Relation between dysbiosis and inborn errors of immunity

Abstract

Inborn errors of immunity (IEI) disorders, formerly primary immune deficiency diseases, are a heterogeneous group of disorders with variable hereditary transitions, clinical manifestations, complications and varying disease severity. Many of the clinical symptoms, signs and complications in IEI patients can be attributed to inflammatory and immune dysregulatory processes due to loss of microbial diversity (dysbiosis). For example, in common variable immunodeficiency patients, the diversity of bacteria, but not fungi, in the gut microbiota has been found to be reduced and significantly altered. Again, this was associated with a more severe disease phenotype. Compromise of the STAT3/Th17 pathway in hyper-IgE syndrome may lead to dysbiosis of the oral microbiota in these patients, causing Candida albicans to switch from commensal to pathogenic. Modification of the microbiota can be used as a therapeutic approach in patients with IEI. Prebiotics, probiotics, postbiotics and fecal microbiota transplantation can be used to restore the balance of the gut microbiota and reduce pathogenicity in IEI patients. Clinical trials are currently underway to understand the impact of this dysbiosis on the phenotype of IEI diseases and its role in their treatment.

Key Words: Immunodeficiency; Microbiome; Microbiota; Fecal microbiota transplantation; Immunoglobulin

Core Tip: Inborn errors of immunity (IEI) disease is associated with microbial dysbiosis and systemic inflammation, especially in the presence of immune dysregulation. Fecal microbiota transplantation in particular, besides not being used as a stand-alone treatment strategy, could be a potential therapeutic tool for dysbiosis in IEI, considering the complications and the complexity of IEI.

INTRODUCTION

Inborn errors of immunity (IEI, formerly primary immunodeficiency) diseases are a heterogeneous group of disorders with variable genetic transmissions, clinical manifestations, complications, and varying disease severity[1]. Many of the clinical symptoms, signs, and complications in IEI patients can be ascribed to inflammatory and immune dysregulation processes due to loss of microbial diversity (dysbiosis) and imbalances in the diet-microbiome-host-immune system axis[2]. The microbiome in IEI patients is reported to have a key role in serving the host immune system preserve homeostasis in the gut. In particular, the intestinal microbiome is a favorable area of study and interest in these aspects in IEI patients. Although the association between the microbiome and humoral immunodeficiency is better known, the relationship between combined immunodeficiency and the microbiome and its possible therapeutic benefits are still under investigation[2,3]. Additional studies investigating the efficacy of microbiota-based approaches and treatments in IEI-related dysbiosis in these patients are needed[2-4].

The contemporary understanding of the microbiome concerning the clinical symptoms and complications found in IEI patients and its potential as a therapeutic approach in IEI forms are the main basis of the aim of this minireview article.

Evaluation tools of microbiome/microbiota in studies

When carrying out microbiome studies, it is important to assess alpha diversity in the sample (single ecosystem) to be studied and beta diversity among individuals. It indicates the quantity and their prevalence of diverse taxa detected in each sample. Beta diversity is an indicator of the variety of the microbial population among different subjects or samples. It is also a marker for the number of different taxa and their prevalence in an environment. In brief, the average species variety of a place at the local measure is called alpha diversity[2,4]. Beta diversity reflects the diversity ratio between regional and local species[2,4].

Microbiome in most common IEI diseases

Here, microbiome and microbiota studies in more common and better-known IEI diseases will be presented in the light of current literature data (Table 1).

Table 1 Microbial dysbiosis on the clinical implications in various inborn errors of immunity.

Inborn errors of immunity/diseases	Microbiota	Clinical findings	Ref.
Hyper-IgE syndrome	Predominance of Candida albicans, decreased abundance of C. parapsilosis, Boletus, and Penicillium	STAT3/Th17 axis play an important role in maintaining C. albicans as a commensal organism	[28]
Wiskott–Aldrich syndrome	Increased abundance of potentially, pathogenic Proteobacteria and Roteobacteria. Decreased levels of protective commensals, e.g., Faecalibacterium prausnitzii, Bacteroidetes and Verrucomicrobia	It may lead to periodontal lesions	[18]
Severe combined immunodeficiency	Increased abundances of Escherichia, Staphylococcus, Enterococcus, Veillonella, Enterobacteriaceae, Adenovirus, and Bocavirus	Increase in disease severity	[16,18]
Selective IgA deficiency	Higher abundance of Firmicutes, Bacteroidetes, Gammaproteobacteria and Prevotella	Increase in systemic inflammation	[1,6,24]
Common variable immunodeficiency	Decreased abundance of beneficial bacteria, e.g., Bifidobacterium and Lactobacillus, Bacteroides and Firmicutes. Increased abundance of Clostridia, Bacilli, Prevotella, and Gammaproteobacteria	Increase in systemic inflammation	[10,14]

Common variable immunodeficiency

The foremost gastrointestinal tract symptom of common variable immunodeficiency (CVID), which is one of the most common immunodeficiencies, is temporary or persistent diarrhea seen in 21%-57% of cases[5]. Detectable pathogens include Cytomegalovirus, Salmonella species, Clostridium difficile, Giardia lamblia, Cryptosporidium parvum, and Campylobacter jejuni[6]. In some studies, Hungatella hathewayi from normal gut microbiota has been related to CVID, like some chronic inflammatory diseases (such as cystic fibrosis and IgA nephropathy)[7]. CVID patients with chronic diarrhea were found to have lower alpha diversity compared to healthy housemates or CVID patients without diarrhea[8]. New research indicates that the immune dysregulation yielding difficulties in CVID patients might be the result of a changed microbiome arrangement and augmented microbial translocation[2].

Decreased bacterial alpha diversity was also found in the more severe CVID phenotype with undetectable low serum IgA levels[2]. IgA production against commensal microbes occurs in Peyer’s patches (PP) where live bacteria are presented by dendritic cell (DC) to B and T cells. Furthermore, secretory IgA selectively adheres to M cells in the gut PP and contributes to exciting the acceptance of IgA-bound pathogen antigens for distribution to DCs, ensuring a positive feedback loop. IgA thus has an essential role in controlling the pro-inflammatory reaction to the bacteria it covers, in establishing and maintaining the integrity of the gut mucosal barrier, and in determining the content of the gut microbiota. IgA-deprived mice were found to have meaningfully lesser gut microbial diversity than wild-type offspring[9].

IgA deficiency detected in CVID patients is highly associated with augmented morbidity from inflammation. Intestinal epithelial damage occurring in CVID cases may be caused by IgA deficiency leading to mucus invasion and epithelial infection. The alpha diversity index of cases with severe IgA deficiency was meaningfully decreased compared with CVID patients with low/normal IgA levels. The 3 bacterial taxa that were more copious in CVID patients than in healthy donors were Clostridia (genera Lachnospiraceae Roseburia and Lachnospiraceae Dorea), Bacilli and Gammaproteobacteria. In contrast, Firmicutes (genus Blautia of Lachnospiraceae and family Christensenellaceae), Actinobacteria (e.g., family Bifidobacteriaceae), and Deltaproteobacteria (genus Desulfovibrionales) were detected to be greatly reduced in CVID[10].

One of the groundbreaking types of research on the microbiome in CVID cases showed low levels of alpha diversity and Bifidobacterium species. However, increased Bacilli, Clostridia, and Gammaproteobacteria species were detected in these cases[10,11]. Among the 3 diverse bacterial taxa, Geobacillus, Acinetobacter baumannii and the otu 15570 bacterium are among those that may contribute to CVID enteropathy[12].

The presence of dysbiosis and reduced alpha diversity is well known, especially in diseases such as CVID. There is no significant difference in beta diversity between adults and children, but alpha diversity is lesser in children than in adults. When compared to adults, the microbiota configuration in children shows a greater diversity of Ruminococcaceae, Bacilli, Actinobacteria, and Bacteroidetes phyla and a lesser diversity of Methanobacteriales phyla[13].

CVID patients have shown a less diverse and significantly altered bacterial, but not fungal, gut microbiota. Again, this has been associated with a more severe disease phenotype[14].

Selective IgA deficiency

Using a metagenomic approach, the researchers compared the intestinal microbial groups in the feces of 21 IgA-deficient cases with 34 age- and sex-matched healthy controls. Seventeen microbial species in the phyla Firmicutes, Bacteroidetes, and Proteobacteria (Gammaproteobacteria only, comprising E. coli) were greater in IgA-deficient patients. Moreover, 3 oral commensal bacteria (Haemophilus parainfluenza, Streptococcus sanguinis and Veillonella parvula) and two Prevotella species were also found at high rates in the selective IgA deficiency cohort. Most of the bacteria lost in IgA-deficient patients (13 of 14) belonged to the phylum Firmicutes (genus Faecalibacterium and family Lachnospiraceae), while one belonged to the phylum Bacteroides. In short, IgA deficiency caused a loss of some typical favorable symbionts and an increase in pathobionts[15].

Faecalibacterium, a genus with anti-inflammatory effects for the intestinal mucosa, was markedly reduced in patients with inflammatory bowel disease (IBD). However, the pro-inflammatory species, Gammaproteobacteria and Prevotella, are increased in patients with selective IgA deficiency. Analysis of the gut microbiota in these cases shows that the oral microbiota is ectopically localized in the lower digestive tract[6].

Severe combined immunodeficiency

A study showed that the bacterial taxonomy of the intestinal microbiota in severe combined immunodeficiency patients changes in long periods of time, resulting in altered microbiome spectrum before and after hematopoietic stem-cell transplantation (HSCT)[6]. Graft-vs-host disease, which can also be seen after HSCT, is affected by different factors, plus the intestinal microbiota. Decreased microbial miscellany after HSCT causes the predominance of Staphylococcus, Escherichia, and Enterococcus species[16,17].

Wiskott–Aldrich syndrome

Bacteroidetes and Verrucomicrobia were less abundant in patients with Wiskott–Aldrich syndrome (WAS), whereas Proteobacteria were significantly more abundant compared to healthy controls[18,19]. Roughly 10% of WAS patients live with dysbiosis causing severe, sporadic, and recurrent gastrointestinal inflammation. Therefore, WAS cases are inclined to develop an acute and early IBD that phenotypically resembles polygenetic IBD[4].

Hyper-IgE syndrome

Candida albicans are more common in autosomal dominant (AD)- Hyper-IgE syndrome (HIES) patients than others (e.g., C. parapsilosis, Boletus, and Penicillium) compared to healthy patients. AD-HIES patients have severe dysbiosis with Candida albicans predominating during active fungal infection. In uninfected patients, the genus Malassezia was predominant. A modification of the skin microbiota towards gram-negative colonization (especially Acinetobacter spp.) is linked with a weak in vitro immune reaction to C. albicans and S. aureus[18].

Immunodeficient cases with defects in the Th17/IL-17 pathway are more inclined to propagate oral fungal infections. Patients with HIES due to STAT3 deficiency have been reported to have low salivary antifungal activity as a result of the reduction of specific antimicrobial effectors containing human β-defensin 2 and multiple histatins. In these patients, the STAT3-Th17 axis is important for C. albicans commensalism and the formation of oral bacterial groups. In these cases, C. albicans forms a symbiotic life with orally present Streptococcus mutans and Streptococcus oralis[18]. A compromised STAT3/Th17 pathway may lead to dysbiosis of the oral microbiota in these patients, causing C. albicans to shift from commensal to pathogenic[4,20]. Selected oral streptococci can increase the virulence of C. albicans by invading oral tissue and causing mucosal lesions[6]. Another study reported a decrease in abundant gram-negative bacteria (such as Fusobacteria and Prevotella) in oral swabs of HIES patients.

In a study, the oral microbiome of a large cohort of 36 patients with AD-HIES (STAT3 deficiency) was analyzed. Oral bacterial groups were also found to be dysbiotic in AD-HIES, especially when active Candida infection was present. Many prevalent oral commensal bacteria, comprising Porphyromonas, Neisseria, and Haemophilus, had lesser comparative copiousness in autosomal dominat-HIES patients, even though the genus Capnocytophaga was unequally represented[19,20].

Management

Modification of the microbiota can be used as a therapeutic approach in IEI patients[4]. Prebiotics, probiotics, postbiotics, and fecal microbiota transplantation (FMT) have been established to renovate the equilibrium of intestinal microbiota and reduce pathogenicity in IEI patients[4,21,22].

Dysbiosis can be treated by oral intake of live, natural probiotic bacteria. Metabolites from prebiotic fibers serve as a material for probiotic commensal bacteria. The ability of prebiotics to modify immunity has been utilized to produce complementary immunomodulatory therapies for a range of IEIs. Probiotics increase the manufacture of bioactive peptides by enabling the interaction of gut epithelial and mucosal immune cells and intestinal microbiota and help protect intestinal epithelial barriers[4].

Secretory IgA and systemic IgG are known to act synergistically in defense against gut microbiota. High serum levels of IgG directed against gut microbiota have been detected in animal models of IEI diseases. Furthermore, IgG antibodies to E. coli have been detected in IBD cases and secretory IgA-deficient mice[23]. Fadlallah et al[24] have also shown that serum anti-microbiota IgG is increased in cases with selective IgA deficiency compared to controls[24]. These circulating IgGs are formed against preserved antigenic motifs and protect against commensal bacteria. It is thought that intravenous immunoglobulin products consisting of selective IgA-deficient individuals in the pool may increase protection against dysbiosis and microbial displacement in CVID patients[4,16,24].

FMT involves the administration of healthy donor feces to the patient to restore spoiled intestinal microbiota and provide therapeutic profits. FMT, which is the standard for the treatment of recurrent Clostridium difficile infections, may not be used as a single treatment modality but as likely management of immune dysregulation in IEI, considering its side effects and the complexity of IEI[2]. A case with immune dysregulation, polyendocrinopathy, enteropathy, X-linked disease, severe enteropathy, and chronic diarrhea was reported to be efficaciously treated with FMT[16,25]. The disadvantage of this type of therapeutic management includes procedure-related risks, such as insufficient prior screening of FMT for multidrug-resistant microorganisms, especially for immunocompromised recipients[2,26]. Gut dysbiosis has been observed in germ-free mice transplanted with feces from CVID cases with non-infectious problems. No dysbiosis was observed with FMT using only feces from CVID cases with an infectious phenotype or from household contacts. Intestinal dysbiosis in non-infectious CVID cases is seen with augmented richness of Dysgonomonas mossii and Bacillus massiliensis[2,27,28].

CONCLUSION

The presence of dysbiosis in different types of IEI patients has been demonstrated in different clinical studies. Studies are ongoing to understand the role of this dysbiosis on the phenotype of the IEI diseases and in their treatment.