The immune system and the microbiome

The role of the gut microbiota for the mammalian immune system – using inborn errors of immunity as a window into co-development and complexity

Inborn errors of immunity (IEI) comprise a group of more than 500 genetic disorders that result in the impairment of host immune responses. IEI display a broad range of manifestations, including recurrent infections, autoimmunity, lymphoproliferation, malignancy, and granulomas, posing challenges for physicians in diagnosis and treatment. Furthermore, the penetrance, expressivity, and severity of IEI vary even among patients carrying the same mutation. However, modifiers determining the disease penetrance, severity, and expressivity remain unknown.

The microbiome appears essential for maintaining host immunity (1). Therefore, especially in patients with a defective immune system, this delicate balance between immune homeostasis and microbial diversity is at stake. Hence, the microbial composition and diversity patients with inborn errors of immunity are under close investigation. Dysbiosis and reduced alpha-diversity are observed particularly in common variable immunodeficiency (CVID), chronic granulomatous disease (CGD) (2-4). However, whether microbial dysbiosis is the key determinant of IEI disease expressivity and severity remains unknown. Answering this question will encourage the development of novel therapies, such as fecal microbiota transplantation (FMT) (5), to restore the balance of the gut microbiota and improve IEI patient fitness.

We combine human cohort studies and mouse models to investigate the role of the microbiota in disease penetrance and severity in patients with inborn errors of immunity, i.e. CTLA-4 insufficiency or NF-κB insufficiency. Through shotgun metagenomics and 16S rRNA sequencing of patient stool samples at different disease stages, we unveil how microbial dysbiosis develops with disease progression. Moreover, by evaluating the immune landscape in ctla4^+/-or nfkb^+/- gnotobiotic and wildling mice, we seek to elucidate the immune pathophysiology of CTLA4 insufficiency or NF-κB insufficiency and determine whether the microbial dysbiosis is cause or consequence of the immune dysregulation.

References

Zhao B, et al. Helicobacter spp. are prevalent in wild mice and protect from lethal Citrobacter rodentium infection in the absence of adaptive immunity. Cell Rep. 2023;42(6):112549. doi: 10.1016/j.celrep.2023.112549.
Sharma M, et al. Microbiome and Its Dysbiosis in Inborn Errors of Immunity. Pathogens. 2023;12(4) doi: 10.3390/pathogens12040518.
Nöltner C, et al. Fecal Immunoglobulin Levels as a Modifier of the Gut Microbiome in Patients with Common Variable Immunodeficiency. J Clin Immunol. 2023;43(6):1208-20. doi: 10.1007/s10875-023-01469-9.
van Schewick CM, et al. Altered Microbiota, Impaired Quality of Life, Malabsorption, Infection, and Inflammation in CVID Patients With Diarrhoea. Front Immunol. 2020;11:1654. doi: 10.3389/fimmu.2020.01654.
Egg D, et al. Therapeutic options for CTLA-4 insufficiency. J Allergy Clin Immunol. 2022;149(2):736-46. doi: 10.1016/j.jaci.2021.04.039.

Funding

This study is supported by the German Research Foundation (DFG), collaborative research center IMPATH, project SFB1160/3_B5.

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Prof. Dr. Michele Proietti
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Dr. Bei Zhao
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