RESUMEN
BACKGROUND: IgA 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. METHODS: In 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. RESULTS: We 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. CONCLUSIONS: This 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.
Asunto(s)
Microbioma Gastrointestinal , Glomerulonefritis por IGA , Humanos , Glomerulonefritis por IGA/microbiología , Estudios Transversales , Masculino , Femenino , Adulto , Persona de Mediana Edad , ARN Ribosómico 16S/genética , Heces/microbiología , Aprendizaje Automático , Estudios de Casos y Controles , Bacterias/aislamiento & purificación , Bacterias/clasificación , Bacterias/genética , Microbiota , Adulto JovenRESUMEN
OBJECTIVE: The aim of this study was to investigate the characteristics and related functional pathways of the gut microbiota in patients with IgA nephropathy (IgAN) through metagenomic sequencing technology. METHODS: We enrolled individuals with primary IgAN, including patients with normal and abnormal renal function. Additionally, we recruited healthy volunteers as the healthy control group. Stool samples were collected, and species and functional annotation were performed through fecal metagenome sequencing. We employed linear discriminant analysis effect size (LEfSe) analysis to identify significantly different bacterial microbiota and functional pathways. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was used to annotate microbiota functions, and redundancy analysis (RDA) was performed to analyze the factors affecting the composition and distribution of the gut microbiota. RESULTS: LEfSe analysis revealed differences in the gut microbiota between IgAN patients and healthy controls. The characteristic microorganisms in the IgAN group were classified as Escherichia coli, with a significantly greater abundance than that in the healthy control group (p < 0.05). The characteristic microorganisms in the IgAN group with abnormal renal function were identified as Enterococcaceae, Moraxella, Moraxella, and Acinetobacter. KEGG functional analysis demonstrated that the functional pathways of the microbiota that differed between IgAN patients and healthy controls were related primarily to bile acid metabolism. CONCLUSIONS: The status of the gut microbiota is closely associated not only with the onset of IgAN but also with the renal function of IgAN patients. The characteristic gut microbiota may serve as a promising diagnostic biomarker and therapeutic target for IgAN.
Asunto(s)
Heces , Microbioma Gastrointestinal , Glomerulonefritis por IGA , Metagenómica , Humanos , Glomerulonefritis por IGA/microbiología , Microbioma Gastrointestinal/genética , Masculino , Femenino , Adulto , Heces/microbiología , Metagenómica/métodos , Estudios de Casos y Controles , Persona de Mediana Edad , Moraxella/aislamiento & purificación , Moraxella/genética , Escherichia coli/aislamiento & purificación , Escherichia coli/genética , Acinetobacter/aislamiento & purificación , Acinetobacter/genética , Metagenoma , Adulto JovenRESUMEN
BACKGROUND: In August 2023, our hospital confirmed a case of IgA nephropathy complicated with pulmonary infection by Mycobacterium abscess. The patient sought medical attention at our hospital due to "gross hematuria for 10 years, recurrence for 10 days, coughing and sputum production". The patient had pulmonary tuberculosis 15 years ago and had been cured. He had bronchiectasis for 10 years. METHODS: Chest CT, fiberoptic bronchoscopy examination, urine routine (urine analysis + sediment quantification), urine trace protein measurement//urine creatinine (random urine), urine protein quantification (24-hour urine), antinuclear antibody measurement (ANA), sputum culture, alveolar lavage fluid bacterial culture, alveolar lavage fluid acid fast staining, and alveolar lavage fluid mNGS. RESULTS: Chest CT: Cystic dilation of bronchi in both lungs, mainly in the lower lungs, with visible phlegm clots inside. Fibrobronchoscopy: A large amount of white foam like secretions can be seen in the lumens of the middle lobe of the right lung and the lower lobes of both lungs. Urinary routine (urine analysis + sediment quantification): protein+↑, occult blood+++. Urine Microprotein Determination//Urine Creatinine (Random Urine): Microalbumin 156.00 mg/L, Urine mALB/Urine Creatinine 132.73 mg/g; Quantitative determination of urine protein (24-hour urine): total protein 0.93 g/24-hour urine; Antinuclear antibody assay (ANA): weakly positive; Sputum bacterial culture: negative; Bacterial culture of bronchoalveolar lavage fluid: Mycobacterium abscess++, NGS in bronchoalveolar lavage fluid: Mycobacterium abscess. Clinical treatment plan: 0.25 g of azithromycin qd po+ 0.4 g of amikacin sulfate qd ivgtt+ 1 g cefmetazole sodium q12hours ivgtt. After 10 days of treatment, the patient improved and was discharged. CONCLUSIONS: This article reports a case of IgA nephropathy complicated with pulmonary abscess mycobacterial infection. Mycobacterium abscess was quickly and accurately identified by mNGS. Reasonable treatment measures were adopted clinically. The patient improved and was discharged. This study has important reference significance for the clinical diagnosis and treatment of Mycobacterium abscess infection. In addition, mNGS, as a novel detection method, has considerable prospects for rapid diagnosis of pathogens.
Asunto(s)
Glomerulonefritis por IGA , Humanos , Masculino , Glomerulonefritis por IGA/complicaciones , Glomerulonefritis por IGA/diagnóstico , Glomerulonefritis por IGA/microbiología , Infecciones por Mycobacterium no Tuberculosas/diagnóstico , Infecciones por Mycobacterium no Tuberculosas/complicaciones , Infecciones por Mycobacterium no Tuberculosas/microbiología , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Mycobacterium abscessus/aislamiento & purificación , Antibacterianos/uso terapéutico , Persona de Mediana EdadRESUMEN
Introduction: Galactose-deficient IgA1 (GdIgA1) is critical in the formation of immunodeposits in IgA nephropathy (IgAN), whereas the origin of GdIgA1 is unknown. We focused on the immune response to fecal microbiota in patients with IgAN. Methods: By running 16S ribosomal RNA gene sequencing, we compared IgAN samples to the control samples from household-matched or non-related individuals. Levels of plasma GdIgA1 and poly-IgA complexes were measured, and candidate microbes that can either incite IgA-directed antibody response or degrade IgA through specific IgA protease activities were identified. Results: The IgAN group showed a distinct composition of fecal microbiota as compared to healthy controls. Particularly, high abundance of Escherichia-Shigella was associated with the disease group based on analyses using receiver operating characteristic (area under curve, 0.837; 95% CI, 0.738-0.914), principle coordinates, and the linear discriminant analysis effect size algorithm (linear discriminant analysis score, 4.56; p < 0.001). Accordingly, the bacterial levels directly correlated with high titers of plasma GdIgA1(r = 0.36, p < 0.001), and patients had higher IgA1 against stx2(2.88 ± 0.46 IU/mL vs. 1.34 ± 0.35 IU/mL, p = 0.03), the main antigen of Escherichia-Shigella. Conversely, the healthy controls showed relatively higher abundance of the commensal bacteria that produce IgA-degrading proteases. Particularly, the abundance of some intestinal bacteria expressing IgA proteases showed an inverse correlation with the levels of plasma GdIgA1 in IgAN. Conclusion: Our data suggest that mucosal IgA production, including those of GdIgA1, is potentially linked to the humoral response to gut Escherichia-Shigella as one of the sources of plasma GdIgA1. Conversely, the IgA protease-producing microbiota in the gut are suppressed in patients with IgAN.
Asunto(s)
Galactosa , Microbioma Gastrointestinal , Glomerulonefritis por IGA , Inmunidad Humoral , Inmunoglobulina A , Glomerulonefritis por IGA/inmunología , Glomerulonefritis por IGA/microbiología , Humanos , Microbioma Gastrointestinal/inmunología , Inmunoglobulina A/inmunología , Inmunoglobulina A/sangre , Masculino , Femenino , Adulto , Heces/microbiología , Persona de Mediana Edad , ARN Ribosómico 16S/genéticaRESUMEN
IgA nephropathy (IgAN) is one of the most common primary glomerulonephritis, and serum Helicobacter pylori (H. pylori) antibody levels are increased in patients with IgA N, but the role of H. pylori infection in the pathogenesis of IgAN is unclear. In this study, we investigated whether there is a causal relationship and reverse causality between IgAN and H. pylori infection by using a bidirectional two-sample Mendelian randomization (MR) analysis. This study was estimated using inverse variance weighted (IVW), MR-Egger and weighted median methods, with the IVW method having the strongest statistical efficacy. Seven common serum H. pylori antibodies were selected as exposure factors for positive MR analysis. The results showed that there was no evidence of a causal relationship between H. pylori infection and IgAN. Reverse MR analysis showed that there was also no evidence that the occurrence of IgAN leads to an increased risk of H. pylori infection.
Asunto(s)
Glomerulonefritis por IGA , Infecciones por Helicobacter , Helicobacter pylori , Análisis de la Aleatorización Mendeliana , Humanos , Infecciones por Helicobacter/complicaciones , Glomerulonefritis por IGA/microbiología , Glomerulonefritis por IGA/genética , Glomerulonefritis por IGA/sangre , Helicobacter pylori/aislamiento & purificación , Anticuerpos Antibacterianos/sangre , Factores de RiesgoRESUMEN
IgA nephropathy, presently recognized as the foremost primary glomerular disorder, emerges as a principal contributor to renal failure globally, with its pathogenesis yet to be fully elucidated. Extensive research has highlighted the critical role of gut microbiome in the onset and progression of IgA nephropathy, underscoring its importance in accurately delineating the disease's etiology. For example, gut microbiome dysbacteriosis can lead to the production of nephritogenic IgA1 antibodies, which form immune complexes that deposit in the kidneys, causing inflammation and damage. The gut microbiome, a source of numerous bioactive compounds, interacts with the host and plays a regulatory role in gut-immune axis modulation, earning it the moniker of the "second brain." Recent investigations have particularly emphasized a significant correlation between IgA nephropathy and gut microbiome dysbacteriosis. This article offers a detailed overview of the pathogenic mechanisms of IgA nephropathy, specifically focusing on elucidating how alterations in the gut microbiome are associated with anomalies in the intestinal mucosal system in IgA nephropathy. Additionally, it describes the possible influence of gut microbiome on recurrent IgA nephropathy following kidney transplantation. Furthermore, it compiles potential therapeutic interventions, offering both theoretical and practical foundations for the management of IgA nephropathy. Lastly, the challenges currently faced in the therapeutic approaches to IgA nephropathy are discussed.
Asunto(s)
Disbiosis , Microbioma Gastrointestinal , Glomerulonefritis por IGA , Inmunidad Mucosa , Glomerulonefritis por IGA/inmunología , Glomerulonefritis por IGA/microbiología , Humanos , Microbioma Gastrointestinal/inmunología , Disbiosis/inmunología , Disbiosis/complicaciones , Inmunidad Mucosa/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Trasplante de RiñónRESUMEN
IgA nephropathy (IgAN) has been considered to have a relationship with infection in the tonsil, because IgAN patients often manifest macro hematuria just after tonsillitis. In terms of oral-area infection, the red complex of periodontal bacteria (Porphyromonas gingivalis (P. gingivalis), Treponema denticol (T. denticola) and Tannerella forsythia (T. forsythia)) is important, but the relationship between these bacteria and IgAN remains unknown. In this study, the prevalence of the red complex of periodontal bacteria in tonsil was compared between IgAN and tonsillitis patients. The pathogenicity of IgAN induced by P. gingivalis was confirmed by the mice model treated with this bacterium. The prevalence of P. gingivalis and T. forsythia in IgAN patients was significantly higher than that in tonsillitis patients (p < 0.001 and p < 0.05, respectively). A total of 92% of tonsillitis patients were free from red complex bacteria, while only 48% of IgAN patients had any of these bacteria. Nasal administration of P. gingivalis in mice caused mesangial proliferation (p < 0.05 at days 28a nd 42; p < 0.01 at days 14 and 56) and IgA deposition (p < 0.001 at day 42 and 56 after administration). Scanning-electron-microscopic observation revealed that a high-density Electron-Dense Deposit was widely distributed in the mesangial region in the mice kidneys treated with P. gingivalis. These findings suggest that P. gingivalis is involved in the pathogenesis of IgAN.
Asunto(s)
Glomerulonefritis por IGA/patología , Inmunoglobulina A/metabolismo , Porphyromonas gingivalis/patogenicidad , Adulto , Animales , ADN Bacteriano/análisis , ADN Bacteriano/metabolismo , Modelos Animales de Enfermedad , Femenino , Glomerulonefritis por IGA/microbiología , Humanos , Riñón/patología , Masculino , Ratones , Persona de Mediana Edad , Porphyromonas gingivalis/genética , Porphyromonas gingivalis/aislamiento & purificación , Tannerella forsythia/genética , Tannerella forsythia/aislamiento & purificación , Tannerella forsythia/patogenicidad , Tonsilitis/microbiología , Tonsilitis/patología , Adulto JovenRESUMEN
Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis. Several observations suggest that gut microbiota could be implicated in IgAN pathophysiology. Aiming at exploring whether microbiota modulation is able to influence disease outcome, we performed fecal microbiota transplantation (FMT) from healthy controls (HC-sbjs), non-progressor (NP-pts) and progressor (P-pts) IgAN patients to antibiotic-treated humanized IgAN mice (α1KI-CD89Tg), by oral gavage. FMT was able to modulate renal phenotype and inflammation. On one hand, the microbiota from P-pts was able to induce an increase of serum BAFF and galactose deficient-IgA1 levels and a decrease of CD89 cell surface expression on blood CD11b+ cells which was associated with soluble CD89 and IgA1 mesangial deposits. On the other hand, the microbiota from HC-sbjs was able to induce a reduction of albuminuria immediately after gavage, an increased cell surface expression of CD89 on blood CD11b+ cells and a decreased expression of KC chemokine in kidney. Higher serum BAFF levels were found in mice subjected to FMT from IgAN patients. The main bacterial phyla composition and volatile organic compounds profile significantly differed in mouse gut microbiota. Microbiota modulation by FMT influences IgAN phenotype opening new avenues for therapeutic approaches in IgAN.
Asunto(s)
Bacterias/metabolismo , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Glomerulonefritis por IGA/terapia , Riñón/microbiología , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Factor Activador de Células B/sangre , Estudios de Casos y Controles , Modelos Animales de Enfermedad , Disbiosis , Glomerulonefritis por IGA/inmunología , Glomerulonefritis por IGA/metabolismo , Glomerulonefritis por IGA/microbiología , Humanos , Inmunoglobulina A/genética , Inmunoglobulina A/metabolismo , Riñón/inmunología , Riñón/metabolismo , Masculino , Ratones Transgénicos , Fenotipo , Receptores Fc/genética , Receptores Fc/metabolismo , Compuestos Orgánicos Volátiles/metabolismoRESUMEN
BACKGROUND: The clinicopathological and prognostic features of IgA-dominant postinfectious glomerulonephritis and its difference from the primary IgA nephropathy remains to be investigated. METHODS: The clinical and pathological data of 6542 patients who underwent renal biopsy from 2009 to 2020 in our hospital were reviewed and 50 patients who met the selection criteria of IgA-dominant postinfectious glomerulonephritis were enrolled to conduct a retrospective and observational single-center study. The selection criteria were: meet the characteristics of IgA dominance or codominance in immunofluorescence, and conform to 3 of the following 5 criteria: 1.Clinical or laboratory evidence show that there is infection before or at the onset of glomerulonephritis; 2.The level of serum complement decreased; 3.Renal pathology is consistent with endocapillary proliferative glomerulonephritis; 4. Glomerular immunofluorescence staining showed complement C3 dominance or codominance; 5. Hump-like subepithelial immune complex deposition was observed under electron microscopy. According to age, sex, renal function (estimated glomerular filtration rate, eGFR) and follow-up time, the control group was constructed with 1:3 matched cases of primary IgA nephropathy. The clinicopathological and prognostic differences between the two groups were analyzed. RESULTS: The most common histological pattern of IgA-dominant postinfectious glomerulonephritis was acute endocapillary proliferative glomerulonephritis and exudative glomerulonephritis. Immunofluorescence showed mainly IgA deposition or IgA deposition only, mainly deposited in the mesangial area (deposition rate 100 %), with typical C3 high-intensity staining (intensity++~+++), mainly deposited in the mesangial area (deposition rate 92.0 %). The fluorescence intensity of kappa is usually not weaker than lambda. The probability of the appearance of typical hump-like electron deposition under electron microscopy is low. Compared to primary IgA nephropathy, patients with IgA-dominant postinfectious glomerulonephritis had higher proportion of crescents (p = 0. 005) and endocapillary hypercellularity (p < 0.001) in pathological manifestations. Using serum creatinine level doubled of the baseline or reached end-stage renal disease as the endpoint, the prognosis of IgA-dominant postinfectious glomerulonephritis patients was worse than that of primary IgA nephropathy patients (p = 0.013). CONCLUSIONS: The clinicopathological features of patients with IgA-dominant postinfectious glomerulonephritis was different from that of primary IgA nephropathy, and the prognosis was worse.
Asunto(s)
Glomerulonefritis por IGA/microbiología , Glomerulonefritis por IGA/patología , Infecciones/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Complejo Antígeno-Anticuerpo , Complemento C3/análisis , Creatinina/sangre , Femenino , Técnica del Anticuerpo Fluorescente , Estudios de Seguimiento , Glomerulonefritis por IGA/inmunología , Humanos , Inmunoglobulina A/análisis , Masculino , Microscopía Electrónica , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: IgA nephropathy(IgAN)) is the common pathological type of glomerular diseases. The role of gut microbiota in mediating "gut-IgA nephropathy" has not received sufficient attention in the previous studies. The purpose of this study was to investigate the changes of fecal short-chain fatty acids(SCFAs), a metabolite of the intestinal microbiota, in patients with IgAN and its correlation with intestinal flora and clinical indicators, and to further investigate the role of the gut-renal axis in IgAN. METHODS: There were 29 patients with IgAN and 29 normal control subjects recruited from January 2018 to May 2018. The fresh feces were collected. The fecal SCFAs were measured by gas chromatography/mass spectrometry and gut microbiota was analysed by16S rDNA sequences, followed by estimation of α- and ß-diversity. Correlation analysis was performed using the spearman's correlation test between SCFAs and gut microbiota. RESULTS: The levels of acetic acid, propionic acid, butyric acid, isobutyric acid and caproic acid in the IgAN patients were significantly reduced compared with control group(P < 0.05). Butyric acid(r=-0.336, P = 0.010) and isobutyric acid(r=-0.298, P = 0.022) were negatively correlated with urea acid; butyric acid(r=-0.316, P = 0.016) was negatively correlated with urea nitrogen; caproic acid(r=-0.415,P = 0.025) showed negative correlation with 24-h urine protein level.Exemplified by the results of α-diversity and ß-diversity, the intestinal flora of IgAN patients was significantly different from that of the control group. Acetic acid was positively associated with c_Clostridia(r = 0.357, P = 0.008), o_Clostridiales(r = 0.357, P = 0.008) and g_Eubacterium_coprostanoligenes_group(r = 0.283, P = 0.036). Butyric acid was positively associated with g_Alistipes (r = 0.278, P = 0.040). The relative abundance of those were significantly decreased in IgAN group compared to control group. CONCLUSIONS: The levels of fecal SCFAs in the IgAN patients were reduced, and correlated with clinical parameters and gut microbiota, which may be involved in the pathogenesis of IgAN, and this finding may provide a new therapeutic approach.
Asunto(s)
Disbiosis/etiología , Ácidos Grasos Volátiles/análisis , Heces/química , Microbioma Gastrointestinal , Glomerulonefritis por IGA/complicaciones , Adulto , Biomarcadores/análisis , Análisis Químico de la Sangre , Estudios de Casos y Controles , Heces/microbiología , Femenino , Glomerulonefritis por IGA/microbiología , Humanos , MasculinoRESUMEN
IgA nephropathy is one of the leading causes of chronic kidney disease in Japan. Since the origin and mechanisms by which IgA nephropathy develops currently remain unclear, a confirmed disease diagnosis is currently only possible by highly invasive renal biopsy. With the background of the salivary microbiome as a rich source of biomarkers for systemic diseases, we herein primarily aimed to investigate the salivary microbiome as a tool for the non-invasive diagnosis of IgA nephropathy. In a comparison of salivary microbiome profiles using 16S rRNA amplicon sequencing, significant differences were observed in microbial diversity and richness between IgA nephropathy patients and healthy controls. Furthermore, recent studies reported that patients with IgA nephropathy are more likely to develop inflammatory bowel diseases and that chronic inflammation of the tonsils triggered the recurrence of IgA nephropathy. Therefore, we compared the salivary microbiome of IgA nephropathy patients with chronic tonsillitis and ulcerative colitis patients. By combining the genera selected by the random forest algorithm, we were able to distinguish IgA nephropathy from healthy controls with an area under the curve (AUC) of 0.90, from the ulcerative colitis group with AUC of 0.88, and from the chronic tonsillitis group with AUC of 0.70. Additionally, the genus Neisseria was common among the selected genera that facilitated the separation of the IgA nephropathy group from healthy controls and the chronic tonsillitis group. The present results indicate the potential of the salivary microbiome as a biomarker for the non-invasive diagnosis of IgA nephropathy.
Asunto(s)
Bacterias/aislamiento & purificación , Disbiosis/microbiología , Glomerulonefritis por IGA/microbiología , Microbiota , Saliva/microbiología , Adulto , Área Bajo la Curva , Bacterias/clasificación , Bacterias/genética , Estudios de Cohortes , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
INTRODUCTION: The alteration of the gut microbiome in the gut-kidney axis has been associated with a pro-inflammatory state and chronic kidney disease (CKD). A small-scaled Italian study has shown an association between the gut microbiome and Immunoglobulin A Nephropathy (IgAN). However, there is no data on gut microbiota in IgAN in the Asian population. This study compares the gut microbial abundance and diversity between healthy volunteers and Malaysian IgAN cohort. METHODS: A comparative cross-sectional study was conducted involving biopsy-proven IgAN patients in clinical remission with matched controls in a Malaysian tertiary centre. Demographic data, routine blood and urine results were recorded. Stool samples were collected and their DNA was extracted by 16S rRNA gene sequencing to profile their gut microbiota. RESULTS: Thirty-six IgAN patients (13 male; 23 female) with the mean age of 45.5 ± 13.4 years and median estimated glomerular filtration rate (eGFR) of 79.0 (62.1-92.2) mls/min/1.73m2 with median remission of 7 years were analysed and compared with 12 healthy controls (4 male; 8 female) with the mean age of 46.5 ± 13.5 years and eGFR of 86.5 (74.2-93.7) mls/min/1.73m2. Other demographic and laboratory parameters such as gender, ethnicity, body mass index (BMI), haemoglobin, serum urea and serum albumin were comparable between the two groups. There were no significant differences seen in the Operational Taxonomic Unit (OTU) and alpha diversity (Shannon index) between IgAN and healthy controls. Alpha diversity increased with increasing CKD stage (p = 0.025). Firmicutes/Bacteroidetes (F/B) ratio was low in both IgAN and healthy cohort. Fusobacteria phylum was significantly increased (p = 0.005) whereas Euryarchaoeota phylum was reduced (p = 0.016) in the IgAN group as compared to the control cohort. CONCLUSION: Although we found no differences in OTU and alpha diversity between IgAN in remission and control cohort, there were some differences between the two groups at phylum level.
Asunto(s)
Pueblo Asiatico , Microbioma Gastrointestinal , Glomerulonefritis por IGA/etnología , Glomerulonefritis por IGA/microbiología , Adulto , Pueblo Asiatico/genética , Estudios Transversales , Femenino , Microbioma Gastrointestinal/genética , Humanos , Malasia , Masculino , Persona de Mediana Edad , ARN Ribosómico 16S , Análisis de Secuencia de ARNRESUMEN
The mechanisms underlying immunoglobulin A nephropathy (IgAN), the most common chronic form of primary glomerulonephritis, remain poorly understood. Streptococcus mutans, a Gram-positive facultatively anaerobic oral bacterium, is a common cause of dental caries. In previous studies, S. mutans isolates that express Cnm protein on their cell surface were frequently detected in IgAN patients. In the present study, inoculation of Cnm-positive S. mutans in the oral cavities of 2-week-old specific-pathogen free Sprague-Dawley rats fed a high-sucrose diet for 32 weeks produced severe dental caries in all rats. Immunohistochemical analyses of the kidneys using IgA- and complement C3-specific antibodies revealed positive staining in the mesangial region. Scanning electron microscopy revealed a wide distribution of electron dense deposits in the mesangial region and periodic acid-Schiff staining demonstrated prominent proliferation of mesangial cells and mesangial matrix. These results suggest that IgAN-like glomerulonephritis was induced in rats with severe dental caries by Cnm-positive S. mutans.
Asunto(s)
Caries Dental/complicaciones , Caries Dental/microbiología , Glomerulonefritis por IGA/complicaciones , Glomerulonefritis por IGA/microbiología , Streptococcus mutans/fisiología , Animales , Anticuerpos/metabolismo , Placa Dental , Modelos Animales de Enfermedad , Glomerulonefritis por IGA/orina , Riñón/patología , Riñón/ultraestructura , Masculino , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis worldwide, characterized by mesangial polymeric IgA1 deposition. IgAN is believed to develop owing to aberrant mucosal immunoreaction against commensals in the tonsils. However, the exact interrelation between pathogenic IgA and mucosal microbiota in IgAN patients is unclear. METHODS: Biopsy-proven IgAN or recurrent tonsillitis (RT) patients who had undergone tonsillectomy were enrolled. We used 16S ribosomal RNA gene amplicon sequencing with a flow cytometry-based bacterial cell sorting technique) and immunoglobulin repertoire sequencing of the IgA heavy chain to characterize IgA-coated bacteria of the tonsillar microbiota (IgA-SEQ) and their corresponding IgA repertoire. Furthermore, we fractionated patient serum using gel-filtration chromatography and performed flow cytometry-based analysis of IgA binding to bacteria cultured from incised tonsils. RESULTS: Tonsillar proliferation-inducing ligand and B-cell activating factor levels were significantly higher in IgAN than in RT patients. IgA-SEQ for tonsillar microbiota revealed the preferential binding ability of IgA to Bacteroidetes in IgAN tonsils compared with those from RT patients. Expression of immunoglobulin heavy (IGH) constant alpha 1 with IGH variable 3-30 was significantly higher in IgAN than that in RT, and positively correlated with the IgA-coated enrichment score of Bacteroidetes. Serum polymeric IgA, comprising high levels of GdIgA1, exhibited considerable binding to Bacteroidetes strains cultured from the tonsils of IgAN patients. CONCLUSIONS: These findings provide evidence that aberrant mucosal immune responses to tonsillar anaerobic microbiota, primarily consisting of members of the phylum Bacteroidetes, are involved in IgAN pathophysiology.
Asunto(s)
Glomerulonefritis por IGA/complicaciones , Inmunidad Mucosa/inmunología , Microbiota , Tonsila Palatina/microbiología , Tonsilitis/complicaciones , Adulto , Femenino , Citometría de Flujo , Glomerulonefritis por IGA/microbiología , Glomerulonefritis por IGA/patología , Humanos , Masculino , Transducción de Señal , Tonsilectomía , Tonsilitis/inmunología , Tonsilitis/microbiologíaRESUMEN
Staphylococcus infection-associated glomerulonephritis (SAGN) and primary IgA nephropathy (IgAN) are separate disease entities requiring different treatment approaches. However, overlapping histologic features may cause a diagnostic dilemma. An exploratory proteomic study to identify potential distinguishing biomarkers was performed on formalin fixed paraffin embedded kidney biopsy tissue, using mass spectrometry (HPLC-MS/MS) (n = 27) and immunohistochemistry (IHC) (n = 64), on four main diagnostic groups-SAGN, primary IgAN, acute tubular necrosis (ATN) and normal kidney (baseline transplant biopsies). Spectral counts modeled as a negative binomial distribution were used for statistical comparisons and in silico pathway analysis. Analysis of variance techniques were used to compare groups and the ROC curve to evaluate classification algorithms. The glomerular proteomes of SAGN and IgAN showed remarkable similarities, except for significantly higher levels of monocyte/macrophage proteins in SAGN-mainly lysozyme and S100A9. This finding was confirmed by IHC. In contrast, the tubulointerstitial proteomes were markedly different in IgAN and SAGN, with a lower abundance of metabolic pathway proteins and a higher abundance of extracellular matrix proteins in SAGN. The stress protein transglutaminase-2 (TGM2) was also significantly higher in SAGN. IHC of differentially-expressed glomerular and tubulointerstitial proteins can be used to help discriminate between SAGN and IgAN in ambiguous cases.
Asunto(s)
Glomerulonefritis por IGA/metabolismo , Glomerulonefritis por IGA/microbiología , Inmunoglobulina A/metabolismo , Infecciones Estafilocócicas/metabolismo , Infecciones Estafilocócicas/microbiología , Adulto , Anciano , Biomarcadores/metabolismo , Biopsia/métodos , Estudios de Casos y Controles , Femenino , Proteínas de Unión al GTP/metabolismo , Tasa de Filtración Glomerular/fisiología , Glomerulonefritis por IGA/patología , Humanos , Glomérulos Renales/metabolismo , Glomérulos Renales/microbiología , Glomérulos Renales/patología , Masculino , Persona de Mediana Edad , Proteína Glutamina Gamma Glutamiltransferasa 2 , Curva ROC , Infecciones Estafilocócicas/patología , Staphylococcus/patogenicidad , Espectrometría de Masas en Tándem/métodos , Transglutaminasas/metabolismoRESUMEN
Immunoglobulin A nephropathy (IgAN) is a common glomerular disease. The pathogenesis of IgAN is associated with dysregulated intestinal mucosal immunity. However, whether gut microbial modifications play a role in IgAN remains unclear. Blood and faecal samples were collected from 52 patients with IgAN and 25 healthy controls (HCs). The gut microbiome was analysed using the 16S ribosomal RNA gene. The levels of galactose-deficient IgA1 (Gd-IgA1), soluble cluster of differentiation 14 (sCD14), lipopolysaccharide binding protein (LBP), intercellular adhesion molecule-1 (ICAM-1), tumour necrosis factor α (TNF-α), interleukin-1, and C-reactive protein were quantified. Substantial differences in the gut microbiota were identified between patients with IgAN and HCs (P < 0.05). Bacteroides and Escherichia-Shigella levels were significantly higher in patients with IgAN than in HCs, while Bifidobacterium and Blautia spp. Levels were lower. Higher proportions of Escherichia-Shigella and lower proportions of Bifidobacterium spp. were observed in patients with IgAN with high urine RBC count (≥10/HP) and proteinuria (≥1 g/24 h) levels. Correlation analysis was used to assess the association between gut microbiota and biomarkers in patients with IgAN. The results showed that Prevotella 7 levels were negatively correlated with Gd-IgA1, LBP, sCD14, ICAM-1, and TNF-α levels, while Bifidobacterium spp. Levels presented a significant inverse relationship with LBP and Gd-IgA1. Additionally, Escherichia-Shigella levels were negatively correlated with Prevotella 7. In patients with IgAN, gut modifications were characterised by an increase in the number of pathogenic bacteria and a reduction in the levels of beneficial bacteria, suggesting that the disturbance of intestinal microflora might be important in the severity of IgAN.
Asunto(s)
Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/inmunología , Glomerulonefritis por IGA/microbiología , Proteínas de Fase Aguda , Adulto , Pueblo Asiatico , Bacterias/clasificación , Bacterias/genética , Bacterias/crecimiento & desarrollo , Biomarcadores/sangre , Biomarcadores/orina , Proteína C-Reactiva/metabolismo , Proteínas Portadoras/sangre , Análisis Discriminante , Heces/microbiología , Femenino , Glomerulonefritis por IGA/sangre , Glomerulonefritis por IGA/diagnóstico , Glomerulonefritis por IGA/orina , Hematuria/microbiología , Interacciones Microbiota-Huesped/inmunología , Humanos , Inmunoglobulina A/sangre , Molécula 1 de Adhesión Intercelular/sangre , Receptores de Lipopolisacáridos/sangre , Masculino , Glicoproteínas de Membrana/sangre , Proteinuria/microbiología , ARN Ribosómico 16S , Índice de Severidad de la EnfermedadRESUMEN
Infections have been considered to play a critical role in the pathogenesis of IgA nephropathy (IgAN) because synpharyngitic hematuria is a common feature in IgAN. However, how infections participate in this process is still debated. More recent studies have also revealed that the alteration of the gut microbiome exerts a profound effect on host immune responses, contributing to the etiology or progression of autoimmunity. Considering IgA as the first line of defense against bacterial and viral antigens, this review evaluates the relationships among intestinal infections, gut microbiome, and IgA for a better understanding of the pathogenesis of IgAN. Moreover, as a prototype of IgA immunity, we provide detailed clarification of IgAN pathogenesis to shed light on other diseases in which IgA plays a role. Finally, we discuss potential therapies focusing on microbes and mucosal immune responses in IgAN.
Asunto(s)
Microbioma Gastrointestinal/inmunología , Glomerulonefritis por IGA/inmunología , Inmunidad Mucosa , Inmunoterapia/métodos , Infecciones/inmunología , Animales , Activación de Complemento/inmunología , Modelos Animales de Enfermedad , Mesangio Glomerular/inmunología , Mesangio Glomerular/patología , Glomerulonefritis por IGA/microbiología , Glomerulonefritis por IGA/patología , Glomerulonefritis por IGA/terapia , Humanos , Inmunoglobulina A/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiologíaRESUMEN
Immunoglobulin A nephropathy (IgAN) involves repeated events of gross haematuria with concurrent upper airway infections. The mucosal immune system, especially the tonsil, is considered the initial site of inflammation, although the role of the tonsillar microbiota has not been established in IgAN. In this study, we compared the tonsillar microbiota of patients with IgAN (n = 21) and other glomerular diseases (n = 36) as well as, healthy controls (n = 23) from three medical centres in Korea. The microbiota was analysed from tonsil swabs using the Illumina MiSeq system based on 16S rRNA gene. Tonsillar bacterial diversity was higher in IgAN than in other glomerular diseases, although it did not differ from that of healthy controls. Principal coordinates analysis revealed differences between the tonsillar microbiota of IgAN and both healthy and disease controls. The proportions of Rahnella, Ruminococcus_g2, and Clostridium_g21 were significantly higher in patients with IgAN than in healthy controls (corrected p < 0.05). The relative abundances of several taxa were correlated with the estimated glomerular filtration rate, blood urea nitrogen, haemoglobin, and serum albumin levels. Based on our findings, tonsillar microbiota may be associated with clinical features and possible immunologic pathogenesis of IgAN.