RESUMEN
Immunoglobulin A (IgA) is acknowledged to play a role in the defence of the mucosal barrier by coating microorganisms. Surprisingly, IgA-deficient humans exhibit few infection-related complications, raising the question if the more specific IgG may help IgM in compensating for the lack of IgA. Here we employ a cohort of IgA-deficient humans, each paired with IgA-sufficient household members, to investigate multi-Ig bacterial coating. In IgA-deficient humans, IgM alone, and together with IgG, recapitulate coating of most bacterial families, despite an overall 3.6-fold lower Ig-coating. Bacterial IgG coating is dominated by IgG1 and IgG4. Single-IgG2 bacterial coating is sparse and linked to enhanced Escherichia coli load and TNF-α. Although single-IgG2 coating is 1.6-fold more prevalent in IgA deficiency than in healthy controls, it is 2-fold less prevalent than in inflammatory bowel disease. Altogether we demonstrate that IgG assists IgM in coating of most bacterial families in the absence of IgA and identify single-IgG2 bacterial coating as an inflammatory marker.
Asunto(s)
Deficiencia de IgA , Humanos , Bacterias , Escherichia coli , Deficiencia de IgA/inmunología , Deficiencia de IgA/microbiología , Inmunoglobulina A , Inmunoglobulina G , Inmunoglobulina MRESUMEN
Immunoglobulin A (IgA) is the dominant antibody found in our mucosal secretions and has long been recognized to play an important role in protecting our epithelium from pathogens. Recently, IgA has been shown to be involved in gut homeostatic regulation by 'recognizing' and shaping our commensal microbes. Paradoxically, yet selective IgA-deficiency is often described as asymptomatic and there is a paucity of studies only focused on the mice and human gut microbiome context fully ignoring other niches of our body and our commensal viruses. Here, we used as a model the human oral cavity and employed a holistic view and studied the impact of IgA deficiency and also common variable IgA and IgM immunodeficiencies (CVID), on both the human virome and microbiome. Unexpectedly, metagenomic and experimental data in human IgA deficiency and CVID indicate minimal-moderate changes in microbiome and virome composition compared to healthy control group and point out to a rather functional, resilient oral commensal viruses and microbes. However, a significant depletion (two fold) of bacterial cells (p-value < 0.01) and viruses was observed in IgA-deficiency. Our results demonstrate that, within the limits of our cohort, IgA role is not critical for maintaining a rather functional salivary microbiome and suggest that IgA is not a major influence on the composition of abundant commensal microbes.
Asunto(s)
Deficiencia de IgA/microbiología , Deficiencia de IgA/virología , Microbiota , Boca/microbiología , Boca/virología , Viroma , Adolescente , Adulto , Anciano , Niño , Femenino , Humanos , Inmunoglobulina A/fisiología , Inmunoglobulina M/deficiencia , Masculino , Metagenómica , Microbiota/genética , Persona de Mediana Edad , Saliva/microbiología , Saliva/virología , Viroma/genética , Adulto JovenRESUMEN
BACKGROUND & AIMS: IgA exerts its primary function at mucosal surfaces, where it binds microbial antigens to regulate bacterial growth and epithelial attachment. One third of individuals with IgA deficiency (IgAD) suffers from recurrent mucosal infections, possibly related to an altered microbiota. We aimed to delineate the impact of IgAD and the IgA-autoantibody status on the composition and functional capacity of the gut microbiota. METHODS: We performed a paired, lifestyle-balanced analysis of the effect of IgA on the gut microbiota composition and functionality based on fecal samples from individuals with IgAD and IgA-sufficient household members (n = 100), involving quantitative shotgun metagenomics, species-centric functional annotation of gut bacteria, and strain-level analyses. We supplemented the data set with 32 individuals with IgAD and examined the influence of IgA-autoantibody status on the composition and functionality of the gut microbiota. RESULTS: The gut microbiota of individuals with IgAD exhibited decreased richness and diversity and was enriched for bacterial species encoding pathogen-related functions including multidrug and antimicrobial peptide resistance, virulence factors, and type III and VI secretion systems. These functional changes were largely attributed to Escherichia coli but were independent of E coli strain variations and most prominent in individuals with IgAD with IgA-specific autoreactive antibodies. CONCLUSIONS: The microbiota of individuals with IgAD is enriched for species holding increased proinflammatory potential, thereby potentially decreasing the resistance to gut barrier-perturbing events. This phenotype is especially pronounced in individuals with IgAD with IgA-specific autoreactive antibodies, thus warranting a screening for IgA-specific autoreactive antibodies in IgAD to identify patients with IgAD with increased risk for gastrointestinal implications.
Asunto(s)
Autoanticuerpos/metabolismo , Microbioma Gastrointestinal/inmunología , Deficiencia de IgA/inmunología , Deficiencia de IgA/microbiología , Inmunoglobulina A/metabolismo , Adulto , Anciano , Estudios de Casos y Controles , Heces/microbiología , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
In a recently published article we report the metagenomic analysis of human gut microbiomes evolved in the absence of immunoglobulin A (IgA). We show that human IgA deficiency is not associated with massive quantitative perturbations of gut microbial ecology. While our study underlines a rather expected pathobiont expansion, we at the same time highlight a less expected depletion in some typically beneficial symbionts. We also show that IgM partially supply IgA deficiency, explaining the relatively mild clinical phenotype associated with the early steps of this condition. Microbiome studies in patients should consider potential issues such as cohort size, human genetic polymorphism and treatments. In this commentary, we discuss how such issues were taken into account in our own study.
Asunto(s)
Microbioma Gastrointestinal/inmunología , Deficiencia de IgA/inmunología , Deficiencia de IgA/microbiología , Inmunoglobulina A/inmunología , Bacterias/clasificación , Bacterias/genética , Bacterias/inmunología , Biodiversidad , Inmunodeficiencia Variable Común/inmunología , Inmunodeficiencia Variable Común/microbiología , Microbioma Gastrointestinal/genética , Humanos , Inmunoglobulina A/metabolismo , Inmunoglobulina M/inmunología , Inmunoglobulina M/metabolismoRESUMEN
Perturbations in gut microbiota of IgA-deficient humans provide insight into how secretory IgA shapes microbiota composition.
Asunto(s)
Microbioma Gastrointestinal , Deficiencia de IgA/microbiología , Animales , Humanos , Inmunoglobulina A SecretoraRESUMEN
Paradoxically, loss of immunoglobulin A (IgA), one of the most abundant antibodies, does not irrevocably lead to severe infections in humans but rather is associated with relatively mild respiratory infections, atopy, and autoimmunity. IgA might therefore also play covert roles, not uniquely associated with control of pathogens. We show that human IgA deficiency is not associated with massive quantitative perturbations of gut microbial ecology. Metagenomic analysis highlights an expected pathobiont expansion but a less expected depletion in some typically beneficial symbionts. Gut colonization by species usually present in the oropharynx is also reminiscent of spatial microbiota disorganization. IgM only partially rescues IgA deficiency because not all typical IgA targets are efficiently bound by IgM in the intestinal lumen. Together, IgA appears to play a nonredundant role at the forefront of the immune/microbial interface, away from the intestinal barrier, ranging from pathobiont control and regulation of systemic inflammation to preservation of commensal diversity and community networks.
Asunto(s)
Deficiencia de IgA/inmunología , Deficiencia de IgA/microbiología , Humanos , Inmunoglobulina A/metabolismo , Inmunoglobulina M/metabolismo , Microbiota/fisiologíaRESUMEN
The intestinal microbiota is a large and diverse microbial community that inhabits the intestine, containing about 100 trillion bacteria of 500-1000 distinct species that, collectively, provide benefits to the host. The human gut microbiota composition is determined by a myriad of factors, among them genetic and environmental, including diet and medication. The microbiota contributes to nutrient absorption and maturation of the immune system. As reciprocity, the host immune system plays a central role in shaping the composition and localization of the intestinal microbiota. Secretory immunoglobulins A (sIgAs), component of the adaptive immune system, are important player in the protection of epithelium, and are known to have an important impact on the regulation of microbiota composition. A recent study published in Immunity by Fransen and colleagues aimed to mechanistically decipher the interrelationship between sIgA and microbiota diversity/composition. This commentary will discuss these important new findings, as well as how future therapies can ultimately benefit from such discovery.
Asunto(s)
Microbioma Gastrointestinal/inmunología , Sistema Inmunológico/fisiología , Animales , Biodiversidad , Humanos , Deficiencia de IgA/inmunología , Deficiencia de IgA/microbiología , Inmunoglobulina A/fisiología , Intestinos/inmunología , Intestinos/microbiología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BLRESUMEN
The composition of the microbiome in health and disease has only recently become a major research focus. Although it is clear that an imbalance or dysbiosis in the microbiota is associated with disease, its interrelatedness to disease penetrance is largely unknown. Inflammatory bowel disease (IBD) is an excellent disease in which to explore these questions because of the extensive genetic studies identifying disease susceptibility loci and the ability to easily sample the intestinal microbiota in IBD patients due to the accessibility of stool samples. In addition, mouse models of IBD have contributed to our understanding of the interrelatedness of the gut microbiota and genes associated with IBD. The power of the mouse studies is that multiple colitis models exist that can be used in combination with genetically modified mice that harbour deficiencies in IBD susceptibility genes. Collectively, these studies revealed that bacterial dysbiosis does occur in human IBD and in mouse colitis models. In addition, with an emphasis on immune genes, the mouse studies provided evidence that specific immune regulatory proteins associated with IBD influence the gut microbiota in a manner consistent with disease penetrance. In this review, we will discuss studies in both humans and mice that demonstrate the impact of immunodeficiences in interleukin-10, interleukin-17, nucleotide-binding oligomerization domain (NOD) 2, NOD-like receptor proteins 3 and 6, Toll-like receptor or IgA have on the interrelatedness between the composition of the gut microbiota and disease penetrance of IBD and its mouse models.
Asunto(s)
Colitis/inmunología , Colitis/microbiología , Disbiosis/inmunología , Microbioma Gastrointestinal/inmunología , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/microbiología , Animales , Modelos Animales de Enfermedad , Disbiosis/microbiología , Humanos , Deficiencia de IgA/inmunología , Deficiencia de IgA/microbiología , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/microbiología , Interleucina-10/deficiencia , Interleucina-10/inmunología , Ratones , Modelos Inmunológicos , Proteínas Adaptadoras de Señalización NOD/deficiencia , Proteínas Adaptadoras de Señalización NOD/inmunología , Penetrancia , Células Th17/inmunología , Receptores Toll-Like/inmunologíaRESUMEN
Mutualism with our intestinal microbiota is a prerequisite for healthy existence. This requires physical separation of the majority of the microbiota from the host (by secreted antimicrobials, mucus, and the intestinal epithelium) and active immune control of the low numbers of microbes that overcome these physical and chemical barriers, even in healthy individuals. In this review, we address how B-cell responses to members of the intestinal microbiota form a robust network with mucus, epithelial integrity, follicular helper T cells, innate immunity, and gut-associated lymphoid tissues to maintain host-microbiota mutualism.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Interacciones Huésped-Patógeno/inmunología , Sistema Inmunológico/fisiología , Microbiota/inmunología , Animales , Autofagia , Subgrupos de Linfocitos B/metabolismo , Microambiente Celular/inmunología , Estrés del Retículo Endoplásmico , Ácidos Grasos/metabolismo , Histona Desacetilasas/metabolismo , Humanos , Deficiencia de IgA/genética , Deficiencia de IgA/inmunología , Deficiencia de IgA/microbiología , Inmunidad Innata , Inmunidad Mucosa , Inmunoglobulina A/inmunología , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/microbiología , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Intestinos/inmunología , Intestinos/microbiología , Moco/microbiología , Moco/fisiología , Ganglios Linfáticos Agregados/inmunología , Simbiosis , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
In IgA deficiency, secretory IgA (S-IgA) is absent from intestinal secretions. S-IgA carbohydrate chains act as receptors for the mannose specific (MS) adhesin fim of Escherichia coli. In IgA deficient (IgAd) individuals, commensal E. coli express less MS adherence to epithelial cells, due both to reduced carriage of the fimH adhesin gene, reduced capacity to switch it on, and reduced adherence of adhesin-expressing bacteria. Here, we show that commensal E. coli microbiota of IgA deficient individuals belong to phylogenetic group A and display low MS adherence. In healthy individuals, group B2 with strong MS adherence dominate.
Asunto(s)
Adhesión Bacteriana/fisiología , Colon/microbiología , Escherichia coli/genética , Escherichia coli/fisiología , Deficiencia de IgA/microbiología , Manosa/metabolismo , Filogenia , Adhesinas de Escherichia coli/genética , Adhesinas de Escherichia coli/metabolismo , Adolescente , Adulto , Anciano , Adhesión Bacteriana/genética , Escherichia coli/clasificación , Femenino , Proteínas Fimbrias/genética , Proteínas Fimbrias/metabolismo , Fimbrias Bacterianas/genética , Células HT29 , Humanos , Inmunoglobulina A , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Lactobacilli are present in the intestine and oral cavity of most adults. Secretory IgA in mucosal secretions may provide carbohydrate receptors for bacterial adhesins. Here, oral and faecal samples from 33 IgA-deficient individuals and 34 controls were cultured for lactobacilli, which were identified using species-specific PCR or partial 16S rDNA sequencing and tested for expression of mannose-specific adhesins. Lactobacilli were found in the oral cavity of 76% of IgA-deficient and 85% of control individuals. Lactobacillus paracasei and Lactobacillus gasseri dominated in both groups. Lactobacillus fermentum was less common in IgA-deficient individuals than in controls (p=0.0055) and Lactobacillus salivarius was less common in symptomatic than in healthy IgA-deficient individuals (p=0.0051). Faecal samples yielded lactobacilli in most individuals. L. paracasei was most frequent, followed by L. gasseri and Lactobacillus plantarum. Mannose-specific adhesins were expressed more frequently by oral than by faecal isolates (p=0.032) and oral isolates adhered in higher numbers than faecal isolates (46 vs. 14 bacteria/cell, p=0.0038). Faecal isolates from IgA-deficient individuals more frequently expressed mannose-specific adhesins than faecal isolates from controls (p=0.039). Mannose-specific adhesins may be a colonisation factor in the oral cavity, and the presence of secretory IgA may modify adhesin expression. However, secretory IgA seems to have little influence on Lactobacillus species distribution.
Asunto(s)
Adhesinas Bacterianas/metabolismo , Heces/microbiología , Deficiencia de IgA/microbiología , Intestinos/microbiología , Lactobacillus/aislamiento & purificación , Boca/microbiología , Adhesinas Bacterianas/genética , Adulto , Anciano , Adhesión Bacteriana , Estudios de Casos y Controles , ADN Bacteriano/química , ADN Bacteriano/genética , ADN Ribosómico/química , ADN Ribosómico/genética , Femenino , Células HT29 , Humanos , Lactobacillus/clasificación , Lactobacillus/genética , Lactobacillus/crecimiento & desarrollo , Masculino , Manosa/metabolismo , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa Multiplex , ARN Ribosómico 16S/genética , Especificidad de la EspecieRESUMEN
The mannose-specific adhesin of type 1 fimbriae is the most common adhesin in Escherichia coli. One receptor for this adhesin is the carbohydrate chains of secretory immunoglobulin A (S-IgA), and intestinal E. coli from IgA-deficient individuals has a reduced capacity to adhere to mannose-containing receptors. Here, we investigated the expression of the mannose-specific adhesin and its capacity to switch to the fimbriated phenotype in colonic resident and transient E. coli strains isolated from control (n = 16) and IgA-deficient (n = 17) persons. Resident E. coli strains from IgA-deficient individuals displayed weaker mannose-specific adherence to colonic cells than resident strains from control individuals (21 versus 44 bacteria/cell, P = 0.0009) due to three mechanisms: a lower carriage rate of the fimH gene (90% versus 97%, not significant), more frequent failure to switch on the fim genes (30% versus 6%, P = 0.02), and the reduced adhesive potential of fimH(+) isolates capable of phase switch (26 versus 46 bacteria/cell, P = 0.02). On the other hand, resident strains from IgA-deficient individuals displayed stronger mannose-resistant adherence than resident strains from control individuals (P = 0.04) and transient strains from IgA-deficient individuals (P = 0.01). The presence of S-IgA appears to favor the establishment of E. coli clones which readily express mannose-specific adhesins in the bowel microbiota.
Asunto(s)
Adhesinas Bacterianas/biosíntesis , Adhesión Bacteriana , Escherichia coli/fisiología , Fimbrias Bacterianas/metabolismo , Deficiencia de IgA/microbiología , Adhesinas Bacterianas/genética , Adolescente , Adulto , Anciano , ADN Bacteriano/genética , Escherichia coli/genética , Escherichia coli/aislamiento & purificación , Femenino , Fimbrias Bacterianas/genética , Células HT29 , Humanos , Masculino , Manosa/metabolismo , Persona de Mediana Edad , Reacción en Cadena de la PolimerasaRESUMEN
Persons with selective IgA deficiency carry an increased risk of coeliac disease, inflammatory bowel disease and perhaps also gastrointestinal malignancies. Inflammatory bowel disease is associated with an increased carriage of adherent and haemolytic Escherichia coli in the intestinal microflora. This study was designed to investigate whether IgA-deficient individuals carry E. coli with virulence-associated properties in their gut flora. The last free-lying colony of E. coli isolates obtained from rectal flora of 25 IgA-deficient and 20 age-matched control individuals was assayed by multiplex PCR for genes for the following adhesins or virulence determinants: P, type 1 and S fimbriae, Dr haemagglutinin, haemolysin, aerobactin and the capsular types K1 and K5. E. coli strains from the intestinal microflora of IgA-deficient individuals more often had the gene for S fimbriae (36% of the strains compared with 0% in control subjects, P=0.003) as well as for haemolysin (40 vs 10% of the strains, P=0.040). IgA-deficient individuals had instead lower frequencies of E. coli carrying genes for type 1 fimbriae in their microflora (68 vs 90%, P=0.14). The results suggest that IgA-deficient individuals carry an increased frequency of E. coli with potentially inflammatogenic properties in their microflora, which may contribute to the development of gastrointestinal disorders such as inflammatory bowel diseases.
Asunto(s)
Infecciones por Escherichia coli/microbiología , Escherichia coli/aislamiento & purificación , Fimbrias Bacterianas/genética , Proteínas Hemolisinas/genética , Deficiencia de IgA/complicaciones , Intestino Grueso/microbiología , Adolescente , Adulto , Anciano , Escherichia coli/genética , Escherichia coli/metabolismo , Escherichia coli/patogenicidad , Femenino , Fimbrias Bacterianas/metabolismo , Proteínas Hemolisinas/metabolismo , Humanos , Deficiencia de IgA/microbiología , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Virulencia/genéticaRESUMEN
Most Escherichia coli isolates can express type 1 fimbriae with mannose-specific adhesins. These adhesins bind to the oligosaccharide chains of secretory immunoglobulin A (IgA). Thus, in addition to specific antibody activity, secretory IgA possesses a broad reactivity with bacteria expressing type 1 fimbriae. The absence of secretory IgA in colonic secretions, as seen in IgA deficiency, might therefore alter the ability of type 1-fimbriated E. coli to colonize the large intestines of these individuals. In the present study, 10 E. coli isolates from each of 17 IgA-deficient and 17 age-matched control individuals were assessed for the carriage of the fim gene cluster by DNA-DNA hybridization and for the expression of type 1 fimbriae by hemagglutination of guinea pig erythrocytes. The contribution of type 1-fimbria-mediated adherence to HT-29 colonic cells was also analyzed. The proportion of fim+ E. coli isolates was lower in IgA-deficient than in control individuals (74 versus 94%, P < 0.05), as was the proportion of isolates expressing type 1 fimbriae in vitro (69% versus 85%, P < 0.05). The median mannose-sensitive adherence to HT-29 cells was lower for isolates from IgA-deficient individuals than from the controls (9 versus 26 bacteria per cell, P < 0.05). Isolates expressing type 1 fimbriae showed lower adherence to HT-29 cells when they were derived from IgA-deficient individuals than when they were derived from control individuals (15 versus 27 bacteria per cell, P < 0.05). The results suggest that the interaction of type 1 fimbriae with secretory IgA contributes to the large intestinal colonization by these bacteria.
Asunto(s)
Adhesinas Bacterianas/metabolismo , Colon/microbiología , Escherichia coli/metabolismo , Deficiencia de IgA/metabolismo , Deficiencia de IgA/microbiología , Manosa/metabolismo , Adhesinas Bacterianas/genética , Adulto , Anciano , Sitios de Unión , Estudios de Casos y Controles , Enterobacteriaceae/aislamiento & purificación , Escherichia coli/genética , Escherichia coli/aislamiento & purificación , Femenino , Fimbrias Bacterianas/genética , Fimbrias Bacterianas/metabolismo , Genes Bacterianos , Genotipo , Humanos , Masculino , Persona de Mediana EdadAsunto(s)
Anticuerpos Antibacterianos/metabolismo , Caries Dental/etiología , Deficiencia de IgA/complicaciones , Deficiencia de IgA/inmunología , Saliva/inmunología , Streptococcus mutans/inmunología , Estudios de Casos y Controles , Niño , Preescolar , Recuento de Colonia Microbiana , Caries Dental/inmunología , Humanos , Deficiencia de IgA/microbiología , Inmunoglobulina A Secretora/metabolismo , Inmunoglobulina G/metabolismo , Inmunoglobulina M/metabolismo , Lactobacillus/aislamiento & purificación , Saliva/microbiología , Streptococcus mutans/aislamiento & purificaciónRESUMEN
Sixteen IgA-deficient German Shepherd Dogs with small intestinal bacterial overgrowth were randomized into 2 groups. One group was fed a chicken-based kibble diet; the other was fed the same diet, but with 1% fructo-oligosaccharides supplemented at the expense of cornstarch. After being exposed to the diets for 46 to 51 days, the group that ate the supplemented diet had significantly (P = 0.04) fewer aerobic/facultative anaerobic bacterial colony-forming units in fluid from the duodenum/proximal part of the jejunum, as well as in the duodenal mucosa. We could not detect significant differences in the species of bacteria found in the intestine of these 2 groups of dogs. We conclude that at least some dietary carbohydrates can affect small intestinal bacterial populations in dogs with small intestinal bacterial overgrowth.
Asunto(s)
Alimentación Animal , Bacterias Aerobias/crecimiento & desarrollo , Bacterias Anaerobias/crecimiento & desarrollo , Carbohidratos de la Dieta , Enfermedades de los Perros , Fructosa/farmacología , Deficiencia de IgA/veterinaria , Yeyuno/microbiología , Oligosacáridos/farmacología , Animales , Bacterias Aerobias/efectos de los fármacos , Bacterias Aerobias/aislamiento & purificación , Bacterias Anaerobias/efectos de los fármacos , Bacterias Anaerobias/aislamiento & purificación , Perros , Femenino , Alimentos Fortificados , Fructosa/administración & dosificación , Deficiencia de IgA/microbiología , Masculino , Oligosacáridos/administración & dosificación , Orquiectomía , OvariectomíaRESUMEN
By comparing the initial colonization of cleaned teeth in immunoglobulin A (IgA)-deficient, IgM-compensating individuals with that in normal individuals, no significant difference in the proportion of IgA1 protease-producing streptococci was found. Thus, as one of several bacterial means of immune evasion, the ability to cleave secretory IgA1 does not appear essential to the successful adherence of oral streptococci.