Modulation of the microbiota by oral antibiotics treats immunoglobulin A nephropathy in humanized mice

2018 ◽  
Vol 34 (7) ◽  
pp. 1135-1144 ◽  
Author(s):  
Jonathan M Chemouny ◽  
Patrick J Gleeson ◽  
Lilia Abbad ◽  
Gabriella Lauriero ◽  
Erwan Boedec ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Antibiotic Treatment ◽  
Bacterial Load ◽  
Immunoglobulin A ◽  
Serum Levels ◽  
Immunoglobulin A Nephropathy ◽  
Intestinal Tissue ◽  
Humanized Mouse Model ◽  
Iga Production

Abstract Background Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. IgA is mainly produced by the gut-associated lymphoid tissue (GALT). Both experimental and clinical data suggest a role of the gut microbiota in this disease. We aimed to determine if an intervention targeting the gut microbiota could impact the development of disease in a humanized mouse model of IgAN, the α1KI-CD89Tg mice. Methods Four- and 12-week old mice were divided into two groups to receive either antibiotics or vehicle control. Faecal bacterial load and proteinuria were quantified both at the beginning and at the end of the experiment, when blood, kidneys and intestinal tissue were collected. Serum mouse immunoglobulin G (mIgG) and human immunoglobulin A1 (hIgA1)-containing complexes were quantified. Renal and intestinal tissue were analysed by optical microscopy after haematoxylin and eosin colouration and immunohistochemistry with anti-hIgA and anti-mouse CD11b antibodies. Results Antibiotic treatment efficiently depleted the faecal microbiota, impaired GALT architecture and impacted mouse IgA production. However, while hIgA1 and mIgG serum levels were unchanged, the antibiotic treatment markedly prevented hIgA1 mesangial deposition, glomerular inflammation and the development of proteinuria. This was associated with a significant decrease in circulating hIgA1–mIgG complexes. Notably, final faecal bacterial load strongly correlated with critical clinical and pathophysiological features of IgAN such as proteinuria and hIgA1–mIgG complexes. In addition, treatment with broad-spectrum antibiotics reverted established disease. Conclusions These data support an essential role of the gut microbiota in the generation of mucosa-derived nephrotoxic IgA1 and in IgAN development, opening new avenues for therapeutic approaches in this disease.

scholarly journals High levels of gut-homing immunoglobulin A–positive+B lymphocytes support the pathogenic role of intestinal mucosal hyperresponsiveness in immunoglobulin A nephropathy patients

2020 ◽  
Author(s):  
Fabio Sallustio ◽  
Claudia Curci ◽  
Nada Chaoul ◽  
Giulia Fontò ◽  
Gabriella Lauriero ◽  
...  
Keyword(s):  
B Cells ◽  
B Lymphocytes ◽  
Immunoglobulin A ◽  
Serum Levels ◽  
Memory B Cells ◽  
Immunoglobulin A Nephropathy ◽  
Pathogenic Role ◽  
Significant Difference ◽  
Activated B Cells

Abstract Background Immunoglobulin A nephropathy (IgAN) is the most frequent primary glomerulonephritis. The role of the microbiota and mucosal immunity in the pathogenesis of IgAN remains a key element. To date, the hypothetical relationship between commensal bacteria, elevated tumour necrosis factor (TNF) superfamily member 13 [also known as B-cell activating factor (BAFF)] levels, perturbed homoeostasis of intestinal-activated B cells and intestinal IgA class switch has not been clearly shown in IgAN patients. Methods We studied the intestinal–renal axis connections, analysing levels of BAFF, TNF ligand superfamily member 13 (APRIL) and intestinal-activated B cells in IgAN patients, healthy subjects (HSs) and patients with non-IgA glomerulonephritides. Results IgAN patients had increased serum levels of BAFF cytokine, correlating with higher amounts of five specific microbiota metabolites, and high APRIL cytokine serum levels. We also found that subjects with IgAN have a higher level of circulating gut-homing (CCR9+ β7 integrin+) regultory B cells, memory B cells and IgA+ memory B cells compared with HSs. Finally, we found that IgAN patients had high levels of both total plasmablasts (PBs) and intestinal-homing PBs. Interestingly, PBs significantly increased in IgAN but not in patients with other glomerulonephritides. Conclusions Our results demonstrate a significant difference in the amount of intestinal-activated B lymphocytes between IgAN patients and HSs, confirming the hypothesis of the pathogenic role of intestinal mucosal hyperresponsiveness in IgAN. The intestinal–renal axis plays a crucial role in IgAN and several factors may contribute to its complex pathogenesis and provide an important area of research for novel targeted therapies to modulate progression of the disease.

scholarly journals Integrated Fecal Microbiome and Serum Metabolomics Analysis Reveals Abnormal Changes in Rats with Immunoglobulin A Nephropathy and the Intervention Effect of Zhen Wu Tang

2021 ◽  
Vol 11 ◽  
Author(s):  
Jicheng Li ◽  
Yiwen Cao ◽  
Ruirui Lu ◽  
Honglian Li ◽  
Yu Pang ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Renal Disease ◽  
Intestinal Microbiota ◽  
Renal Damage ◽  
Immunoglobulin A ◽  
Metabolic Phenotype ◽  
Immunoglobulin A Nephropathy ◽  
Metabolic Phenotypes ◽  
Potential Relationship ◽  
Rdna Sequencing

Immunoglobulin A nephropathy (IgAN), an autoimmune renal disease with complicated pathogenesis, is one of the principal reasons for end-stage renal disease in the clinic. Evidence has linked apparent alterations in the components of the microbiome and metabolome to renal disease in rats. However, thus far, there is insufficient evidence that supports the potential relationship between gut microbiome, circulating metabolites, and IgAN. This study was designed to probe the effects of IgAN on intestinal microecology and metabolic phenotypes and to understand the possible underlying mechanisms. Fecal and serum samples were collected from IgAN rats. Composition of the gut microbiota and biochemical changes in the metabolites was analyzed using 16S rDNA sequencing and untargeted metabolomics. The IgAN rats exhibited renal insufficiency and increased concentration of 24-h urine protein, in addition to deposition of IgA and IgG immune complexes in the kidney tissues. There was a disturbance in the balance of gut microbiota in IgAN rats, which was remarkably associated with renal damage. Marked changes in microbial structure and function were accompanied by apparent alterations in 1,403 serum metabolites, associated with the disorder of energy, carbohydrate, and nucleotide metabolisms. Administration of Zhen Wu Tang ameliorated microbial dysbiosis and attenuated the renal damage. Besides, treatment with Zhen Wu Tang modulated the metabolic phenotype perturbation in case of gut microbiota dysbiosis in IgAN rats. In conclusion, these findings provided a comprehensive understanding of the potential relationship between the intestinal microbiota and metabolic phenotypes in rats with IgAN. Elucidation of the intestinal microbiota composition and metabolic signature alterations could identify predictive biomarkers for disease diagnosis and progression, which might contribute to providing therapeutic strategies for IgAN.

scholarly journals Probiotics Stimulate Production of Natural Antibodies in Chickens

2006 ◽  
Vol 13 (9) ◽  
pp. 975-980 ◽  
Author(s):  
Hamid R. Haghighi ◽  
Jianhua Gong ◽  
Carlton L. Gyles ◽  
M. Anthony Hayes ◽  
Huaijun Zhou ◽  
...  
Keyword(s):  
Immune Response ◽  
Immunoglobulin A ◽  
Serum Levels ◽  
Natural Antibodies ◽  
Commensal Bacteria ◽  
Lymphoid Tissues ◽  
Alpha Toxin ◽  
Igg Antibodies ◽  
Significant Difference

ABSTRACT Commensal bacteria in the intestine play an important role in the development of immune response. These bacteria interact with cells of the gut-associated lymphoid tissues (GALT). Among cells of the GALT, B-1 cells are of note. These cells are involved in the production of natural antibodies. In the present study, we determined whether manipulation of the intestinal microbiota by administration of probiotics, which we had previously shown to enhance specific systemic antibody response, could affect the development of natural antibodies in the intestines and sera of chickens. Our findings demonstrate that when 1-day-old chicks were treated with probiotics, serum and intestinal antibodies reactive to tetanus toxoid (TT) and Clostridium perfringens alpha-toxin in addition to intestinal immunoglobulin A (IgA) reactive to bovine serum albumin (BSA) were increased in unimmunized chickens. Moreover, IgG antibodies reactive to TT were increased in the intestines of probiotic-treated chickens compared to those of untreated controls. In serum, IgG and IgM reactive to TT and alpha-toxin were increased in probiotic-treated, unimmunized chickens compared to levels in untreated controls. However, no significant difference in serum levels of IgM or IgG response to BSA was observed. These results are suggestive of the induction of natural antibodies in probiotic-treated, unimmunized chickens. Elucidating the role of these antibodies in maintenance of the chicken immune system homeostasis and immune response to pathogens requires further investigation.

scholarly journals Antepartum Antibiotic Treatment Increases Offspring Susceptibility to Experimental Colitis: A Role of the Gut Microbiota

PLoS ONE ◽  
2015 ◽  
Vol 10 (11) ◽  
pp. e0142536 ◽  
Author(s):  
Peris Mumbi Munyaka ◽  
N. Eissa ◽  
Charles Noah Bernstein ◽  
Ehsan Khafipour ◽  
Jean-Eric Ghia
Keyword(s):  
Gut Microbiota ◽  
Antibiotic Treatment ◽  
Experimental Colitis

Role of Tenascin in Human Immunoglobulin a Nephropathy

1997 ◽  
Vol 25 (5) ◽  
pp. 247-254 ◽  
Author(s):  
T Masaki ◽  
N Yorioka ◽  
Y Taniguchi ◽  
T Ogawa ◽  
T Naito ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Steroid Therapy ◽  
Activity Index ◽  
Immunoglobulin A ◽  
Human Immunoglobulin ◽  
Immunoglobulin A Nephropathy ◽  
Chronicity Index

Tenascin is a component of the extracellular matrix that responds rapidly to inflammation or injury. The activity index and chronicity index of immunoglobulin A nephropathy are mainly used to decide whether or not steroid therapy is indicated, but are sometimes difficult to evaluate histologically. We investigated whether tenascin staining of the glomeruli was an indicator of the activity or chronicity indices in patients with immunoglobulin A nephropathy. Tenascin staining was evaluated immunohistochemically in 38 renal specimens, including 32 from patients with immunoglobulin A nephropathy and six from control kidneys, and the extent of staining was scored. Tenascin staining was correlated with the chronicity index ( r = 0.643, P < 0.0003) but not with the activity index.

scholarly journals The mucosal immune system and IgA nephropathy

2021 ◽  
Author(s):  
Loreto Gesualdo ◽  
Vincenzo Di Leo ◽  
Rosanna Coppo
Keyword(s):  
Immune Response ◽  
Mucosal Immunity ◽  
Lymphoid Tissue ◽  
Genetic Factors ◽  
Immunoglobulin A ◽  
Mucosal Immune Response ◽  
Immunoglobulin A Nephropathy ◽  
Food Antigen ◽  
The Relationship

Abstract The precise pathogenesis of immunoglobulin A nephropathy (IgAN) is still not clearly established but emerging evidence confirms a pivotal role for mucosal immunity. This review focuses on the key role of mucosa-associated lymphoid tissue (MALT) in promoting the onset of the disease, underlying the relationship among microbiota, genetic factors, food antigen, infections, and mucosal immune response. Finally, we evaluate potential therapies targeting microbes and mucosa hyperresponsiveness in IgAN patients.

A Comparative Study of the Gut Microbiota Associated with Immunoglobulin A Nephropathy and Membranous Nephropathy

2020 ◽  
Author(s):  
shiren sun ◽  
Ruijuan Dong ◽  
Ming Bai ◽  
Jin Zhao ◽  
Di Wang ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Membranous Nephropathy ◽  
Kidney Biopsy ◽  
Immunoglobulin A ◽  
Amplicon Sequencing ◽  
Healthy Controls ◽  
Immunoglobulin A Nephropathy ◽  
Positive Correlation ◽  
16S Rdna Amplicon Sequencing ◽  
The Oxford Classification

Abstract Background The pathogenesis of immunoglobulin A nephropathy (IgAN) and membranous nephropathy (MN) is characterized by immune dysregulation, which is related to gut dysbiosis. The aim of the study was to compare the gut microbiota of patients with IgAN and MN versus healthy controls. We used 16S rDNA amplicon sequencing to investigate the bacterial communities of 44 patients with kidney biopsy-proven IgAN, 40 patients with kidney biopsy-proven MN, and 30 matched healthy controls (HC). Results The abundance of Escherichia-Shigella and Defluviitaleaceae_incertae_sedis were significantly higher in IgAN than in HC, whereas lower abundances were observed for Roseburia, Lachnospiraceae_ unclassified, Clostridium_sensu_stricto_1, and Fusobacterium . Furthermore, the abundance of Escherichia-Shigella, Peptostreptococcaceae_incertae_sedis , Streptococcus, and Enterobacteriaceae_ unclassified increased, while that of Lachnospira, Lachnospiraceae_ unclassified, Clostridium_sensu_stricto_1, and Veillonella decreased in MN. The abundance of Megasphaera and Bilophila was higher, whereas that of Megamonas, Veillonella, Klebsiella, and Streptococcus was lower in patients with IgAN than in those with MN. Analysis of the correlations showed that in the IgAN group, Prevotella was positively correlated, while Klebsiella , Citrobacter, and Fusobacterium were negatively correlated with the level of serum albumin. Positive correlation also existed between Bilophila and Crescents in the Oxford classification of IgAN. In the MN group, negative correlation was observed between Escherichia-Shigella and proteinuria, Bacteroides and Klebsiella showed positive correlation with the MN stage. Conclusions Patients with IgAN and MN exhibited gut microbial signatures distinct from healthy controls. Our study suggests the potential of gut microbiota as specific biomarker and contributor in the pathogenesis of IgAN and MN.

scholarly journals Monoclonal immunoglobulin A antibody directed against serotype-specific epitope of Shigella flexneri lipopolysaccharide protects against murine experimental shigellosis.

1995 ◽  
Vol 182 (3) ◽  
pp. 769-778 ◽  
Author(s):  
A Phalipon ◽  
M Kaufmann ◽  
P Michetti ◽  
J M Cavaillon ◽  
M Huerre ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Shigella Flexneri ◽  
Bacterial Load ◽  
Immunoglobulin A ◽  
Mucosal Immune Response ◽  
Hybridoma Cells ◽  
Infection Model ◽  
Local Concentration ◽  
Iga Antibody

To determine the role of humoral mucosal immune response in protection against shigellosis, we have obtained a monoclonal dimeric immunoglobulin A (IgA) antibody specific for Shigella flexneri serotype 5a lipopolysaccharide (mIgA) and used a murine pulmonary infection model that mimics the lesions occurring in natural intestinal infection. Adult BALB/c mice challenged with 10(7) S. flexneri organisms developed a rapid inflammatory response characterized by polymorphonuclear cell infiltration around and within the bronchi and strong systemic interleukin 6 response. Implantation of hybridoma cells in the back of mice, resulting in the development of a myeloma tumor producing mIgA in the serum and subsequently secretory mIgA in local secretions, or direct intranasal administration of these antibodies, protected the animals against subsequent intranasal challenge with S. flexneri serotype 5a. Absence of histopathological lesion and significant decrease in bacterial load of the lungs and of systemic interleukin 6 response were the three major criteria of protection. This protection was shown to be serotype-specific and dependent on local concentration of mIgA. These data demonstrate that mucosal antibodies directed against a single polysaccharidic surface epitope of Shigella can protect against the disease.

Sign in / Sign up

Export Citation Format

Share Document