Why Target the Gut to Treat IgA Nephropathy?
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ABSTRACT:
SUBMITTER: Barratt J
PROVIDER: S-EPMC7569689 | biostudies-literature | 2020 Oct
REPOSITORIES: biostudies-literature
Publications
Why Target the Gut to Treat IgA Nephropathy?
Barratt Jonathan J Rovin Brad H BH Cattran Daniel D Floege Jürgen J Lafayette Richard R Tesar Vladimir V Trimarchi Hernán H Zhang Hong H
Kidney international reports 20200820 10
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Project description: Not available
| S-EPMC9435972 | biostudies-literature
Project description:IgA nephropathy (IgAN) is a leading cause of CKD and renal failure. Recent international collaborative efforts have led to important discoveries that have improved our understanding of some of the key steps involved in the immunopathogenesis of IgAN. Furthermore, establishment of multicenter networks has contributed to rigorous design and execution of clinical trials that have provided important insights regarding immunotherapy in IgAN. In this article, we review emerging developments in clinical and translational IgAN research and describe how these novel findings will influence future strategies to improve the outcome of patients with IgAN.
| S-EPMC5383386 | biostudies-literature
Project description:Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis and one of the leading causes of renal failure worldwide. The pathophysiology of IgAN involves nephrotoxic IgA1-immune complexes. These complexes are formed by galactose-deficient (Gd) IgA1 with autoantibodies against the hinge region of Gd-IgA1 as well as soluble CD89, an immune complex amplifier with an affinity for mesangial cells. These multiple molecular interactions result in the induction of the mesangial IgA receptor, CD71, injuring the kidney and causing disease. This review features recent immunological and microbiome studies that bring new microbiota-dependent mechanisms developing the disease based on data from IgAN patients and a humanized mouse model of IgAN. Dysbiosis of the microbiota in IgAN patients is also discussed in detail. Highlights of this review underscore that nephrotoxic IgA1 in the humanized mice originates from mucosal surfaces. Fecal microbiota transplantation (FMT) experiments in mice using stools from patients reveal a possible microbiota dysbiosis in IgAN with the capacity to induce progression of the disease whereas FMT from healthy hosts has beneficial effects in mice. The continual growth of knowledge in IgAN patients and models can lead to the development of new therapeutic strategies targeting the microbiota to treat this disease.
| S-EPMC9031807 | biostudies-literature
Project description:BackgroundIgA nephropathy (IgAN) has been associated with gut dysbiosis, intestinal membrane disruption, and translocation of bacteria into blood. Our study aimed to understand the association of gut and blood microbiomes in patients with IgAN in relation to healthy controls.MethodsWe conducted a case-control study with 20 patients with progressive IgAN, matched with 20 healthy controls, and analyzed bacterial DNA quantitatively in blood using 16S PCR and qualitatively in blood and stool using 16S metagenomic sequencing. We conducted between-group comparisons as well as comparisons between the blood and gut microbiomes.ResultsHigher median 16S bacterial DNA in blood was found in the IgAN group compared with the healthy controls group (7410 versus 6030 16S rDNA copies/μl blood, P=0.04). α- and β-Diversity in both blood and stool was largely similar between the IgAN and healthy groups. In patients with IgAN, in comparison with healthy controls, we observed higher proportions of the class Coriobacteriia and species of the genera Legionella, Enhydrobacter, and Parabacteroides in blood, and species of the genera Bacteroides, Escherichia-Shigella, and some Ruminococcus in stool. Taxa distribution were markedly different between the blood and stool samples of each subject in both IgAN and healthy groups, without any significant correlation between corresponding gut and blood phyla.ConclusionsImportant bacterial taxonomic differences, quantitatively in blood and qualitatively in both blood and stool samples, that were detected between IgAN and healthy groups warrant further investigation into their roles in the pathogenesis of IgAN. Although gut bacterial translocation into blood may be one of the potential sources of the blood microbiome, marked taxonomic differences between gut and blood samples in each subject in both groups confirms that the blood microbiome does not directly reflect the gut microbiome. Further research is needed into other possible sites of origin and internal regulation of the blood microbiome.
| S-EPMC8676391 | biostudies-literature
Project description:BackgroundRecently, a few studies have indicated a relationship between the gut microbiota and IgA nephropathy (IgAN). Whether the gut microbiota participates in the pathogenesis of IgAN and whether probiotics are effective in treating IgAN are still controversial. Therefore, this study aimed to identify the differences in the structure of the gut microbiota between IgAN and controls and to evaluate the efficacy and mechanism of probiotics in the treatment of IgAN.MethodsTo address this question, 35 IgAN patients and 25 healthy volunteers were enrolled, and a mouse IgAN model was also constructed. The stool microbes were analyzed by 16S rRNA high-throughput sequencing to identify the differential strains between IgAN and healthy controls. The impact of probiotics on the structure of the intestinal flora and the efficacy of the probiotics in the treatment of IgAN were evaluated.ResultsAlthough the microflora structure of mice and humans was not the same, both patients and mice with IgAN exhibited gut microbiota dysbiosis, with all subjects presenting an evident decrease in Bifidobacterium levels. The Bifidobacterium proportion was negatively correlated with proteinuria and hematuria levels, indicating that the decreased Bifidobacterium abundance could be related to IgAN severity. Probiotic treatment containing Bifidobacterium in IgAN mice could significantly alleviate gut dysbiosis, specifically by increasing the proportion of beneficial bacteria and reducing the abundance of potentially pathogenic bacteria. Moreover, both probiotics and their metabolites, short-chain fatty acids (SCFAs), could attenuate IgAN clinicopathological manifestations by inhibiting the NLRP3/ASC/Caspase 1 signaling pathway.ConclusionsSupplementation with probiotics mainly containing Bifidobacterium could markedly improve gut dysbiosis in IgAN. Moreover, both probiotics and their SCFA metabolites could attenuate the clinicopathological manifestations of IgAN by inhibiting the NLRP3/ASC/Caspase 1 signaling pathway. Therefore, probiotics have potential as an adjunctive therapy for IgAN.
| S-EPMC9422169 | biostudies-literature
Project description:BackgroundIgA nephropathy (IgAN) is intimately linked to mucosal immune responses, with nasopharyngeal and intestinal lymphoid tissues being crucial for its abnormal mucosal immunity. The specific pathogenic bacteria in these sites associated with IgAN, however, remain elusive. Our study employs 16S rRNA sequencing and machine learning (ML) approaches to identify specific pathogenic bacteria in these locations and to investigate common pathogens that may exacerbate IgAN.MethodsIn this cross-sectional analysis, we collected pharyngeal swabs and stool specimens from IgAN patients and healthy controls. We applied 16SrRNA sequencing to identify differential microbial populations. ML algorithms were then used to classify IgAN based on these microbial differences. Spearman correlation analysis was employed to link key bacteria with clinical parameters.ResultsWe observed a reduced microbial diversity in IgAN patients compared to healthy controls. In the gut microbiota of IgAN patients, increases in Bacteroides, Escherichia-Shigella, and Parabacteroides, and decreases in Parasutterella, Dialister, Faecalibacterium, and Subdoligranulum were notable. In the respiratory microbiota, increases in Neisseria, Streptococcus, Fusobacterium, Porphyromonas, and Ralstonia, and decreases in Prevotella, Leptotrichia, and Veillonella were observed. Post-immunosuppressive therapy, Oxalobacter and Butyricoccus levels were significantly reduced in the gut, while Neisseria and Actinobacillus levels decreased in the respiratory tract. Veillonella and Fusobacterium appeared to influence IgAN through dual immune loci, with Fusobacterium abundance correlating with IgAN severity.ConclusionsThis study revealing that changes in flora structure could provide important pathological insights for identifying therapeutic targets, and ML could facilitate noninvasive diagnostic methods for IgAN.
| S-EPMC11385635 | biostudies-literature
Project description:IntroductionGalactose-deficient IgA1 (Gd-IgA1) and related IgA/IgG immune complexes have been identified as the key drivers in the pathogenesis of IgA nephropathy (IgAN). However, their roles in the development of secondary IgAN are still unknown.MethodsIn this study, we measured the plasma Gd-IgA1 level, IgA/IgG complex, and Gd-IgA1 glomerular deposits in 100 patients with various kinds of secondary IgAN. Plasma Gd-IgA1 was measured using a lectin-based enzyme-linked immunosorbent assay, and Gd-IgA1 in glomerular deposits was examined by double immunofluorescent staining using its specific monoclonal antibody KM55.ResultsPatients with secondary IgAN presented with higher plasma Gd-IgA1 levels compared to healthy controls (median, 354.61 U/ml; interquartile range [IQR], 323.93, 395.57 U/ml vs. median, 303.17 U/ml; IQR, 282.24, 337.92 U/ml, P < 0.001) or patients with other kidney diseases (median, 314.61 U/ml; IQR, 278.97, 343.55 U/ml, P < 0.001). A similar trend was observed in plasma IgA/IgG immune complexes or IgA1. There were no differences between secondary and primary IgAN in plasma Gd-IgA1 levels (median, 378.54 U/ml; IQR, 315.96, 398.33 U/ml, P = 0.700) and IgA1-IgG complex levels (median, 18.76 U/ml; IQR, 14.51, 22.83 U/ml vs. median, 19.11 U/ml; IQR, 13.21, 22.37 U/ml, P = 0.888). Co-localized IgA1 and Gd-IgA1 of both secondary and primary IgAN indicated that they both share the feature of Gd-IgA1 deposits on the glomerular mesangium.ConclusionOur study strongly suggests that secondary IgAN shares a similar galactose-deficient IgA1-oriented pathogenesis with primary IgAN.
| S-EPMC7000803 | biostudies-literature
Project description:Purpose of the reviewImmunoglobulin A (IgA) nephropathy (IgAN) is the most common primary glomerular kidney disease. Children and adults are presumed to have the same disease and are treated similarly. However, there are differences between childhood IgAN and adult IgAN that may require unique treatment considerations, even after transition to adult nephrology services. A narrative review was conducted to compare childhood and adult IgAN and to describe the distinct characteristics of childhood IgAN. Reframing childhood IgAN can inform guideline recommendations unique to childhood IgAN, the development of targeted therapies, and clinical trial design.Sources of informationMedline and Embase were searched for reports on children and adults with IgAN published between January 2013 and December 2023 (updated May 2024). The search was not restricted by age group, outcomes reported, language, or study design. Randomized controlled trials (RCTs), observational studies, review articles, and nephrology conference abstracts were included. A total of 3104 reports were retrieved. Forty-seven reports (37 primary studies and 10 reviews) were included in the review. Two RCTs and 35 observational studies included a total of 45 085 participants (9223 children and 35 862 adults).MethodData were extracted for primary IgAN and not for IgA vasculitis-associated nephritis. Findings were described with no statistical comparisons due to variations in interventions and outcome definitions.Key findingsGross hematuria was the obvious clinical difference between childhood IgAN and adult (60-88% vs 15-20%). Nephrotic syndrome was more common in children, approaching up to 44%, while <18% of adults had nephrotic syndrome. Children were biopsied sooner (6 vs 15 months) and had more inflammatory kidney lesions (mesangial hypercellularity: 41-82% vs 38-64%; endocapillary hypercellularity: 39-58% vs 17-34%). Chronic kidney lesions were more prevalent in adults (segmental sclerosis: 62-77% vs 8-51%; interstitial fibrosis/tubular atrophy: 34-37% vs 1-18%). The use of immunosuppressive therapy was higher in children (46-84% vs 35-56%). Children were started on immunosuppressive therapy sooner than adults. Adults were more likely to be optimized with renin-angiotensin system inhibitors (87-94% vs 49-75%). Children had better kidney function than adults at diagnosis (estimated glomerular filtration rate of 90-128 vs 50-88 ml/min/1.73 m2), and children also had better kidney survival, with kidney failure of 3.1% vs 13.4% at 5 years. Children had more risk alleles for IgAN and higher levels of mannose-binding lectin than adults.LimitationsMost studies were retrospective and observational, with limited data on children and disease mechanisms. Data were not pooled for analysis because of important differences in definitions and measurements of baseline characteristics and outcomes. Data from countries with established urine screening programs were different compared to countries without urine screening programs. Some observed differences may be due to practice variation and delayed diagnosis in adults (lead-time bias). Well-designed prospective studies and standardized measures for kidney function assessment and outcomes can reduce heterogeneity and improve results from reviews.ConclusionInherent differences between childhood IgAN and adult IgAN may be due to distinct disease mechanisms. Approaching childhood IgAN as a separate condition could lead to the discovery of targeted therapies and improve management during childhood and after the transition to adult care.
| S-EPMC11898040 | biostudies-literature
Project description:BackgroundTherapeutic approaches that target the gut microbiota (GM) may be helpful in the potential prevention and treatment of IgA nephropathy (IgAN). Meanwhile, relevant studies demonstrated a correlation between GM and IgAN, however, these confounding evidence cannot prove a causal relationship between GM and IgAN.MethodsBased on the data from the GM genome-wide association study (GWAS) of MiBioGen and the IgAN GWAS data from the FinnGen research. A bi-directional Mendelian randomization (MR) study was performed to explore the causal relationship between GM and IgAN. We used inverse variance weighted (IVW) method as the primary method to determine the causal relationship between exposure and outcome in our MR study. Besides, we used additional analysis (MR-Egger, weighted median) and sensitivity analysis (Cochrane's Q test, MR-Egger and MR-PRESSO) to select significant results, followed by Bayesian model averaging (MR-BMA) to test the results of MR study. Finally, a reverse MR analysis was conducted to estimate the probability of reverse causality.ResultsAt the locus-wide significance level, the results of IVW method and additional analysis showed that Genus Enterorhabdus was a protective factor for IgAN [OR: 0.456, 95% CI: 0.238-0.875, p=0.023], while Genus butyricicoccus was a risk factor for IgAN [OR: 3.471, 95% CI: 1.671-7.209, p=0.0008]. In the sensitivity analysis, no significant pleiotropy or heterogeneity of the results was found.ConclusionOur study revealed the causal relationship between GM and IgAN, and expanded the variety of bacterial taxa causally related to IgAN. These bacterial taxa could become novel biomarkers to facilitate the development of targeted therapies for IgAN, developing our understanding of the "gut-kidney axis".
| S-EPMC10185820 | biostudies-literature
Project description:BackgroundRecent data indicate the importance of gut-kidney axis in the pathogenesis of Immunoglobulin A nephropathy (IgAN). Growing evidence suggests the alterations of diversity and composition of gut microbiome among patients with IgAN, however, the details are not yet fully understood.MethodsEligible studies comparing the gut microbiome between patients with IgAN and non-IgAN individuals were systematically searched from PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, and ClinicalTrials.gov. The primary outcomes were alpha- and beta-diversity, and the differences in gut microbiota composition between patients with IgAN and non-IgAN persons. Qualitative analysis and meta-analysis were performed according to available data.ResultsEleven cross-sectional studies, including 409 patients with IgAN and 243 healthy controls, were enrolled. No significant differences in the diversity and enrichment of gut bacteria were found between IgAN and healthy individuals, whereas the beta-diversity consistently showed significant microbial dissimilarities among the two groups. Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia were the dominant phyla, however, no significant differences were found between IgAN patients and healthy controls at the phylum level. The genera, Streptococcus and Paraprevotella showed a higher proportion in patients with IgAN compared to healthy individuals, whereas Fusicatenibacter showed a lower abundance according to meta-analysis. Qualitative analyses suggested that Escherichia-Shigella might be increased in IgAN patients; the genera, Clostridium, Prevotella 9,and Roseburia, members of Ruminococcaceae and Lachnospiraceae families, were likely to have decreased abundances in patients with IgAN compared to healthy individuals.ConclusionGut microbiota dysbiosis was demonstrated in IgAN, which might be involved in the pathogenesis of IgAN. Further studies are needed to confirm the findings of this study, due to the substantial heterogeneity.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier PROSPERO (CRD42022304034).
| S-EPMC9152155 | biostudies-literature