Gut Microbiota–Host Interactions in Inborn Errors of Immunity
Open accessAbstract
Inborn errors of immunity (IEI) are a group of disorders that are mostly caused by genetic mutations affecting immune host defense and immune regulation. Although IEI present with a wide spectrum of clinical features, in about one third of them various degrees of gastrointestinal (GI) involvement have been described and for some IEI the GI manifestations represent the main and peculiar clinical feature. The microbiome plays critical roles in the education and function of the host’s innate and adaptive immune system, and imbalances in microbiota-immunity interactions can contribute to intestinal pathogenesis. Microbial dysbiosis combined to the impairment of immunosurveillance and immune dysfunction in IEI, may favor mucosal permeability and lead to inflammation. Here we review how immune homeostasis between commensals and the host is established in the gut, and how these mechanisms can be disrupted in the context of primary immunodeficiencies. Additionally, we highlight key aspects of the first studies on gut microbiome in patients affected by IEI and discuss how gut microbiome could be harnessed as a therapeutic approach in these diseases.
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Microbiota alterations and reduced alpha diversity may be associated with infectious, inflammatory, and metabolic sequelae.
“While these findings can be potentially harnessed to remodel the microbiota to a more desirable configuration, they might also raise a safety concern as microbiota alterations and reduced alpha diversity may be associated with infectious, inflammatory, and metabolic sequelae.96”
From Emerging issues in probiotic safety: 2023 perspectives (2023) · cites this paper as [96]
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BackgroundMyD88 Signaling in T Cells Directs IgA-Mediated Control of the Microbiota to Promote Health
Kubinak, J. L., Petersen, C., Stephens, W. Z., Soto, R., Bake, E., O’Connell, R. M., & Round, J. L. (2015) · Cell Host & Microbe · doi:10.1016/j.chom.2014.12.009 · Cited by 328 · cited 1× · see citing works
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“Common variable immunodeficiency (CVID) is a clinically heterogeneous primary immunodeficiency characterized by hypogammaglobulinemia and impaired antibody responses to vaccine antigens [112,113].”
BackgroundThe Intestine Harbors Functionally Distinct Homeostatic Tissue-Resident and Inflammatory Th17 Cells
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“In this context, Fadlallah et al. showed that IgM can compensate sIgAD for some, but not all bacteria.”
BackgroundInfluentialAlterations in the gut microbiome of children with severe ulcerative colitis
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“In particular, SFBs can promote Tfh differentiation by limiting access of CD4+ cells to IL-2, thereby enhancing the expression of the Tfh master regulator Bcl-6 [56].”
BackgroundSecretory IgA in Intestinal Mucosal Secretions as an Adaptive Barrier against Microbial Cells
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“This clinical heterogeneity is due to the effect of different combinations of recurrent infections, autoimmunity, inflammatory manifestations, lymphoproliferation, atopy, and malignancy [1].”
BackgroundSelf-citationMicrobial ecology perturbation in human IgA deficiency
Fadlallah, J., Kafsi, H. E., Sterlin, D., Juste, C., Parizot, C., Dorgham, K., Autaa, G., Gouas, D. A., Almeida, M., Lepage, P., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aan1217 · Cited by 274 · cited 1× · see citing works
“However, microbial translocation was not reported in patients with selective IgA deficiency (sIgAD), with one study reporting no increase in serum LPS levels [129,130].”
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BackgroundGenetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency
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Gene therapy using haematopoietic stem and progenitor cells
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“In the absence of therapy (specifically, hematopoietic stem cell transplantation (HSCT) [81], gene therapy (GT) [82] or enzyme replacement therapy [83]), patients with SCID usually die within the first years of life.”
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“The microenvironment of Peyer’s patches germinal centers, rich in cytokines, chemokines and various metabolites, drives B cells to proliferate and undergo class-switch to produce preferentially IgA from IgM [46,47].”
BackgroundHuman RAG mutations: biochemistry and clinical implications
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BackgroundSevere combined immunodeficiencies and related disorders
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“SCID usually present in the first year of life with severe opportunistic infections, failure to thrive and chronic diarrhea [78].”
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“CVID typically manifests with recurrent respiratory tract infections [114]; gastrointestinal involvement is common and may mark clinical onset of the disease [115,116].”
BackgroundInflammatory manifestations in a single-center cohort of patients with chronic granulomatous disease
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“The reported prevalence of CGD-associated IBD (CGD-IBD) ranges from 31% [143] to 88% [144], being one of the main clinical manifestations especially in patients with p40phox deficiency [145].”
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“Elevated concentrations of the gut microbiota-dependent metabolite TMAO is associated with systemic inflammation and increased gut microbial abundance of Gammaproteobacteria in CVID patients A single broad-spectrum antibiotic (rifaximin) does not modify microbial translocation, immune cell activation, and immune dysre…”
BackgroundInfluentialChen, R., Giliani, S. C., Lanzi, G., Mias, G. I., Lonardi, S., Dobbs, K., Manis, J. P., Im, H., Gallagher, J. E. G., Phanstiel, D. H., et al. (2013) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2013.06.013 · Cited by 164 · see citing works
Self-citationThe role of bacteria and pattern-recognition receptors in Crohn's disease
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Comparison of Diagnostic Criteria for Common Variable Immunodeficiency Disorder
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“Common variable immunodeficiency (CVID) is a clinically heterogeneous primary immunodeficiency characterized by hypogammaglobulinemia and impaired antibody responses to vaccine antigens [112,113].”
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“Interstingly, SFB colonization is age-dependent in humans, with most individuals colonized within the first 2 years of life, but this colonization disappears by the age of 3 years [51].”
BackgroundEvaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond
de Valles‐Ibáñez, G., Esteve‐Solé, A., Piquer, M., González‐Navarro, E. A., Hernández-Rodríguez, J., Laayouni, H., González‐Roca, E., Plaza-Martín, A. M., Deyà‐Martínez, À., Martín‐Nalda, A., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00636 · Cited by 153 · cited 1× · see citing works
“A genetic cause has been identified in 10–30% of CVID patients, depending on the cohort analyzed [117,119,120], including mutations in NFKB1, NFKB2, ICOS, TNFRSF13B, TNFRSF13C, CD19, CR2, MS4A1, CD81, IL21, LRBA, CTLA4, PRKCD, and IKZF1.”
BackgroundSerum amyloid A is a retinol binding protein that transports retinol during bacterial infection
Derebe, M. G., Zlatkov, C. M., Gattu, S., Ruhn, K. A., Vaishnava, S., Diehl, G. E., MacMillan, J. B., Williams, N. S., & Hooper, L. V. (2014) · eLife · doi:10.7554/elife.03206 · Cited by 147 · cited 1× · see citing works
“Serum amyloid A also works as a carrier of both high-density lipoprotein and retinol, delivering these molecules to APCs and amplifying the induction of IL-17 (Th17) responses within tissues [53].”
BackgroundXIAP deficiency syndrome in humans
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BackgroundInherited p40phox deficiency differs from classic chronic granulomatous disease
van de Geer, A., Nieto-Patlán, A., Kuhns, D. B., Tool, A. T. J., Arias, A. A., Bouaziz, M., de Boer, M., Franco, J. L., Gazendam, R. P., van Hamme, J. L., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci97116 · Cited by 140 · cited 1× · see citing works
“The reported prevalence of CGD-associated IBD (CGD-IBD) ranges from 31% [143] to 88% [144], being one of the main clinical manifestations especially in patients with p40phox deficiency [145].”
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“The pre-symptomatic identification of infants with SCID through newborn screening has significantly improved the clinical management of these conditions [84].”
BackgroundTregopathies: Monogenic diseases resulting in regulatory T-cell deficiency
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“In the absence of therapy (specifically, hematopoietic stem cell transplantation (HSCT) [81], gene therapy (GT) [82] or enzyme replacement therapy [83]), patients with SCID usually die within the first years of life.”
BackgroundSelf-citationThe Variable in Common Variable Immunodeficiency: A Disease of Complex Phenotypes
Jolles, S. R. A. (2013) · The Journal of Allergy and Clinical Immunology In Practice · doi:10.1016/j.jaip.2013.09.015 · Cited by 131 · cited 1× · see citing works
“CVID typically manifests with recurrent respiratory tract infections [114]; gastrointestinal involvement is common and may mark clinical onset of the disease [115,116].”
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Fostering of advanced mutualism with gut microbiota by Immunoglobulin A
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“The secreted IgAs are transcytosed across epithelial cells [42], where they contribute to impede bacteria attachment to the mucosa.”
BackgroundThe gut microbiota and graft-versus-host disease
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“Compelling evidence shows that the gut microbiota has a role in the development of graft-versus-host disease (GvHD) both in adult and pediatric patients [92,93], but the exact mechanisms of this relationship need to be elucidated [94].”
BackgroundSynergistic convergence of microbiota-specific systemic IgG and secretory IgA
Fadlallah, J., Sterlin, D., Fieschi, C., Parizot, C., Dorgham, K., Kafsi, H. E., Autaa, G., Ghillani‐Dalbin, P., Juste, C., Lepage, P., et al. (2018) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2018.09.036 · Cited by 111 · see citing works
Inborn Errors of Immunity With Immune Dysregulation: From Bench to Bedside
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Self-citationEmerging concepts and future challenges in innate lymphoid cell biology
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“ILCs are enriched in mucosal tissues and are specialized in cytokine and chemokine production against infectious agents, as well as in promoting tissue repair [23].”
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“Other variable clinical manifestations include severe infectious mononucleosis, splenomegaly, fistulating skin abscesses, and antibody deficiency contributing to recurrent infections [147].”
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“In this context, the manipulation of the gut microbiota, through pharmacologic modification/decontamination [95,96] or fecal microbiota transplantation (FMT) [97,98], may shape the microbiota composition and modulate immune responses after HSCT to benefit the host.”
BackgroundAdvanced model systems and tools for basic and translational human immunology
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BackgroundGastrointestinal Histopathology in Chronic Granulomatous Disease
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“WAS is caused by mutations in the WAS gene, encoding the WAS protein (WASP), which is involved in signal transduction and cytoskeleton remodeling [102].”
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“In this context, the manipulation of the gut microbiota, through pharmacologic modification/decontamination [95,96] or fecal microbiota transplantation (FMT) [97,98], may shape the microbiota composition and modulate immune responses after HSCT to benefit the host.”
BackgroundCD3bright signals on γδ T cells identify IL‐17A‐producing Vγ6Vδ1+ T cells
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“In another study, mucosal IgA deficiency in CVID has been associated with GI inflammation and malabsorption [127], providing a link between IgA deficiency in CVID and mucosal barrier damage that may facilitate microbial translocation [128].”
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“Compelling evidence shows that the gut microbiota has a role in the development of graft-versus-host disease (GvHD) both in adult and pediatric patients [92,93], but the exact mechanisms of this relationship need to be elucidated [94].”
BackgroundIlett, E. E., Jørgensen, M., Noguera-Julián, M., Nørgaard, J. C., Daugaard, G., Helleberg, M., Paredes, R., Murray, D. D., Lundgren, J. D., MacPherson, C. R., et al. (2020) · Blood Advances · doi:10.1182/bloodadvances.2020002677 · Cited by 74 · cited 1× · see citing works
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Intestinal microbiota sustains inflammation and autoimmunity induced by hypomorphic RAG defects
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“Excessive inflammation in the gut could be partially rescued by administration of broad range antibiotics [63].”
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“A recent report from the Primary Immune Deficiency Treatment Consortium (PIDTC) showed that HSCT is curative for CGD colitis, and importantly, that colitis itself is not a contraindication to HSCT as it does not lead to an increased risk of mortality [146].”
BackgroundSelf-citationRAG gene defects at the verge of immunodeficiency and immune dysregulation
VILLA, A. M., & Notarangelo, L. D. (2018) · Immunological Reviews · doi:10.1111/imr.12713 · Cited by 64 · see citing works
Self-citationMicrobial Dysbiosis in Common Variable Immune Deficiencies: Evidence, Causes, and Consequences
Berbers, R.-M., Nierkens, S., van Laar, J. M., Bogaert, D., & Leavis, H. L. (2016) · Trends in Immunology · doi:10.1016/j.it.2016.11.008 · Cited by 62 · cited 3× · see citing works
“This chronic and aberrant systemic immune activation seems to be, at least in part, a consequence of increased microbial translocation [61,124,125].”
BackgroundJørgensen, S. F., Fevang, B., & Aukrust, P. (2018) · Journal of Clinical Immunology · doi:10.1007/s10875-018-0574-z · Cited by 61 · see citing works
Zheng, S., Zhao, T., Yuan, S., Yang, L., Ding, J., Cui, L., & Xu, M. (2019) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.02415 · Cited by 61 · cited 1× · see citing works
“used SCID mice and NOD/SCID mice (with defects restricted to adaptive immunity, or involving both adaptive and innate immunity, respectively) to investigate the interactions between the host immune system and the gut microbiome [60].”
MethodImmune dysregulation in patients with RAG deficiency and other forms of combined immune deficiency
Delmonte, O. M., VILLA, A. M., & Notarangelo, L. D. (2020) · Blood · doi:10.1182/blood.2019000923 · Cited by 61 · see citing works
Self-citationGut microbiota and hematopoietic stem cell transplantation: where do we stand?
Zama, D., Biagi, E., Masetti, R., Gasperini, P., Prete, A., Candela, M., Brigidi, P., & Pession, A. (2016) · Bone Marrow Transplantation · doi:10.1038/bmt.2016.173 · Cited by 60 · see citing works
Macpherson, M. E., Hov, J. R., Ueland, T., Dahl, T. B., Kummen, M., Otterdal, K., Holm, K., Berge, R. K., Mollnes, T. E., Trøseid, M., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.574500 · Cited by 60 · see citing works
Gastrointestinal manifestations of chronic granulomatous disease
Huang, A., Abbasakoor, F., & Vaizey, C. J. (2006) · Colorectal Disease · doi:10.1111/j.1463-1318.2006.01030.x · Cited by 59 · see citing works
Yu, J. E., Ravin, S. S. D., Uzel, G., Landers, C. J., Targan, S. R., Malech, H. L., Holland, S. M., Cao, W., Harpaz, N., & Mayer, L. (2010) · Clinical Immunology · doi:10.1016/j.clim.2010.08.003 · Cited by 56 · see citing works
Wang, F., Kaplan, J. L., Gold, B. D., Bhasin, M., Ward, N. L., Kellermayer, R., Kirschner, B. S., Heyman, M. B., Dowd, S. E., Cox, S. B., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2015.12.088 · Cited by 56 · see citing works
Al–Herz, W., Chou, J. S., Delmonte, O. M., Massaad, M. J., Bainter, W., Castagnoli, R., Klein, C., Bryceson, Y. T., Geha, R. S., & Notarangelo, L. D. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2018.03146 · Cited by 55 · see citing works
Self-citationThe microbiome and immunodeficiencies: Lessons from rare diseases
Pellicciotta, M., Rigoni, R., Falcone, E. L., Holland, S. M., VILLA, A. M., & Cassani, B. (2019) · Journal of Autoimmunity · doi:10.1016/j.jaut.2019.01.008 · Cited by 52 · cited 1× · see citing works
“In this context, the study of gut microbiota-host interactions in IEI may help understand the factors involved in the maintenance of intestinal homeostasis [8,9].”
BackgroundSelf-citationNovel Mutations of the Tetratricopeptide Repeat Domain 7A Gene and Phenotype/Genotype Comparison
Lien, R., Lin, Y., Lai, M.-W., Weng, H.-Y., Wu, R., Jaing, T., Huang, J., Tsai, S., & Lee, W. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01066 · Cited by 50 · cited 1× · see citing works
“Pathological findings include structural abnormalities of the enterocytes, increased apoptosis of intestinal cells, reduced proliferation of intestinal crypts, and defects of thymic architecture associated with lymphoid depletion [154,155].”
BackgroundFiedorová, K., Radvanský, M., Bosák, J., Grombiříková, H., Němcová, E., Králíčková, P., Černochová, M., Kotásková, I., Lexa, M., Litzman, J., et al. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01914 · Cited by 46 · cited 1× · see citing works
“This chronic and aberrant systemic immune activation seems to be, at least in part, a consequence of increased microbial translocation [61,124,125].”
BackgroundRay, A., & Dittel, B. (2015) · Immunology · doi:10.1111/imm.12511 · Cited by 44 · cited 1× · see citing works
“In this context, the study of gut microbiota-host interactions in IEI may help understand the factors involved in the maintenance of intestinal homeostasis [8,9].”
BackgroundDichotomous regulation of group 3 innate lymphoid cells by nongastric <i>Helicobacter</i> species
Bostick, J. W., Wang, Y., Shen, Z., Ge, Y., Brown, J., Chen, Z.-M. E., Mohamadzadeh, M., Fox, J. G., & Zhou, L. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1908128116 · Cited by 44 · see citing works
Berbers, R.-M., Drylewicz, J., Ellerbroek, P. M., van Montfrans, J. M., Dalm, V. A. S. H., van Hagen, P. M., Keller, B., Warnatz, K., van de Ven, A., van Laar, J. M., et al. (2020) · Journal of Clinical Immunology · doi:10.1007/s10875-020-00908-1 · Cited by 43 · cited 1× · see citing works
“In addition to immunodeficiency, more than half of all CVID patients develop non-infectious complications such as autoimmune diseases, lymphoproliferation, granulomatous disease and malignancies, with significant morbidity and mortality [117,118].”
BackgroundGastrointestinal Disorders Associated with Primary Immunodeficiency Diseases
Hartono, S. P., Ippoliti, M. R., Mastroianni, M. A., Torres, R., & Rider, N. L. (2018) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-018-8689-9 · Cited by 41 · cited 3× · see citing works
“Multiple etiologies contribute to GI pathology in IEI including infections related to the underlying host defense impairment, immune dysregulation, and malignancy [3].”
BackgroundKabelitz, D. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00371 · Cited by 40 · cited 1× · see citing works
“recognition of lipid antigens, which are often microbiota-derived metabolites [30].”
BackgroundColitis susceptibility in p47 phox−/− mice is mediated by the microbiome
Falcone, E. L., Abusleme, L., Swamydas, M., Lionakis, M. S., Ding, L., Hsu, A. P., Zelazny, A. M., Moutsopoulos, N. M., Kuhns, D. B., Deming, C., et al. (2016) · Microbiome · doi:10.1186/s40168-016-0159-0 · Cited by 40 · see citing works
Cysteine and hydrophobic residues in CDR3 serve as distinct T-cell self-reactivity indices
Daley, S. R., Koay, H., Dobbs, K., Bosticardo, M., Wirasinha, R. C., Pala, F., Castagnoli, R., Rowe, J. H., de Bruin, L. M. O., Keleş, S., et al. (2019) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2019.03.022 · Cited by 40 · see citing works
Self-citationIntestinal dysbiosis in inflammatory bowel disease associated with primary immunodeficiency
Sokol, H., Mahlaoui, N., Aguilar, C., Bach, P., Join‐Lambert, O., Garraffo, A., Seksik, P., Danion, F., Jégou, S., Straube, M., et al. (2018) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2018.09.021 · Cited by 35 · see citing works
Henig, I. J., Yehudai‐Ofir, D., & Zuckerman, T. (2020) · Haematologica · doi:10.3324/haematol.2020.247395 · Cited by 34 · cited 8× · see citing works
“Of note, most experience with FMT has been in the treatment of recurrent Clostridium difficile infections; patients with IEI were included in four of these studies [166–169] two of which reported lack of safety concerns and successful resolution of C. difficile [168,169].”
BackgroundInfluentialClarke, E., Connell, A. J., Six, E. M., Kadry, N. A., Abbas, A. A., Hwang, Y., Everett, J. K., Hofstaedter, C. E., Marsh, R. A., Armant, M. A., et al. (2018) · Genome Medicine · doi:10.1186/s13073-018-0580-z · Cited by 33 · cited 1× · see citing works
“analyzed the parallel development of the microbiome and of the immune system in six patients with X-SCID treated by GT [99].”
Self-citationHe, B., Liu, Y., Hoang, T. K., Tian, X., Taylor, C. M., Luo, M., Tran, D. Q., Tatevian, N., & Rhoads, J. M. (2019) · Microbiome · doi:10.1186/s40168-019-0751-1 · Cited by 33 · cited 2× · see citing works
“A recent study showed that antibiotics impact positively on the survival and lethal inflammation in sf mice despite their effect of reducing microbial diversity [64].”
BackgroundMerli, P., Putignani, L., Ruggeri, A., CHIERICO, F. D., Gargiullo, L., Galaverna, F., Gaspari, S., Pagliara, D., Russo, A., Pane, S., et al. (2020) · Haematologica · doi:10.3324/haematol.2019.244210 · Cited by 33 · cited 8× · see citing works
“Of note, most experience with FMT has been in the treatment of recurrent Clostridium difficile infections; patients with IEI were included in four of these studies [166–169] two of which reported lack of safety concerns and successful resolution of C. difficile [168,169].”
BackgroundInfluentialMultiple intestinal atresia with combined immune deficiency
Notarangelo, L. D. (2014) · Current Opinion in Pediatrics · doi:10.1097/mop.0000000000000159 · Cited by 29 · cited 1× · see citing works
“Pathological findings include structural abnormalities of the enterocytes, increased apoptosis of intestinal cells, reduced proliferation of intestinal crypts, and defects of thymic architecture associated with lymphoid depletion [154,155].”
BackgroundSelf-citationNielsen, O. H., & LaCasse, E. C. (2016) · Genetics in Medicine · doi:10.1038/gim.2016.82 · Cited by 28 · cited 1× · see citing works
“Patients with XIAP deficiency are at high risk for hemophagocytic lymphohistiocytosis [149] and usually present with inflammatory manifestations, including Crohn’s-like bowel disease [150].”
BackgroundApplications of gut microbiota in patients with hematopoietic stem-cell transplantation
Yu, J., Sun, H., Cao, W., Han, L., Song, Y., Wan, D., & Jiang, Z. (2020) · Experimental Hematology & Oncology · doi:10.1186/s40164-020-00194-y · Cited by 25 · cited 1× · see citing works
“Of note, the effect of gut microbiota in HSCT is an active research field, also in diseases other than IEI [90,91].”
BackgroundPatron, R. L., Hartmann, C., Allen, S., Griesbach, C. L., Kosiorek, H., DiBaise, J. K., & Orenstein, R. (2017) · Clinical Infectious Diseases · doi:10.1093/cid/cix511 · Cited by 24 · see citing works
Immune/microbial interface perturbation in human IgA deficiency
Sterlin, D., Fieschi, C., Malphettes, M., Larsen, M., Gorochov, G., & Fadlallah, J. (2018) · Gut Microbes · doi:10.1080/19490976.2018.1546520 · Cited by 24 · cited 1× · see citing works
“However, microbial translocation was not reported in patients with selective IgA deficiency (sIgAD), with one study reporting no increase in serum LPS levels [129,130].”
BackgroundLane, J. P., Stewart, C. J., Cummings, S. P., & Gennery, A. R. (2015) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2015.01.024 · Cited by 22 · cited 12× · see citing works
“The patient finally achieved complete recovery after HSCT [162].”
BackgroundMethodInfluentialOhya, T., Yanagimachi, M. D., Iwasawa, K., Umetsu, S., Sogo, T., Inui, A., Fujisawa, T., & Ito, S. (2017) · World Journal of Gastroenterology · doi:10.3748/wjg.v23.i48.8544 · Cited by 21 · cited 1× · see citing works
“Moreover, up to 5–10% of these patients develop IBD which may present as Crohn’s disease or ulcerative colitis [103].”
BackgroundImmunoglobulin A and microbiota in primary immunodeficiency diseases
Berbers, R.-M., Franken, I. A., & Leavis, H. L. (2019) · Current Opinion in Allergy and Clinical Immunology · doi:10.1097/aci.0000000000000581 · Cited by 18 · cited 1× · see citing works
“In another study, mucosal IgA deficiency in CVID has been associated with GI inflammation and malabsorption [127], providing a link between IgA deficiency in CVID and mucosal barrier damage that may facilitate microbial translocation [128].”
BackgroundIntestinal dysbiosis in pediatric Crohn's disease patients with IL10RA mutations
Xue, A., Miao, S., Sun, H., Qiu, X., Wang, S., Wang, L., Ye, Z., Zheng, C., Huang, Z., Wang, Y., et al. (2020) · World Journal of Gastroenterology · doi:10.3748/wjg.v26.i22.3098 · Cited by 18 · cited 2× · see citing works
“Microbiota composition was investigated in 17 patients with IL10RA mutations, 17 patients with pediatric Crohn’s disease, and 26 healthy children [158].”
BackgroundAbdel‐Motal, U. M., Al‐Shaibi, A., Elawad, M., & Lo, B. (2018) · Immunological Reviews · doi:10.1111/imr.12717 · Cited by 14 · see citing works
Faecal microbial dysbiosis in children with Wiskott‐Aldrich syndrome
Zhang, L., Li, Y. Y., Tang, X., & Zhao, X. (2019) · Scandinavian Journal of Immunology · doi:10.1111/sji.12805 · Cited by 13 · cited 11× · see citing works
“WAS is an X-linked IEI characterized by immunodeficiency, eczema, and thrombocytopenia with small platelets [101].”
BackgroundInfluentialWu, W., Shen, N., Luo, L., Deng, Z., Chen, J., Tao, Y., Mo, X., & Cao, Q. (2020) · Pediatrics & Neonatology · doi:10.1016/j.pedneo.2020.11.003 · Cited by 11 · cited 3× · see citing works
“The patient finally achieved complete recovery after HSCT [162].”
BackgroundThe long road to optimal management for chronic granulomatous disease
Notarangelo, L. D. (2013) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2013.08.035 · Cited by 10 · cited 1× · see citing works
“The main clinical features of CGD encompass recurrent bacterial and fungal infections and a high rate of inflammatory complications [137,138].”
BackgroundSelf-citationLane, J. P., Stewart, C. J., Cummings, S. P., & Gennery, A. R. (2016) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2016.02.019 · Cited by 10 · see citing works
Loke, P., Heine, R. G., McWilliam, V. L., Cameron, D. J. S., Tang, M. L. K., & Allen, K. J. (2016) · Pediatric Allergy and Immunology · doi:10.1111/pai.12619 · Cited by 6 · see citing works
Sacco, K. A., Pongdee, T., Binnicker, M. J., Espy, M., Pardi, D., Khanna, S., & Joshi, A. Y. (2017) · Diagnostic Microbiology and Infectious Disease · doi:10.1016/j.diagmicrobio.2017.11.020 · Cited by 5 · see citing works
Delmonte, O. M., Rowe, J. H., Dobbs, A. K., Palterer, B., Castagnoli, R., & Notarangelo, L. D. (2020) · Journal of Clinical Immunology · doi:10.1007/s10875-020-00918-z · Cited by 5 · see citing works
Self-citationCombined immune deficiencies (CIDs)
Pïcard, C., Fusaro, M., Kashef, S., Ziegler, J. B., Su, H. C., & Lenardo, M. J. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-816768-7.00008-9 · Cited by 2 · see citing works
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Emerging issues in probiotic safety: 2023 perspectives
Merenstein, D., Pot, B., Leyer, G., Ouwehand, A. C., Preidis, G. A., Elkins, C. A., Hill, C., Lewis, Z. T., Shane, A. L., Zmora, N., et al. (2023) · Gut Microbes · doi:10.1080/19490976.2023.2185034 · Cited by 481 · see citing works
“While these findings can be potentially harnessed to remodel the microbiota to a more desirable configuration, they might also raise a safety concern as microbiota alterations and reduced alpha diversity may be associated with infectious, inflammatory, and metabolic sequelae.(96) Furthermore, a post-hoc analysis of th…”
BackgroundNeutrophils: from IBD to the gut microbiota
Danne, C., Skerniškytė, J., Marteyn, B. S., & Sokol, H. (2023) · Nature reviews: Gastroenterology & hepatology · doi:10.1038/s41575-023-00871-3 · Cited by 227 · see citing works
Zeiser, R., Warnatz, K., Rosshart, S. P., Sagar, & Tanriver, Y. (2022) · European Journal of Immunology · doi:10.1002/eji.202149530 · Cited by 28 · see citing works
Understanding immunoactinopathies: A decade of research on WAS gene defects
Vieira, R. C., Pinho, L. G., & Westerberg, L. S. (2023) · Pediatric Allergy and Immunology · doi:10.1111/pai.13951 · Cited by 24 · see citing works
Ouahed, J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1026511 · Cited by 21 · see citing works
Microbiome and Its Dysbiosis in Inborn Errors of Immunity
Sharma, M., Dhaliwal, M., Tyagi, R., Goyal, T., Sharma, S., & Rawat, A. K. (2023) · Pathogens · doi:10.3390/pathogens12040518 · Cited by 19 · see citing works
Stability of gut microbiome after COVID-19 vaccination in healthy and immuno-compromised individuals
Boston, R. H., Guan, R., Kalmár, L., Beier, S., Horner, E. C., Covarrubias, N. B., Yam‐Puc, J. C., Gerber, P. P., Faria, L., Kuroshchenkova, A., et al. (2024) · Life Science Alliance · doi:10.26508/lsa.202302529 · Cited by 15 · see citing works
“In line with the studies investigating the gut microbiome of patients with primary immunode fi ciencies (28), we also observed decreased diversity in our cohort compared with control samples.”
ResultLópez, C. H., Martín, M., Moreta, A. H., Urrutia, M. C., García, I. C., Morillo, C. D., Blanco-Rojo, R., Sáez, M. E., Olivares, M. M., Arroyo, R., et al. (2025) · Nutrients · doi:10.3390/nu17111860 · Cited by 13 · see citing works
“It has been postulated that such probiotic-related microbiota alterations may predispose or be a risk factor for infectious, inflammatory, and metabolic conditions later in life [43].”
Napiórkowska-Baran, K., Biliński, J., Pujanek, M., Hałakuc, P., Pietryga, A., Szymczak, B., Deptuła, A., Rosada, T., & Bartuzi, Z. (2024) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2024.1456672 · Cited by 12 · see citing works
“The disruption of gastrointestinal tract homeostasis in patients with IEI is not solely attributable to the immunode fi ciency itself but is also in fl uenced by the pharmacological agents employed, including immunosuppressants and antimicrobial drugs (Castagnoli et al., 2021).”
BackgroundTaietti, I., Catamerò, F., Lodi, L., Giovannini, M., & Castagnoli, R. (2025) · Current Opinion in Allergy and Clinical Immunology · doi:10.1097/aci.0000000000001059 · Cited by 12 · see citing works
Self-citationInborn Errors of Immunity in the Premature Infant: Challenges in Recognition and Diagnosis
Gordon, S. M., & O’Connell, A. E. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.758373 · Cited by 12 · see citing works
“Disorders of the Digestive Tract The digestive tract is frequently affected in the setting of IEI through a variety of mechanisms (58).”
BackgroundYang, P. C., Lu, T., Liang, X., Huang, T., Wu, L., He, Z., Xiao, X., & Fan, S. (2024) · BMC Pregnancy and Childbirth · doi:10.1186/s12884-024-06353-x · Cited by 11 · see citing works
Lai, X., Huang, J., Li, Y., & Dong, L. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1649857 · Cited by 10 · see citing works
“Recent studies have shown that skin surface symbiotic bacteria (e.g., S. aureus ) can directly activate DCs and LCs through pattern recognition receptors, promote antigen presentation and T cell differentiation, and lead to the occurrence of AD (57, 58).”
Pulvirenti, F., Giufrè, M., Pentimalli, T. M., Camilli, R., Milito, C., Villa, A., Sculco, E., Cerquetti, M., Pantosti, A., & Quinti, I. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1371118 · Cited by 10 · see citing works
“In patients with Inborn Errors of Immunity (IEI), adaptive or innate immune system defects led to gastrointestinal, respiratory, and cutaneous involvement frequently associated with dysbiosis (11, 12).”
BackgroundMethodSelf-citationEosinophilic Gastrointestinal Diseases in Inborn Errors of Immunity
Votto, M., Naso, M., Brambilla, I., Caimmi, S. M. E., Filippo, M. D., Licari, A., Marseglia, G. L., & Castagnoli, R. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12020514 · Cited by 10 · see citing works
“Although IEI present with a broad spectrum of clinical features, in about one-third of them, various degrees of gastrointestinal (GI) involvement have been described, and for some IEI, the GI manifestations represent the characteristic clinical feature [6,7].”
BackgroundSelf-citationInborn errors of immunity and related microbiome
Hazime, R., Eddehbi, F.-E., Elmojadili, S., Lakhouaja, N., Souli, I., Salami, A., M’raouni, B., Brahim, I., Oujidi, M., Guennouni, M., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.982772 · Cited by 9 · see citing works
“The first pathway typically occurs in Peyer’s patches and microbiota-specific, whereas the second pathway mostly takes place in the lamina propria and isolated lymphoid follicles, leading to the exclusion of microorganisms from the gut (52).”
BackgroundLeveraging Systems Immunology to Optimize Diagnosis and Treatment of Inborn Errors of Immunity
Mauracher, A. A., & Henrickson, S. E. (2022) · Frontiers in Systems Biology · doi:10.3389/fsysb.2022.910243 · Cited by 8 · see citing works
Primary immunodeficiency and the microbiome
Al‐Nesf, M. A., Morgan, D., & Mohamed‐Ali, V. (2021) · Current Opinion in Pediatrics · doi:10.1097/mop.0000000000001067 · Cited by 8 · see citing works
“The drawback of such management [28] includes procedural risks with previously reported fatal feculent aspiration, colonoscopy-induced superficial mucosal tear, and nasogastric tube-related bowel perforation and FMT material risks, especially for immunocompromised recipients, and poor screening of the FMT for multidru…”
BackgroundResultInfluentialUpdates of cancer hallmarks in patients with inborn errors of immunity
Wang, Y., & Abolhassani, H. (2022) · Current Opinion in Allergy and Clinical Immunology · doi:10.1097/aci.0000000000000863 · Cited by 8 · see citing works
HyperIgE in hypomorphic recombination-activating gene defects
Castiello, M. C., Brandas, C., Capo, V., & VILLA, A. M. (2022) · Current Opinion in Immunology · doi:10.1016/j.coi.2022.102279 · Cited by 3 · see citing works
Self-citationRelation between dysbiosis and inborn errors of immunity
Özdemır, Ö. (2024) · World Journal of Methodology · doi:10.5662/wjm.v14.i4.96380 · Cited by 3 · see citing works
Liu, Y., Liu, S., Liu, Y., Li, Q., & Xu, K. (2025) · Clinical Immunology · doi:10.1016/j.clim.2025.110568 · Cited by 2 · see citing works
Changes in the Intestinal Microbiome in Primary Immunodeficiency: Review of Current Data
Скоповец, Е. Я., & Белевцев, М. В. (2022) · Лабораторная диагностика Восточная Европа · doi:10.34883/pi.2022.11.3.010 · Cited by 1 · see citing works
Dissecting the role of gut microbiota heterogeneity in the onset of chronic lung diseases
Lin, Y., Zhang, X., Zuo, Z., & Xiao, Y. (2025) · AMB Express · doi:10.1186/s13568-025-01930-5 · Cited by 1 · see citing works
“…functions in the cardiovascular (Yang et al. 2021; Zhao et al. 2022; Meyer and Bennett 2016), digestive (Vicen-tini et al. 2021), immunological (Castagnoli et al. 2021; Shim et al. 2023), metabolic (Meyer and Bennett 2016), neurological (Wang et al. 2022; Liu et al. 2023) and psychiatric…”
Roncareggi, S., Fioredda, F., Girardi, K., Serrao, S., Capitoli, G., Fumagalli, R., Nobile, M., Fazio, G., Guerra, F., Valsecchi, M. G., et al. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27104294 · Cited by 1 · see citing works
“…gastrointestinal involvement—such as CTLA-4 deficiency [14], chronic granulomatous disease [15], Wiskott– Aldrich syndrome [23], or common variable immunodeficiency [16,24]—an expansion of Proteobacteria and other inflammatory taxa alongside reduced beneficial commensals has been described [13].”
Jappe, U., Risha, M. A., Agache, I. O., Bachert, C., Bröker, B. M., Castagnoli, R., Gadermaier, G., Goodman, R. E., Guemari, A., Hilger, C., et al. (2026) · Allergy · doi:10.1111/all.70510 · Cited by 1 · see citing works
Self-citationDistribution of intraepithelial lymphocytes, mast cells, and goblet cells in the intestine of alpaca
Ma, M., Bai, X., Wang, Z., Dong, Y., Chen, Y., & Cao, J. (2022) · Anatomia Histologia Embryologia · doi:10.1111/ahe.12823 · Cited by 1 · see citing works
“…et al., 2019), but are also involved in intercellular signalling transduction and the regulation of intestinal mucosa- associated immune factors (Castagnoli et al., 2021), which can be divided into the secreted mucins and the membrane- bound mucins according to their existing forms (Etzold &…”
BackgroundInhibitory Effect of Portulaca oleracea L. Polysaccharide on Porcine Rotavirus
Ma, G., Zhou, X., Lu, L., Zhang, X., Yang, X., Luo, X., Li, Z., Cao, J., Li, Y., Zhao, R., et al. (2023) · SAS Journal of Medicine · doi:10.36347/sasjm.2023.v09i05.014
Yang, P., Lu, T., Liang, X., Huang, T., Wu, L., He, Z., Xiao, X., & 樊尚荣 (2024) · Figshare · doi:10.6084/m9.figshare.26687100
Yang, P., Lu, T., Liang, X., Huang, T., Wu, L., He, Z., Xiao, X., & 樊尚荣 (2024) · Figshare · doi:10.6084/m9.figshare.26687103
Impaired mucosal IgA response to SARS-CoV-2 in patients with inborn errors of immunity
Zuo, F., Delavari, S., Shokri, S., Wang, Y., Abolnezhadian, F., Iranparast, S., Salami, F., Sharafian, S., Chavoshzadeh, Z., Rezaei, N., et al. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1696834
“SIgAD is the most prevalent IEI and is associated with recurrent mucosal infections, dysregulated gut microbiota, and increased in fl ammatory markers due to impaired epithelial barrier function and immune regulation (6).”
Wu, Z., Huang, Z.-W., Cao, Z.-J., Sun, Y., Xin-xian, Z., Xu, W.-F., Chen, S., Zhang, Y., & Zhao, S. (2026) · World Journal of Gastroenterology · doi:10.3748/wjg.118595
The Structure of Vertebrate Antigen Receptor Repertoires: An Evolutionary Perspective
Boehm, T. L. J., & Giorgetti, O. B. (2026) · Immunological Reviews · doi:10.1111/imr.70154
Gut microbiota in genetic diseases: from Mendelian disorders to complex traits
Chen, G., Li, J., Huang, T., Zeng, D., Mo, L., Li, J., & Zhu, C. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1908644
“Similarly, monogenic immune defects such as interleukin-10 (IL-10) receptor de fi ciency disrupt host – commensal balance, leading to mucosal permeability and intestinal in fl ammation (83).”
- Authors
- Castagnoli, R., Pala, F., Bosticardo, M., Licari, A., Delmonte, O. M., Villa, A., Marseglia, G. L., & Notarangelo, L. D.
- Affiliations
- National Institutes of Health (US)
- University of Pavia (IT)
- Institute of Genetic and Biomedical Research (IT)
- Corresponding author
- Notarangelo, Luigi Daniele
- ORCID
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2021-01-31
- Volume
- 22
- Issue
- 3
- Pages
- 1416
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC7866830
- OpenAlex
- W3127285656
- Cited by
- 34
- References
- 170
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 7 · 2023: 6 · 2022: 8 · 2021: 2
- FWCI
- 0.60
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (BENCH-TO-BEDSIDE (BTB) PROJECT; RAG deficiency: From pathophysiology to precise gene correction)
- National Health Research Institutes (Division of Intramural Research, NIAID)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- gut microbiota, microbiota-host interactions, primary immunodeficiency, gastrointestinal manifestations, dysbiosis, mucosal permeability, intestinal inflammation, immune homeostasis, commensal bacteria, microbiota-based therapy
- MeSH terms
- Gastrointestinal Microbiome, Host Microbial Interactions, Primary Immunodeficiency Diseases, Homeostasis, Humans, Gastrointestinal Tract, Adaptive Immunity, Dysbiosis
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