can be associated with the landscape of the nephritogenic immune response. Beyond impaired immune responses and genetic factors, recent evidence indicates that microbiota can be contributed to the pathogenesis of GN and patients’ outcomes by impacting many aspects of the innate and adaptive immune systems. It is still unknown whether dysbiosis induces GN or it is a secondary effect of the disease. Several factors such as drugs and nutritional problems can lead to dysbiosis in GN patients. It has been postulated that gut dysbiosis activates immune responses, promotes a state of systemic inflammation, and produces uremic toxins contributing to kidney tissue inflammation, apoptosis, and subsequent proteinuric nephropathy. In this review, the impact of gastrointestinal tract (GI) microbiota on the pathogenesis of the primary GN will be highlighted. The application of therapeutic interventions based on the manipulation of gut microbiota with special diets and probiotic supplementation can be effective in GN.

      Key Indexing Terms

      Introduction

      Glomerulonephritis (GN) as a common term encompasses a wide range of glomerular diseases. GN is an important cause of chronic kidney diseases (CKD) worldwide and has a wide range of etiologies including; infection, metabolic disease, and an immunological cause.
      • Herrnstadt G.R.
      • Steinmetz O.M.
      The role of Treg subtypes in glomerulonephritis.
      GN can be classified as primary or secondary. Primary GN is kidney limited disease and histologically it is further classified as; minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS),  membranous nephropathy (MN), membranoproliferative GN (MPGN), and IgA nephropathy (IgAN). However, secondary type occurs following systemic immunologic disorders (e.g., systemic lupus erythematosus [SLE]), infections, or exposure to particular medications. The presence or absence of proliferative histological alternations results in GN classification as below: primary and secondary proliferative and non-proliferative types. Proliferative GN is characterized as increased cellularity of the glomerulus, as a result of intrinsic glomerular cells proliferation, infiltration of leucocytes, or both. Non-proliferative GN lacks glomerular cell proliferation and usually presents with nephrotic syndrome (NS).
      From a pathophysiological point of view, an important proportion of GN is caused by the deregulated complement system, immune complex deposition, glomerular damage due to autoantibodies, and imbalance between regulatory T cells (Treg) and effector T cell subsets (Th1 and Th17).
      • Couser W.G.
      • Johnson R.J.
      The etiology of glomerulonephritis: roles of infection and autoimmunity.
      ,
      • Kaartinen K.
      • Safa A.
      • Kotha S.
      • et al.
      Complement dysregulation in glomerulonephritis.
      Beyond an impaired immunity, related aetiological antigen or agent, and genetic factors, it is evident that the extent and nature of exposure to pathogens in early life are also involved in the incidence of diverse forms of GN throughout the world.
      • Johnson R.J.
      • Hurtado A.
      • Merszei J.
      • et al.
      Hypothesis: dysregulation of immunologic balance resulting from hygiene and socioeconomic factors may influence the epidemiology and cause of glomerulonephritis worldwide.
      In other words, the susceptibility of individuals to the development of Th1 or Th2 responses is defined by the context of their early exposures to antigens.
      • Jones P.D.
      • Gibson P.G.
      • Henry R.L.
      The prevalence of asthma appears to be inversely related to the incidence of typhoid and tuberculosis: hypothesis to explain the variation in asthma prevalence around the world.
      Accordingly, the hygiene hypothesis may describe the fairly high incidence of primary GN including MCD, MPGN, and IgAN in developing and developed countries, respectively.
      • Holdsworth S.R.
      • Kitching A.R.
      • Tipping P.G.
      Th1 and Th2 T helper cell subsets affect patterns of injury and outcomes in glomerulonephritis.
      Recently, evidence has specified that the microbiota can be contributed to the pathogenesis of GN and patients outcome
      • Dong R.
      • Bai M.
      • Zhao J.
      • et al.
      A comparative study of the gut microbiota associated with immunoglobulin a nephropathy and membranous nephropathy.
      • Park J.I.
      • Kim T.Y.
      • Oh B.
      • et al.
      Comparative analysis of the tonsillar microbiota in IgA nephropathy and other glomerular diseases.
      • Kaneko K.
      • Tsuji S.
      • Kimata T.
      Role of gut microbiota in idiopathic nephrotic syndrome in children.
      • Rahbar Saadat Y.
      • Hejazian M.
      • Bastami M.
      • et al.
      The role of microbiota in the pathogenesis of lupus: dose it impact lupus nephritis?.
      • Ahmadian E.
      • Rahbar Saadat Y.
      • Hosseiniyan Khatibi S.M.
      • et al.
      Pre-Eclampsia: microbiota possibly playing a role.
      by impacting many aspects of the innate and adaptive immune systems. The connection between immune system and microbiota can also impact kidney allograft autcome.
      In addition to diabetes and coronary artery disease, gastrointestinal tract (GI) disorders are among the chronic diseases that patients with CKD and ESRD often suffer. The common GI symptoms include nausea, vomiting, abdominal pain, constipation, and diarrhea. Moreover, irritable bowel syndrome (IBS), upper gastrointestinal lesions, acute and chronic episodes of GI bleeding, pancreatitis, and ischemic colitis are highly prevalent in CKD patients. Alternations in lifestyle due to renal dysfunction, (i.e., lower activity, reduced fiber intake (because of potassium-restricted diets), the use of phosphate binders, etc.) contributes to the GI disorders in CKD patients (reviewed in reference
      • Ardalan M.
      • Vahed SZ.
      Gut microbiota and renal transplant outcome.
      ).
      Treg cells are generally induced by microbiota-derived short-chain fatty acids (SCFAs) and kids with allergies have abnormal gut microbiota. On this basis, it is reported that gut microbiota dysbiosis resulting in defective T cell imbalance can affect the development of IgAN, lupus nephritis, and idiopathic NS (INS).
      • Rahbar Saadat Y.
      • Hejazian M.
      • Bastami M.
      • et al.
      The role of microbiota in the pathogenesis of lupus: dose it impact lupus nephritis?.
      ,
      • Omenetti S.
      • Pizarro T.T.
      The Treg/Th17 axis: a dynamic balance regulated by the gut microbiome.
      ,
      • Mu Q.
      • Zhang H.
      • Liao X.
      • et al.
      Control of lupus nephritis by changes of gut microbiota.
      Furthermore, the development of kidney amyloidosis can be supported by chronic inflammation induced by gut dysbiosis resulting in serum amyloid A (SAA) production.
      • Reigstad C.S.
      • Lundén G.O.
      • Felin J.
      • et al.
      Regulation of serum amyloid A3 (SAA3) in mouse colonic epithelium and adipose tissue by the intestinal microbiota.
      Moreover, the translocation of bacterial products (metabolites, lipopolysaccharide (LPS), or the bacteria themselves) through the gut barrier initiates the innate immune response and increases the systematical inflammatory response that can be associated with IgAN, CKD, and end-stage kidney disease.
      • Chen Y.Y.
      • Chen D.Q.
      • Chen L.
      • et al.
      Microbiome-metabolome reveals the contribution of gut-kidney axis on kidney disease.
      ,
      • Ramezani A.
      • Raj D.S.
      The gut microbiome, kidney disease, and targeted interventions.
      Beyond gut microbiota, some studies provide important data for understanding the role of tonsillar and salivary microbiota in the development of GN.
      • Park J.I.
      • Kim T.Y.
      • Oh B.
      • et al.
      Comparative analysis of the tonsillar microbiota in IgA nephropathy and other glomerular diseases.
      ,
      • Watanabe H.
      • Goto S.
      • Mori H.
      • et al.
      Comprehensive microbiome analysis of tonsillar crypts in IgA nephropathy.
      ,
      • Zhu A.
      • Yang X.
      • Bai L.
      • et al.
      Analysis of microbial changes in the tonsillar formalin-fixed paraffin-embedded tissue of Chinese patients with IgA nephropathy.
      The challenge remains to fully understand the consequence of the dysbiosis and responses of T cell subsets to the spectrum of GN and to relate this knowledge to the development of preventive and selective therapeutic strategies. In this review, we highlight the impact of gastrointestinal (GI) microbiota on the pathogenesis of the primary GN with a focus on MN and IgAN. Then, the modulation of gut microbiota in these diseases puts forward.

      Microbiota and T cell responses

      Different metabolites such as uremic toxins [p-cresol sulfate (PCS), and indoxyl sulfate (IS)] and SCFAs are generated by gut microbiota, exhibiting pro- or anti-inflammatory impacts and playing pivotal roles in the pathogenesis of renal injuries. As a result of microbial fermentation, SCFAs are generated. SCFAs are key components of ATP metabolism and exert a protective role against colonic diseases by hampering the inflammatory response during the normal development of epithelial cells in the colon.
      • Rose D.J.
      • DeMeo M.T.
      • Keshavarzian A.
      • et al.
      Influence of dietary fiber on inflammatory bowel disease and colon cancer: importance of fermentation pattern.
      Moreover, SCFAs have an important regulatory role in the differentiation of T cells particularly the generation of Th1, Th2, and Tregs in different cytokine milieus. They can also block the function of histone deacetylase and thus prohibit the generation of pro-inflammatory cytokines by intestinal macrophages.
      • Sun M.
      • Wu W.
      • Liu Z.
      • et al.
      Microbiota metabolite short chain fatty acids, GPCR, and inflammatory bowel diseases.
      Butyrate, an SCFA, has been reported to be crucial in preserving the gut microbiome through maintaining the integrity of intestinal epithelium and also generating the required energy supplies for their respiration. Butyrate exhibits anti-inflammatory effects through activation of colonic regulatory T cell differentiation.
      • Furusawa Y.
      • Obata Y.
      • Fukuda S.
      • et al.
      Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells.

      Effect of the gut microbiota on Treg and Th17 cells

      The barrier surfaces in the intestinal mucosa contain Th17 and Treg cells that restrain extra effector T-cell responses and thus protect the host from pathogenic microorganisms. Th17 and Treg cells display parallel developmental requirements but they have different functional properties.
      • Omenetti S.
      • Pizarro T.T.
      The Treg/Th17 axis: a dynamic balance regulated by the gut microbiome.
      Pivotal cellular mediators such as transforming growth factor-beta (TGF-β), interleukin 6 (IL-6), and all-trans retinoic acid determine the differentiation of antigen-naïve T-cells to Th17 or Treg lineages.
      • Omenetti S.
      • Pizarro T.T.
      The Treg/Th17 axis: a dynamic balance regulated by the gut microbiome.
      ,
      • Mucida D.
      • Park Y.
      • Kim G.
      • et al.
      Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid.
      Both adaptive and innate immune responses could be activated via the immune-stimulatory signals produced from the gut microbiome. On the other hand, the gut microbiome has been implicated in the generation of pro-inflammatory cytokines and further production and expansion of Th17 by an innate immune response. Likewise, commensal bacteria and their related metabolites are involved in the generation of intestinal Tregs that actively stimulate mucosal tolerance. Th17 might also be generated through the intestinal epithelial cell (IEC)-derived SAA, cytokines, and antigen presentation by dendritic cells (DCs) after the colonization of segmented filamentous bacteria (SFB).
      • Atarashi K.
      • Tanoue T.
      • Ando M.
      • et al.
      Th17 cell induction by adhesion of microbes to intestinal epithelial cells.
      The adhesion of SFB to IEC can induce a cycle in which IL-22 is generated through the stimulatory effect of DC-derived IL-23 on type 3 innate lymphoid cells (ILC3).
      • Sano T.
      • Huang W.
      • Hall J.A.
      • et al.
      An IL-23R/IL-22 circuit regulates epithelial serum amyloid a to promote local effector Th17 responses.
      This subsequently induces the production of SAA from IEC and further differentiation of Th17. Contrarily, de novo formation of Tregs and downregulation of Th17 immune responses occur after colonization of the beneficial commensal bacteria. Butyrate generated by commensal bacteria (mainly clostridia species) inhibits the production of pro-inflammatory cytokines through de novo generation of Tregs.
      • Omenetti S.
      • Pizarro T.T.
      The Treg/Th17 axis: a dynamic balance regulated by the gut microbiome.
      The underlying mechanism includes the production of retinoic acid by DCs and stimulating the transcription of Foxp3. Polysaccharide A expressing Bacteroides fragilis strains can regulate the TLR2-related Tregs generation, whereas B. fragilis toxin (BFT) prodused by B. fragilis strains alters the activity of tight junction proteins in IEC, leading to increased intestinal permeability.
      • Round J.L.
      • Lee S.M.
      • Li J.
      • et al.
      The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota.
      Disruption of the function of cellular barriers leads to the dissemination of microbial products, which upon recognition by microbe-associated molecular patterns (MAMPs) induce the IL-23 cascade and a further repair of barrier and activation of Th17 responses,
      • Omenetti S.
      • Pizarro T.T.
      The Treg/Th17 axis: a dynamic balance regulated by the gut microbiome.
      Fig. 1.
      Fig 1
      Fig. 1The gut microbiota influences the Treg and Th17 immune responses and glomerulonephritis. (A) Gut microbiota plays important role in the regulation of a dynamic balance between Treg and Th17 Cells. Several mediators (e. g. IL-6 and all-trans retinoic acid) results in antigen-naïve T-cells differentiation into Th17 or Treg lineages. (B) Mechanisms linking glomerulonephritis risk factors (drugs, decreased consumption of water to prevent water overload, vegetables, dietary fibers, and fruits) and GI dysbiosis with the progression of glomerulonephritis. IEC-derived SAA, different cytokines, and antigen presentation by DCs after SFB colonization, result in Th17 generation. The adhesion of SFB to ECs may stimulate a cycle in which IL-22 is generated through the stimulatory role of DC-derived IL-23 on ILC3 that in turn stimulates the production of SAA from IEC and further differentiation of Th17. Gut dysbiosis can stimulate immunological responses that results in abnormal immune functions and several immune-related inflammatory disorders. DCs: dendritic cells, ECs: intestinal epithelial cell, ILC3: type 3 innate lymphoid cells, GI: gastrointestinal, LPS: lipopolysaccharide, MAMPs: microbe-associated molecular patterns, NO: nitric oxide, PSA: polysaccharide A, SAA: serum amyloid A, SCFAs: short-chain fatty acids, SFB: segmented filamentous bacteria, Th: T-helper cell, Treg: T-regulatory cell.

      Glomerulonephritis and gut dysbiosis

      Glomerulonephritis is the leading cause of inflammation and adaptive responses in the kidney resulting in renal failure. By altering the Th1/Th2 balance of nephritogenic immune responses, cytokines can direct kidney inflammation; moreover, they can be involved in histologic changes and clinical outcomes of GN patients. Additionally, cytokine production by the intrinsic kidney cells further amplifies kidney inflammation in GN models.
      • Ahmadian E.
      • Rahbar Saadat Y.
      • Dalir Abdolahinia E.
      • et al.
      The Role of Cytokines in Nephrotic Syndrome.
      ,
      • Tipping P.G.
      • Holdsworth S.R.
      Cytokines in glomerulonephritis.
      The altered composition of the intestinal microbial community is referred to gut dysbiosis that can stimulate immunological responses continuously, resulting in abnormal immune functions and several immune-related inflammatory disorders including MN, MCD, and IgAN.
      • Forbes J.D.
      • Van Domselaar G.
      • Bernstein C.N.
      The gut microbiota in immune-mediated inflammatory diseases.
      Therefore, the prognosis of GN would be influenced by gut dysbiosis. In the following sections, we have discussions on the etiology of the common form of GN and highlight the impact of GI dysbiosis on the development and prognosis of these pathological conditions Figs. 1 and 2.
      Fig 2
      Fig. 2Gastrointestinal dysbiosis and glomerulonephritis. When the balance of microbiota alters, the protective role of SCFAs in kidney is suppressed; bacterial endotoxins can provoke a systemic inflammation implicated in the production of autoantibodies. Microbes also produce the uremia toxins that can increase the progression of inflammation. Impact of GI dysbiosis on (A) MN and (B) IgAN development. GBM: glomerular basement membrane, GI: gastrointestinal, IgAN: IgA nephropathy, LPS: lipopolysaccharide, MN: membranous nephropathy, PMN: polymorphonuclear leukocytes, SD: slit diagram, TLR4: toll-like receptor 4.

      Idiopathic Nephrotic Syndrome (INS)

      Although it is hypothesized that impaired T cell activity is involved in the mechanism of INS, the exact etiology of the disease remains vague.
      • Herrnstadt G.R.
      • Steinmetz O.M.
      The role of Treg subtypes in glomerulonephritis.
      The role of cytokines in the development and progression of proteinuria in INS has not been approved by numerous reports. Instead, the presence of a complex interaction among immune cells and different cytokines has been proposed.
      • Tsuji S.
      • Kimata T.
      • Yamanouchi S.
      • et al.
      Regulatory T cells and CTLA-4 in idiopathic nephrotic syndrome.
      A recent study investigated the effect of Treq suppression on the extent of proteinuria in INS. Release of immunosuppressive cytokines by Tregs, contact-dependent inhibition by cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and modulation of antigen-presenting cells (APC) have been suggested as potential mechanisms of Treg-related immune suppression. The partial role of glucocorticoids in enhancing the Treg number in INS should be also taken into account.
      • Tsuji S.
      • Kimata T.
      • Yamanouchi S.
      • et al.
      Regulatory T cells and CTLA-4 in idiopathic nephrotic syndrome.
      Immunological stimuli can activate podocytes and initiate pathways leading to proteinuria. The expression of functional markers (TLR4, CD49, and CD80) on podocytes during the stress circumstances might be directly implicated in the promotion of immune response. Podocytes also express CD40 that results in the redistribution and loss of nephrin and enhances the permeability of albumin in glomeruli in vivo.
      • Bertelli R.
      • Bonanni A.
      • Di Donato A.
      • et al.
      Regulatory T cells and minimal change nephropathy: in the midst of a complex network.
      The production of oxidants via circulating cells during the primary immune response might induce toxicity in podocytes. The role of Treg in metabolizing ATP to adenosine could alleviate this toxicity.
      It is still unknown whether dysbiosis induces INS or is a secondary effect of the disease. Several reasons such as the presence of edema in the intestinal wall, the consumption of certain drug classes (antibiotics, immunosuppressants, and steroids), slow colonic transit, and nutritional problems can lead to dysbiosis in INS patients.
      • Wu M.J.
      • Chang C.S.
      • Cheng C.H.
      • et al.
      Colonic transit time in long-term dialysis patients.
      ,
      • Jernberg C.
      • Löfmark S.
      • Edlund C.
      • et al.
      Long-term impacts of antibiotic exposure on the human intestinal microbiota.
      Metabolic acidosis could also be observed in some cases.
      • Goraya N.
      • Wesson D.E.
      Acid-base status and progression of chronic kidney disease.
      Accumulation of waste materials due to impaired renal function and the subsequent ischemic situation in the intestinal mucosa results in mucosal barrier injuries and, thus, enhanced intestinal permeability.
      • Ramezani A.
      • Raj D.S.
      The gut microbiome, kidney disease, and targeted interventions.
      It has been postulated that dysbiosis-associated Tregs dysfunction might play a key role in pediatric INS development.
      • Kaneko K.
      • Tsuji S.
      • Kimata T.
      Role of gut microbiota in idiopathic nephrotic syndrome in children.
      The enrichment of distinct genera from the Proteobacteria phylum has been shown in many diseases. These bacteria can generate pro-inflammatory components and serotonin, uremic toxins,
      • Poveda J.
      • Sanchez-Niño M.D.
      • Glorieux G.
      • et al.
      p-cresyl sulphate has pro-inflammatory and cytotoxic actions on human proximal tubular epithelial cells.
      and disrupt the function of the gut barrier.
      • Shi K.
      • Wang F.
      • Jiang H.
      • et al.
      Gut bacterial translocation may aggravate microinflammation in hemodialysis patients.
      Proteobacteria population increment can lead to several chronic inflammatory disorders and subsequent proteinuric nephropathy.
      • Kanbay M.
      • Onal E.M.
      • Afsar B.
      • et al.
      The crosstalk of gut microbiota and chronic kidney disease: role of inflammation, proteinuria, hypertension, and diabetes mellitus.
      However, different types of NS show different patterns of microbial dysbiosis in the GI.
      In adult patients with INS (n = 35), gut microbial diversity was reduced compared to healthy controls (n = 35) and there were correlations between microbial taxa and clinical parameters, Fig. 3. Lachnoclostridium, Bilophila, Enterococcus, Parabacteroides, Eubacterium ventriosum, and Pasteurellales were increased significantly in INS cases compared to controls. However, other bacteria including Lachnospira, Acidobacteria, Megamonas, Alloprevotella, Clostridium, Ruminiclostridium, Rombousia, Dialister, Clostridiaceae, Veillonellaceae, Selenomonadales, and Negativicutes were reduced in INS patients. There were negative correlations between serum creatinine and Barnesiella, Alcaligenaceae, and Burkholderiales. Proteinuria was associated negatively with Alcaligenaceae, Burkholderiales, and Betaproteobacteria, while it was positively associated with Blautia, Coriobacteriaceae, Nitrosomonadales, Verrucomicrobia, Coriobacteriales, Ignavibacteria, Thermoleophilia, and Coriobacteriia.
      • He H.
      • Lin M.
      • You L.
      • et al.
      Gut microbiota profile in adult patients with idiopathic nephrotic syndrome.
      Fig 3
      Fig. 3Different taxa in the microbiota from the stool samples of INS and healthy controls. (A) LDA score (B) Cladogram generated by LDA. INS: idiopathic nephrotic syndrome (green), HC: healthy controls (red), LDA: linear discriminant analysis. Reprinted from “Gut Microbiota Profile in Adult Patients with Idiopathic Nephrotic Syndrome”, by H. He, 2021, Biomed Research International, 2021, 8854969. Copyright © 2021 by Hanchang He et al. This is an open access article distributed under the Creative Commons Attribution License.

      Membranous nephropathy

      One of the most common causes of NS is MN, which occurs due to the autoimmune response to the phospholipase A2 receptor (PLA2R) and thrombospondintype-1 domain-containing 7A (THSD7A)
      • Beck L.H.
      • Bonegio R.G.
      • Lambeau G.
      • et al.
      M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy.
      where the IgG4 types are the predominant autoantibodies to these target antigens. In MN, the proportion of Tregs is decreased while in primary responsiveness to rituximab, they are increased in the peripheral blood.
      • Rosenzwajg M.
      • Languille E.
      • Debiec H.
      • et al.
      B- and T-cell subpopulations in patients with severe idiopathic membranous nephropathy may predict an early response to rituximab.
      Moreover, an increased number of T cells secreting IL-4 or IL-10, production of IgG4 in response to Th2 cytokines, and a large number of the IgG4 subclass among deposited and circulating anti-THSD7A and anti-PLA2R antibodies imply the involvement of Th2 cells in the pathogenesis of MN.
      • Kuroki A.
      • Iyoda M.
      • Shibata T.
      • et al.
      Th2 cytokines increase and stimulate B cells to produce IgG4 in idiopathic membranous nephropathy.
      ,
      • Masutani K.
      • Taniguchi M.
      • Nakashima H.
      • et al.
      Up-regulated interleukin-4 production by peripheral T-helper cells in idiopathic membranous nephropathy.
      It is suggested that the key antigen, cationic bovine serum albumin in pediatric MN could derive from milk formula, intestinal cells, and microbiota.
      • Debiec H.
      • Lefeu F.
      • Kemper M.J.
      • et al.
      Early-childhood membranous nephropathy due to cationic bovine serum albumin.
      Additionally, the mucosa-associated lymphoid tissue (MALT)-expanded B cells colons
      • Cesta MF.
      Normal structure, function, and histology of mucosa-associated lymphoid tissue.
      may stimulate the production of autoantibodies by cooperating with genetic polymorphisms.
      • Fresquet M.
      • Jowitt T.A.
      • Gummadova J.
      • et al.
      Identification of a major epitope recognized by PLA2R autoantibodies in primary membranous nephropathy.
      With this background, it can be assumed that gut dysbiosis is probably involved in the etiopathogenesis of MN.
      The gut bacterial flora of patients with MN has shown differences mainly in Coprococcus, Bifidobacterium, Parabacteroides, Escherichia-Shigella, Dorea, Christensenellaceae_R- 7_group, and Bifidobacterium genera with normal individuals, suggesting the disruption of the intestinal microbiota in this disease.
      • Lang R.
      • Wang X.H.
      • Li A.F.
      • et al.
      Effects of Jian Pi Qu Shi Formula on intestinal bacterial flora in patients with idiopathic membranous nephropathy: a prospective randomized controlled trial.
      The diversity and quantity of microbiota in primary MN patients have been also investigated and compared with control and CKD groups.
      • Zhang J.
      • Luo D.
      • Lin Z.
      • et al.
      Dysbiosis of gut microbiota in adult idiopathic membranous nephropathy with nephrotic syndrome.
      Lower species richness was observed in MN cases compared to CKD and healthy groups. At the phylum level, the Firmicutes/Bacteroidetes ratios were significantly lower in CKD and MN patients in comparison with the healthy controls. The initial metabolic end-product in the Firmicutes phylum was butyrate, while the Bacteroidetes phylum generates p-cresol enzymes.
      • Rosenzwajg M.
      • Languille E.
      • Debiec H.
      • et al.
      B- and T-cell subpopulations in patients with severe idiopathic membranous nephropathy may predict an early response to rituximab.
      ,
      • Kuroki A.
      • Iyoda M.
      • Shibata T.
      • et al.
      Th2 cytokines increase and stimulate B cells to produce IgG4 in idiopathic membranous nephropathy.
      Moreover, MN patients exhibited an enriched Fusobacteria and Proteobacteria phyla in comparison with the control group while the healthy group contained more Proteobacteria, Fusobacteria, Bacteroidetes, Firmicutes Verrucomicrobia and Actinobacteria phyla. Proteobacteria can produce urease enzyme
      • Wong J.
      • Piceno Y.M.
      • DeSantis T.Z.
      • et al.
      Expansion of urease- and uricase-containing, indole- and p-cresol-forming and contraction of short-chain fatty acid-producing intestinal microbiota in ESRD.
      that stimulates inflammatory uremic toxins.
      • Onal E.M.
      • Afsar B.
      • Covic A.
      • et al.
      Gut microbiota and inflammation in chronic kidney disease and their roles in the development of cardiovascular disease.
      At the genus level, Megasphaera Megamonas, Akkermansia, and the butyrate-generating microorganisms Fusobacterium, Roseburia, and Lachnospira were shown at lower levels in MN and CKD patients. Dong et al. also investigated the microbiota composition in MN and IgAN patients and compared them with healthy controls.
      • Dong R.
      • Bai M.
      • Zhao J.
      • et al.
      A comparative study of the gut microbiota associated with immunoglobulin a nephropathy and membranous nephropathy.
      According to their results, MN patients showed lower levels of taxa such as Ruminococcaceae_incertae_sedis. Furthermore, MN cases exhibited decreased levels of Veillonella, Lachnospira, Lachnospiraceae_unclassified, and Clostridium_sensu_stricto_1, but were enriched in Streptococcus, Peptostreptococcaceae_incertae_sedis, Escherichia-Shigella, and Enterobacteriaceae_unclassified. Correspondingly, a higher abundance of Streptococcus, Klebsiella, Megamonas, and Veillonella was shown in MN compared to IgAN.
      • Dong R.
      • Bai M.
      • Zhao J.
      • et al.
      A comparative study of the gut microbiota associated with immunoglobulin a nephropathy and membranous nephropathy.
      Although Klebsiella and Bacteroides were exerted a positive correlation with the MN stages and proteinuria, no significant relationship was found regarding Escherichia-Shigella.
      • Dong R.
      • Bai M.
      • Zhao J.
      • et al.
      A comparative study of the gut microbiota associated with immunoglobulin a nephropathy and membranous nephropathy.
      It has been also reported that the tonsillar microbiota might be involved in the pathogenesis of MN since tonsil shows immunological activities. The abundance of Lachnoanaerobaculum, Faecalibacterium, Tannerella, Eubacterium_g10, Acinetobacter, Citrobacter, and uncultured Veillonellaceae, and Moraxellaceae was significantly different between the MN, diabetic nephropathy, and control groups.
      • Park J.I.
      • Kim T.Y.
      • Oh B.
      • et al.
      Comparative analysis of the tonsillar microbiota in IgA nephropathy and other glomerular diseases.

      The role of the gut microbiota in mesangial proliferative glomerulonephritis (MsPGN)

      Alterations in the microbial community were identified between INS cases with MN and mesangial proliferative glomerulonephritis (MsPGN). Different taxa significantly were changed between the studied groups. In the MsPGN group, some taxa including Mesorhizobium, TerrimonasRhodobacteraceaePhyllobacteriaceae, and Rhodobacterales  were increased compared to the MN group. However, some other taxa were reduced in the MsPGN group, for instance, Ruminococcaceae, Alistipes, Anaerotruncus, Odorlibacter, Lachnospira, Tyzzerella, Chloroplast, Rikenellaceae, Enterobacteriaceae, Erysipelotrichales, Enterobacteriales, Coriobacteriia, Gammaproteobacteria, and Proteobacteria.
      • He H.
      • Lin M.
      • You L.
      • et al.
      Gut microbiota profile in adult patients with idiopathic nephrotic syndrome.

      The role of the gut microbiota in IgA nephropathy

      IgAN, the main primary GN, is a common cause of nephritic syndrome
      • Couser W.G.
      • Johnson R.J.
      The etiology of glomerulonephritis: roles of infection and autoimmunity.
      ,
      • Khanna R.
      Clinical presentation & management of glomerular diseases: hematuria, nephritic & nephrotic syndrome.
      that may result in end-stage renal failure. Dysregulated intestinal mucosal immunity and mesangial IgA deposition are related to the disease pathogenies.
      • Fresquet M.
      • Jowitt T.A.
      • Gummadova J.
      • et al.
      Identification of a major epitope recognized by PLA2R autoantibodies in primary membranous nephropathy.
      The clinical manifestations of IgAN consist of gross hematuria with simultaneous upper airway infections.
      • Holdsworth S.R.
      • Kitching A.R.
      • Tipping P.G.
      Th1 and Th2 T helper cell subsets affect patterns of injury and outcomes in glomerulonephritis.
      Inflammatory responses, chronic bacterial infections, and immune-related reactions are considered important etiologies of IgAN. Furthermore, T-cell dependent IgA generation leads to the elevation of circulatory Th17 and Th22 in patients with IgAN.
      • Peng Z.
      • Tian J.
      • Cui X.
      • et al.
      Increased number of Th22 cells and correlation with Th17 cells in peripheral blood of patients with IgA nephropathy.
      IgAN has been reported to be induced by Staphylococcus aureus.
      • Koyama A.
      • Sharmin S.
      • Sakurai H.
      • et al.
      Staphylococcus aureus cell envelope antigen is a new candidate for the induction of IgA nephropathy.
      The dysbiosis phenomena and/or chronic bacterial infections trigger(s) the immune response in gut mucosa resulting in an increased secretion of B cell-activating factor and proliferation-inducing ligand from the epithelial cells, which in turn, lead to the generation of excess IgA. Patients with IgAN exhibit distinct differences in the microbiome profile of GI and the related metabolome compared to normal individuals.
      • De Angelis M.
      • Montemurno E.
      • Piccolo M.
      • et al.
      Microbiota and metabolome associated with immunoglobulin a nephropathy (IgAN).
      ,
      • Piccolo M.
      • De Angelis M.
      • Lauriero G.
      • et al.
      Salivary microbiota associated with immunoglobulin a nephropathy.
      In addition, substantial alterations of urinary metabolites have been shown in progressive IgAN patients in comparison with non-progressive cases.
      • Brito J.S.
      • Borges N.A.
      • Dolenga C.J.
      • et al.
      Is there a relationship between tryptophan dietary intake and plasma levels of indoxyl sulfate in chronic kidney disease patients on hemodialysis?.
      The pathophysiology of IgAN has been postulated to be in close connection with surged free amino acids, decreased GI protein absorption, and subsequently, elevated microbial proteolysis that alters the normal microbiota and increases the p-cresol level in feces. Another important issue is the relationship between IgA hypogalactosylation and bacterial LPS which can induce the inflammatory response. Ig A hypogalactosylation is tightly involved in the pathogenesis of the disease.
      • Ayanga B.A.
      • Badal S.S.
      • Wang Y.
      • et al.
      Dynamin-related protein 1 deficiency improves mitochondrial fitness and protects against progression of diabetic nephropathy.
      The reported dysbiosis in IgAN has been in favor of pathogenic bacteria increment.
      • De Angelis M.
      • Montemurno E.
      • Piccolo M.
      • et al.
      Microbiota and metabolome associated with immunoglobulin a nephropathy (IgAN).
      ,
      • Zhong Z.
      • Tan J.
      • Tan L.
      • et al.
      Modifications of gut microbiota are associated with the severity of IgA nephropathy in the Chinese population.
      Treponema and Campylobacter rectus are important bacterial species in the development of IgAN.
      • Nagasawa Y.
      • Iio K.
      • Fukuda S.
      • et al.
      Periodontal disease bacteria specific to tonsil in IgA nephropathy patients predicts the remission by the treatment.
      Moreover, the level of Porphyromonas, Prevotella, and Treponema are increased in IgAN patients.
      • Watanabe H.
      • Goto S.
      • Mori H.
      • et al.
      Comprehensive microbiome analysis of tonsillar crypts in IgA nephropathy.
      Butyrate exerts a crucial role in the pathogenesis of IgAN through its effects on Treg cells and also its anti-inflammatory impacts, helping the maintenance of normal balance in gut microbiota.
      • Ruszkowski J.
      • Lisowska K.A.
      • Pindel M.
      • et al.
      T cells in IgA nephropathy: role in pathogenesis, clinical significance and potential therapeutic target.
      Attenuation of the butyrate-generating bacterial community disturbs the intestinal mucosal barrier leading to IgAN. It has been shown that the abundance of Bifidobacterium genera is higher in IgAN compared to the normal controls.
      • Dong R.
      • Bai M.
      • Zhao J.
      • et al.
      A comparative study of the gut microbiota associated with immunoglobulin a nephropathy and membranous nephropathy.
      As mentioned, butyrate-producing genera (Faecalibacterium and Roseburia) have been plunged in IgAN while ethanol-generating Escherichia-Shigella which increases gut leakiness, oxidative damages, and hampers butyrate synthesis show an upward trend in the flor of these patients.
      • Dong R.
      • Bai M.
      • Zhao J.
      • et al.
      A comparative study of the gut microbiota associated with immunoglobulin a nephropathy and membranous nephropathy.
      ,
      • De Angelis M.
      • Montemurno E.
      • Piccolo M.
      • et al.
      Microbiota and metabolome associated with immunoglobulin a nephropathy (IgAN).
      Moreover, Prevotella is positively correlated with IgAN, whereas a negative correlation has been observed between serum albumin and Citrobacter, Fusobacterium, and Klebsiella. The MEST classification of IgAN has been positively correlated with the Bilophila.
      • Dong R.
      • Bai M.
      • Zhao J.
      • et al.
      A comparative study of the gut microbiota associated with immunoglobulin a nephropathy and membranous nephropathy.
      In another study, the connection between gut microbiota composition and the clinical outcomes of the disease has been reported.
      • Zhong Z.
      • Tan J.
      • Tan L.
      • et al.
      Modifications of gut microbiota are associated with the severity of IgA nephropathy in the Chinese population.
      The gut microbiota of 52 IgAN patients was analyzed and it was shown that the levels of Escherichia-Shigella and Bacteroides were notably higher in these patients, whereas Blautia spp and Bifidobacterium exhibited lower levels. These alterations were concurrent with increased hematuria and proteinuria levels. A negative coloration was found between the levels of Prevotella 7 and the number of distinct factors (galactose deficient (IgA1), intercellular adhesion molecule-1, tumor necrosis factor α, and soluble cluster of differentiation 14).
      • Zhong Z.
      • Tan J.
      • Tan L.
      • et al.
      Modifications of gut microbiota are associated with the severity of IgA nephropathy in the Chinese population.
      Moreover, a significant counter relation was observed between Bifidobacterium spp. levels and IgA1. Likewise, a negative correlation was shown between Escherichia-Shigella levels and Prevotella 7. So, the generated dysbiosis might affect the development and prognosis of IgAN.
      • Zhong Z.
      • Tan J.
      • Tan L.
      • et al.
      Modifications of gut microbiota are associated with the severity of IgA nephropathy in the Chinese population.
      In another research, a diminished richness of Dialister was connected with higher Gd-IgA1 levels in serum of patients with IgAN. The results of this research provide pilot evidence that in IgAN, the gut microbiota can be impacted by host genetics suggesting a new approach for upcoming pathogenesis and interventions.
      • He J.W.
      • Zhou X.J.
      • Li Y.F.
      • et al.
      Associations of genetic variants contributing to gut microbiota composition in immunoglobin a nephropathy.
      Tonsillar microbiota as the primary site of inflammation might be also closely connected to the pathogenesis of IgAN in the context of immune responses.
      • Park J.I.
      • Kim T.Y.
      • Oh B.
      • et al.
      Comparative analysis of the tonsillar microbiota in IgA nephropathy and other glomerular diseases.
      Although the microbiota composition of tonsils of recurrent tonsillitis and IgAN were not distinguishable, some strains including Sphingomonas spp, Fusobacterium spp, Prevotella spp, and Treponema spp were dominant in IgAN cases.
      • Watanabe H.
      • Goto S.
      • Mori H.
      • et al.
      Comprehensive microbiome analysis of tonsillar crypts in IgA nephropathy.
      The results of another study reported 8 genera that could distinguish IgAN from healthy individuals. The genus f_Prevotellaceae and Methylocaldum showed an increase in IgAN patients in comparison with the control group, while Halomonas, Peptostreptococcus, Anaerosphaera, norank_f_Synergistaceae, Trichococcus spp., and unclassified_k_norank_d_Bacteria were markedly lower in the patient group. In the early diagnosis of IgAN cases, the levels of Trichococcus spp, norank_f_Synergistaceae spp, and unclassified_f_Prevotellaceae spp were detected in higher levels.
      • Zhu A.
      • Yang X.
      • Bai L.
      • et al.
      Analysis of microbial changes in the tonsillar formalin-fixed paraffin-embedded tissue of Chinese patients with IgA nephropathy.
      A recent investigation evaluated the tonsil microbiota in IgAN patients and compared them with MN, diabetic nephropathy and healthy controls.
      • Park J.I.
      • Kim T.Y.
      • Oh B.
      • et al.
      Comparative analysis of the tonsillar microbiota in IgA nephropathy and other glomerular diseases.
      Both IgAN cases and the control group showed a richer bacterial population compared to the two other groups. A relative abundance of Ruminococcus_g2, Rahnella, and Clostridium_g21 were detected in IgAN cases. It has also been shown that Porphyromonas spp. are more often coated with Ig A in the tonsil tissue. Besides, the subset of anaerobic microbiota in particular Bacteroidetes in tonsil is firmly implicated in the pathophysiology of IgAN.
      • Yamaguchi H.
      • Goto S.
      • Takahashi N.
      • et al.
      Aberrant mucosal immunoreaction to tonsillar microbiota in immunoglobulin a nephropathy.
      Additionally, the clinical function of the kidney was tightly linked with the microbiota composition of the tonsil.
      • Park J.I.
      • Kim T.Y.
      • Oh B.
      • et al.
      Comparative analysis of the tonsillar microbiota in IgA nephropathy and other glomerular diseases.
      Importantly, saliva microbiota has also been associated with IgAN.
      • Piccolo M.
      • De Angelis M.
      • Lauriero G.
      • et al.
      Salivary microbiota associated with immunoglobulin a nephropathy.
      ,
      • Luan S.
      • Zhang S.
      • Zhong H.
      • et al.
      Salivary microbial analysis of Chinese patients with immunoglobulin a nephropathy.
      According to the current knowledge, dysbiosis in the intestinal microbiota can result in an increment of uremic toxin-generating bacteria through the diminution of SCFA-forming GI microorganisms. Also, LPS and other microbiota-derived endotoxins can trigger the IgA1 hypogalactosylation and inflammatory response which in turn end ups with IgAN.
      • Ayanga B.A.
      • Badal S.S.
      • Wang Y.
      • et al.
      Dynamin-related protein 1 deficiency improves mitochondrial fitness and protects against progression of diabetic nephropathy.
      Collectively, in IgAN, a kidney–gut axis is active where genetic, dietary, and microbial factors can alter the GI mucosal immune system favoring the IgAN development.
      • Coppo R.
      The gut-kidney axis in IgA nephropathy: role of microbiota and diet on genetic predisposition.
      These data suggest that definite specific microbiota may be a potential therapeutic target for IgAN.
      • Jiang X.S.
      • Chen X.M.
      • Hua W.
      • et al.
      PINK1/Parkin mediated mitophagy ameliorates palmitic acid-induced apoptosis through reducing mitochondrial ROS production in podocytes.

      Alterations of gut microbiota after GN therapy

      INS has been also classified according to the responses of patients to steroid therapy. Steroid-resistant NS (SRNS) is accompanied by increased proteinuria and the loss of immunoglobulins from urine, which in turn, increases the risk of infection.
      • Goonewardene S.T.
      • Tang C.
      • Tan L.T.
      • et al.
      Safety and efficacy of pneumococcal vaccination in pediatric nephrotic syndrome.
      It has been reported that gut microbiota dysbiosis and T-cell dysfunction are implicated in the development of NS. The effect of initial NS treatment on gut microbiota is unclear. In this context, Kang and coworkers compared the gut microbiota composition of primary NS children before and post-treatment in feces samples. According to their result, no significant change was observed in the diversity and richness of microbiota before and after initial therapy. However, children after treatment exhibited an elevated level of Acidobacteria and Deinococcus-Thermus phylum. Also, SCA-generating bacteria (Stomatobaculum, Cloacibacillus, Romboutsia) were shown an increased abundance after the treatment; however, selenocompound metabolism, isoflavonoid biosynthesis, and phosphatidylinositol signaling cascades as pivotal microbial metabolism pathway were decreased.
      • Kang Y.
      • Feng D.
      • Law H.K.
      • et al.
      Compositional alterations of gut microbiota in children with primary nephrotic syndrome after initial therapy.
      The results propose the possibility of applying novel therapeutic options to modulate gut microbiota in NS.
      The decreased quantity of butyrate-generating microbiota, a lower proportion of fecal butyrate level, and dysbiosis occur in children with INS on relapse leading to the activation and differentiation of circulatory stimulated Treg during relapse.
      • Tsuji S.
      • Suruda C.
      • Hashiyada M.
      • et al.
      Gut microbiota dysbiosis in children with relapsing idiopathic nephrotic syndrome.
      It has been reported that immunosuppressive therapy and distinct traditional medicine can alter intestinal flora in MN patients.
      • Lang R.
      • Wang X.H.
      • Li A.F.
      • et al.
      Effects of Jian Pi Qu Shi Formula on intestinal bacterial flora in patients with idiopathic membranous nephropathy: a prospective randomized controlled trial.

      Modulation of microbiota

      According to reported data, initiation of INS is connected with gut dysbiosis
      • Kaneko K.
      • Tsuji S.
      • Kimata T.
      Role of gut microbiota in idiopathic nephrotic syndrome in children.
      ,
      • Tsuji S.
      • Akagawa S.
      • Akagawa Y.
      • et al.
      Idiopathic nephrotic syndrome in children: role of regulatory T cells and gut microbiota.
      through both genetic and environmental factors. Genetic factors such as histocompatibility complex (MHC) antigens and human leukocyte antigens have been involved in the development of several diseases,
      • Kubinak J.L.
      • Stephens W.Z.
      • Soto R.
      • et al.
      MHC variation sculpts individualized microbial communities that control susceptibility to enteric infection.
      ,
      • Bolnick D.I.
      • Snowberg L.K.
      • Caporaso J.G.
      • et al.
      Major Histocompatibility Complex class IIb polymorphism influences gut microbiota composition and diversity.
      whereas numerous studies have described that the diet content can alter the gut microbiota.
      • Wu G.D.
      • Chen J.
      • Hoffmann C.
      • et al.
      Linking long-term dietary patterns with gut microbial enterotypes.
      Moreover, other studies have proposed a link between genetic factors, particularly MHC class II molecules, and the etiology of MCNS.
      • Jia X.
      • Horinouchi T.
      • Hitomi Y.
      • et al.
      Strong association of the HLA-DR/DQ locus with childhood steroid-sensitive Nephrotic syndrome in the Japanese population.
      ,
      • Lane B.M.
      • Cason R.
      • Esezobor C.I.
      • et al.
      Genetics of childhood steroid sensitive nephrotic syndrome: an update.
      Recent evidence demonstrates an important connection between food sensitivity and GI microbiome content in children with NS. The proteinuria level has plummeted in NS patients who use a gluten-free oligonucleotide diet and eliminate cow's milk.
      • Uy N.
      • Graf L.
      • Lemley K.V.
      • et al.
      Effects of gluten-free, dairy-free diet on childhood nephrotic syndrome and gut microbiota.
      However, the underlying mechanism of this connection is unknown.
      Diet contents and some other epigenetic factors can affect gut microbiota equilibrium since gluten- and dairy-excluded diets decrease gut microbiota imbalance. It has been shown that the number of pathogenic bacteria and the bacterial-related IL-10 production could be ameliorated via a gluten-free diet. Therefore, this type of diet might alter the composition and also the immunological features of gut microbiota. Dairy products could also induce a significant imbalance in gut microbiota resulting in an allergic situation.
      • Uy N.
      • Graf L.
      • Lemley K.V.
      • et al.
      Effects of gluten-free, dairy-free diet on childhood nephrotic syndrome and gut microbiota.
      Additional studies are required to determine the role of dietary intervention in the pathogenesis of NS and further decrease the potential immunosuppressant-related therapies in children. It has been reported that the aforementioned diets could also induce remission in MCD patients.
      • Leon J.
      • Pérez-Sáez M.J.
      • Uffing A.
      • et al.
      Effect of combined gluten-free, dairy-free diet in children with steroid-resistant nephrotic syndrome: an open pilot trial.
      The results of different studies in this area propose that diet management could be favorable in controlling relapse.
      • Tsuji S.
      • Akagawa S.
      • Akagawa Y.
      • et al.
      Idiopathic nephrotic syndrome in children: role of regulatory T cells and gut microbiota.
      ,
      • Jia X.
      • Horinouchi T.
      • Hitomi Y.
      • et al.
      Strong association of the HLA-DR/DQ locus with childhood steroid-sensitive Nephrotic syndrome in the Japanese population.
      Dysbiosis and inadequate differentiation of Treg have been observed in frequent relapsing NS cases.
      • Tsuji S.
      • Akagawa S.
      • Akagawa Y.
      • et al.
      Idiopathic nephrotic syndrome in children: role of regulatory T cells and gut microbiota.
      Immunosuppression as the second-line therapy of SRNS is considered to be toxic and exerts restricted efficiency. Instead, the dietary intervention has shown promising effects and negligible risks and could potentially improve the outcomes in pediatric SRNS.
      • Leon J.
      • Pérez-Sáez M.J.
      • Uffing A.
      • et al.
      Effect of combined gluten-free, dairy-free diet in children with steroid-resistant nephrotic syndrome: an open pilot trial.
      Although it is unknown how dietary interventions attenuate proteinuria, food sensitivity is connected to perturbation in the immune system.
      • Leon J.
      • Pérez-Sáez M.J.
      • Uffing A.
      • et al.
      Effect of combined gluten-free, dairy-free diet in children with steroid-resistant nephrotic syndrome: an open pilot trial.
      ,
      • Lemley K.V.
      • Faul C.
      • Schramm K.
      • et al.
      The effect of a gluten-free diet in children with difficult-to-manage nephrotic syndrome.
      The release of inflammatory cytokines upon exposure to sensitive food can induce a direct podocytopathy.
      • Lemley K.V.
      • Faul C.
      • Schramm K.
      • et al.
      The effect of a gluten-free diet in children with difficult-to-manage nephrotic syndrome.
      Microbiota, at least partially, is involved in this effect.
      • Sanz Y.
      Effects of a gluten-free diet on gut microbiota and immune function in healthy adult humans.
      For instance, gluten consumption can result in the secretion of zonulin, a key modulator of tight junctions.
      • Fasano A.
      • Not T.
      • Wang W.
      • et al.
      Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease.
      Intestinal-cell-derived zonulin can disrupt tight junctions in the podocytes and induce proteinuria by disturbing the slit diagram.
      • Trachtman H.
      • Gipson D.S.
      • Lemley K.V.
      • et al.
      Plasma zonulin levels in childhood nephrotic syndrome.
      Increased serum level of zonulin can also increase the attachment of the ligand to upregulated Protease-activated receptor 2 (PAR2) in a gluten-contained diet which in turn might interfere with different cell signaling pathways leading to podocyte injury.
      • Madhusudhan T.
      • Wang H.
      • Straub B.K.
      • et al.
      Cytoprotective signaling by activated protein C requires protease-activated receptor-3 in podocytes.
      ,
      • Tripathi A.
      • Lammers K.M.
      • Goldblum S.
      • et al.
      Identification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2.
      The changes in podocyte function and cytoskeleton affect cell motility and binding to GBM, resulting in proteinuria.
      • Schell C.
      • Huber TB.
      The evolving complexity of the podocyte cytoskeleton.
      On the other hand, the disruption of tight junctions in the epithelial cells of the intestine might escalate the permeability of the gut, which results in the entrance of microbiota-produced toxin into the peripheral blood and further activation of the immune system and generation of cytokines that induce podocytopathy.
      • Madhusudhan T.
      • Wang H.
      • Straub B.K.
      • et al.
      Cytoprotective signaling by activated protein C requires protease-activated receptor-3 in podocytes.
      In summary, these data support the importance of dietary interventions in targeting specific pathways implicated in the pathogenesis of podocyte damages.
      • Leon J.
      • Pérez-Sáez M.J.
      • Uffing A.
      • et al.
      Effect of combined gluten-free, dairy-free diet in children with steroid-resistant nephrotic syndrome: an open pilot trial.
      The genera Bifidobacterium and Lactobacillus are well-known probiotics with several valuable functions such as protecting the structure of gut barrier generation of SCFA,
      • Ramezani A.
      • Raj D.S.
      The gut microbiome, kidney disease, and targeted interventions.
      and SCFA-regulated components like glucagon-like peptide-1 (GLP-1), GLP-2, and peptide YY (PYY),
      • Lemley K.V.
      • Faul C.
      • Schramm K.
      • et al.
      The effect of a gluten-free diet in children with difficult-to-manage nephrotic syndrome.
      vitamin B and nitric oxide (NO).
      • de Andrade J.A.A.
      • Gayer C.R.M.
      • Nogueira N.P.A.
      • et al.
      The effect of thiamine deficiency on inflammation, oxidative stress and cellular migration in an experimental model of sepsis.
      These bacteria are considered as anti-inflammatory species that protect the host from several inflammation-related diseases such as hypertension, pre-eclampsia, and autoimmune disorders which might also end up with proteinuria.
      • de Andrade J.A.A.
      • Gayer C.R.M.
      • Nogueira N.P.A.
      • et al.
      The effect of thiamine deficiency on inflammation, oxidative stress and cellular migration in an experimental model of sepsis.
      Also, probiotics can notably decrease the level of uremic toxins in CKD cases. Additionally, serum levels of pro-inflammatory cytokines and endotoxins have plummeted via probiotic supplementations in peritoneal dialysis patients.
      • Jia L.
      • Jia Q.
      • Yang J.
      • et al.
      Efficacy of probiotics supplementation on chronic kidney disease: a systematic review and meta-analysis.
      ,
      • Lopes R.
      • Balbino K.P.
      • Jorge M.P.
      • et al.
      Modulation of intestinal microbiota, control of nitrogen products and inflammation by pre/probiotics in chronic kidney disease: a systematic review.
      L. Plantarum has been shown to decrease serum lipid level and modulate the function of the immune system in nephrotic and dyslipidemic pediatric subjects.
      • Fortes P.M.
      • Teles Filho R.V.
      • Azevêdo L.H.S.
      • et al.
      Inflammatory cytokines and lipid profile in children and adolescents with nephrotic syndrome receiving L. Plantarum: a randomized, controlled feasibility trial.
      Probiotic and also prebiotic use has improved dysbiosis, and surged the rate of Tregs enhancement and thus avoiding the occurrence of frequent relapses.
      • Tsuji S.
      • Akagawa S.
      • Akagawa Y.
      • et al.
      Idiopathic nephrotic syndrome in children: role of regulatory T cells and gut microbiota.
      The underlying mechanisms include the competition of probiotics with pathogenic bacteria for nutrients, prohibiting their adhesion, preserving the integrity of the gut barrier, and finally modulation of the immune system.
      The administration of antibiotics has significantly decreased fecal microbiota, disrupted the structure of gut-associated lymphoid tissue, and influenced the generation of IgA in an experimental humanized IgAN model. Also, the deposition of human IgA1 was blocked, glomerular inflammation and proteinuria were decreased but the serum levels of hIgA1 and mouse IgG did not change. However, the circulatory level of hIgA1– mIgG complexes was notably plunged which was also in connection with the final fecal load of bacteria and clinical signs of the disease. Reduced generation of anti-Tn antigen-specific IgG and also alleviated the effect of bacterial antigens on immune complex production were proposed as the mechanisms of the protective effects of probiotics on gut microbiota. The streptococcal M protein has been detected in the glomeruli of patients with IgAN
      • Schmitt R.
      • Carlsson F.
      • Mörgelin M.
      • et al.
      Tissue deposits of IgA-binding streptococcal M proteins in IgA nephropathy and henoch-schonlein purpura.
      suggesting that bacterial antigens may stimulate the generation of these nephrotoxic immune complexes and the important role of changes in microbiota composition IgAN.
      • Chemouny J.M.
      • Gleeson P.J.
      • Abbad L.
      • et al.
      Modulation of the microbiota by oral antibiotics treats immunoglobulin a nephropathy in humanized mice.

      Future outlook

      Despite the current challenges regarding the understanding of exact bacterial patterns involved in the progression of GN, the modulation of gut microbiota seems to be a promising treatment strategy and can diminish the deleterious toxic effects of conventional immunosuppressive agents. The application of therapeutic interventions based on gut microbiota including special diets and probiotic supplementation has efficiently decreased the level of proteinuria. However, interventional studies and robust follow-up are needed to address these challenges. More research is required to clear out the connections between the gut microbiota and epigenetic factors, environmental exposures, and genetic alterations in the induction of immune dysregulation in GN. Identification of microbiome-derived markers for the early diagnosis, the prognosis of GN, and therapeutic targets would be other worthwhile goals. Additionally, finding the functions of these bacteria requires further study. Moreover, future research has to focus on translational and mechanistic studies between the gut INS and microbiota, for instance, germ-free animal models, transplantation of fecal microbiota from INS patients and healthy individuals, and microbial metabolites. Potential therapeutic approaches that target the gut microbiota in MN and IgAN patients and other types of GN need to be investigated.

      Conclusions

      Evidence from immunologic, epigenetic, genetic, animal, and clinical reports supports a role for bacterial dysbiosis in the pathogenesis of primary GN. Available data reveal modifications in gut microbiota in INS patients and detect associations between clinical parameters and altered taxa in these patients. Considering the dissimilar pathological patterns of GN, certain taxa, genera, and even specious can be different in patients with MN and IgAN. Hence, the distinct microorganisms may be potential diagnostic and prognostic markers and also therapeutic targets for different types of GN diseases. The results may point out the direction for the development of novel therapeutics and diagnostics approaches for glomerulonephritis based on the altered gut, tonsillar, and salivary microbiota.

      CRediT authorship contribution statement

      Mohammadreza Ardalan: Conceptualization, Visualization, Writing – original draft, Writing – review & editing. Elham Ahmadian: Writing – review & editing, Writing – original draft. Seyed Mahdi Hosseiniyan Khatibi: Writing – review & editing, Writing – original draft. Yalda Rahbar Saadat: Writing – review & editing, Writing – original draft. Milad Bastami: Writing – review & editing, Writing – original draft. Yasin Bagheri: Writing – review & editing, Writing – original draft. Fatemeh Zununi Vahed: . Mohammadali M. Shoja: Writing – review & editing, Writing – original draft. Sepideh Zununi Vahed: Conceptualization, Visualization, Writing – review & editing.

      Declaration of Competing Interest

      The authors declare that there is no conflict of interest.

      Acknowledgments

      The authors gratefully acknowledge the Kidney Research Center of Tabriz University of Medical Sciences, Tabriz, Iran. This study is financially supported by the Kidney Research Center of Tabriz University of Medical Sciences, Tabriz, Iran (Grant No. # 69776).

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