Granulomatosis with polyangiitis (GPA), formerly known as Wegener’s granulomatosis, is a rare autoimmune disease that causes inflammation of the blood vessels (vasculitis) and the formation of granulomas, which are clumps of immune cells. This disease primarily affects the respiratory tract and kidneys, but it can also involve other organs.
The human microbiome refers to the community of microorganisms (bacteria, viruses, fungi, etc.) that live on and in the human body. These microorganisms are crucial in maintaining human health by influencing various physiological processes, including immune regulation, metabolism, and protection against pathogens.
Recent studies have suggested that alterations in the microbiome may be associated with the development and progression of various autoimmune diseases, including GPA. However, the exact microbiome signature associated with GPA is poorly defined, and research in this area is still emerging.
In general, studies on the microbiome in autoimmune diseases like GPA often focus on characterizing the composition and function of the microbiome in affected individuals compared to healthy controls. Researchers may analyze microbial communities in different body sites, such as the gut, oral cavity, or respiratory tract, to identify differences in microbial diversity, abundance, and function that may be associated with the disease.
It’s worth noting that various factors, including diet, medication use, and other environmental factors, influence the microbiome. Additionally, the relationship between the microbiome and autoimmune diseases like GPA is likely bidirectional, meaning that alterations in the microbiome may contribute to the development or progression of the disease, and the disease itself or its treatment may also impact the microbiome.
In summary, while there is growing interest in understanding the microbiome signature associated with GPA and other autoimmune diseases, this is a relatively new area of research, and the exact microbial alterations associated with GPA are not yet well defined.
1. The Microbiome Signature of Granulomatosis with Polyangiitis (GPA)
1.1 Anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitides (AAV)
The anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides (AAV) are autoimmune diseases characterized by systemic inflammation and subsequent destruction of small to medium blood vessels within target organs, particularly the kidneys and respiratory tract. It is a rare but life-threatening condition, with an incidence of 13–20 people per million per year worldwide, and a peak age of onset of 65–74 years (1).
Syndromically, AAV can present as granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) or eosinophilic granulomatosis with polyangiitis (EGPA). If untreated, mortality of AAV may be as high as 80% within one year of diagnosis [x]. Treatment involves potent immunosuppressive agents that may have significant associated adverse effects, including infection and malignancy. Infection accounts for almost half of the deaths in treated patients in the first year [x]. AAV-related glomerulonephritis (GN) is an important cause of end-stage kidney disease and commonly defines outcomes in AAV.
Granulomatosis with polyangiitis (GPA) is a potentially fatal systemic vasculitis marked by granulomatous inflammation and a high recurrence rate. Up to 90% of individuals with GPA experience rhinosinusitis, linked to an increased likelihood of disease recurrence. Although significant advancements have been made in elucidating the immune-related mechanisms of GPA, the factors that instigate disease activity remain largely unclear.
However, studies focusing on the underlying mechanisms and disease patterns indicate that microorganisms, specifically those found in the nasal cavity, could be a crucial environmental factor in triggering GPA. A phenomenon known as cross-reactivity, where peptides (short chains of amino acids) from both the host and bacteria interact, may produce harmful antibodies called anti-neutrophil cytoplasmic antibodies (ANCA), which have a known association with GPA. Further, low-grade infections can also trigger the release of inflammatory cytokines, which prepare neutrophils (a type of white blood cell) for activation by ANCA or prompt the neutrophils to release neutrophil extracellular traps (NETs) that contain ANCA antigens. This process further disrupts immune tolerance and produces autoantibodies— antibodies that mistakenly target and react with a person’s own tissues or organs.
ANCAs are primarily of two types: 1) C-ANCA, where ‘C’ denotes cytoplasmic, and 2) P-ANCA, where ‘P’ signifies perinuclear. C-ANCAs are especially strongly associated with Granulomatosis with Polyangiitis, as these antibodies are found in up to 80% of patients, and this prevalence may be even higher in those with active disease.
1.2 GPA microbiome vs healthy controls
The most abundant bacteria at the genera-level were (in decreasing order of abundance) Corynebacterium, Staphylococcus, and Propionibacterium, similar to previously published studies of nasal microbial composition in healthy individuals. However, species-level findings reveal significantly altered nasal mycobiota and microbiota between GPA study participants and healthy controls. Table 1 details the current knowledge of the Microbiome Signature of Granulomatosis with polyangiitis (GPA).
More Firmicutes Streptococcus
More Proteobacteria Neisseriaceae
More Proteobacteria Moraxella
More Firmicutes Alloiociccus
More Proteobacteria Haemophilus
More Firmicutes Clostridiales
Less Firmicutes Peptoniphilus
More Firmicutes Anaerococcus
More Firmicutes Lactobacillus
Gram-positive, aerobically growing rods belonging to the genus Corynebacterium colonize humans’ skin and mucosal surfaces. Lipophilic corynebacteria are a particularly relevant subgroup of corynebacteria since they are often involved in infections of hospitalized patients, showing multi-resistance to antimicrobials [x].
Species-level analyses identify an association between a higher abundance of nasal Corynebacterium tuberculostearicum and higher PR3-ANCA levels [x] in patients with Granulomatosis with polyangiitis (GPA).
Staphylococcus aureus is a bacterium with a spherical shape and a Gram-positive classification, belonging to the Bacillota group. It is commonly present in the body’s microbial community, often in the upper respiratory tract and skin. Characterization of the nasal microbiota in GPA found higher relative abundance of Staph aureus [x], and that chronic nasal carriage of Staphylococcus aureus is associated with a higher risk of relapse [x].
In the animal model of ANCA Associated Vasculitis (AAV), Staphylococcus aureus also induced anti-MPO autoimmunity and vasculitis [x].
Staphylococcus aureus may be a direct pathogenetic factor in granulomatosis with polyangiitis (former Wegener’s granulomatosis)[x]. Chronic bacterial colonization or chronic infections of the upper respiratory tract have been suspected to be a trigger of autoimmune vasculitis. [x]
|Staphylococcus pseudintermedius||S. pseudintermedius is a gram-positive, coagulase-positivecommensal and opportunistic pathogen commonly found on the skin and in the nares, mouth, pharynx of cats and dogs that causes skin and soft tissue infections. |
GPA patients show a significant association with colonization by Staphylococcus pseudintermedius. However, s. pseudintermedius’ contribution to GPA pathogenesis is unclear [x].
However, genome sequencing of s. pseudintermedius isolates revealed penicillin (blaZ), tetracycline (tetM), aminoglycosides (aacA-aphD), and trimethoprim-resistance genes. All isolates were susceptible to methicillin [x].
Cutibacterium acnes, previously known as Propionibacterium acnes, is a Gram-positive bacterial species that naturally resides on the skin as a commensal organism. Research has shown that C. acnes can provoke the formation of granulomas [x].
|Planococcaceae||Planococcaceae produce a yellow-like pigment as a secondary metabolite to protect the cell, but to also reduce the cytotoxicity of heavy metal ions such as copper .**** |
Disease activity in participants with GPA was linked to a lower abundance of fungal order Malasseziales compared with participants with GPA who were in remission [x].
Compared with healthy controls, participants with GPA exhibited significantly different microbial composition, and a lower relative abundance of Propionibacterium acnes [x].
Compared with healthy controls, participants with GPA exhibited significantly different microbial composition, and a lower relative abundance of Staphylococcus epidermidis [x].
Pharamcological Treatment Modalities
|Trimethoprim/sulfamethoxazole (SXT) or Bactrim||Trimethoprim/sulfamethoxazole (SXT) or Bactrim, is used to treat infectious diseases caused by Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA). Trimethoprim/sulfamethoxazole prevents relapse in patients with GPA [x].|
However, treatment with antibiotics alters the microbiome. A study investigating the role of trimethoprim-sulfamethoxazole on the gut microbiome found that the Shannon diversity at a phylum level declined by 17.95%, and especially patients with high baseline diversity were more likely to lose diversity. Long-term treatment with trimethoprim-sulfamethoxazole might exhibit detrimental effects on the commensal microbiome, fueling the inflammatory response in some cases. During treatment with trimethoprim-sulfamethoxazole, an increase in Proteus vulgaris, Actinomyces meyeri and Acinetobacter lwoffii was observed .
Further, data suggests that germ-free mice, when subjected to ischemia-induced acute kidney injury, have significantly worse structural/functional renal injuries and inflammation compared with control mice. Furthermore, the microbiota may have a wider influence and role in autoimmune disease through immunomodulatory effects, recognized by its influence on the polarization of T-cell subsets and natural killer cells [x].
ANCA is pathogenic by binding to neutrophils and monocytes and inducing cellular activation, with resultant microvascular endothelial injury. However, depletion of the autoantibody alone may not be effective in disease control, and disease can be quiescent while the antibody remains detectable, suggesting redundancy in injurious autoimmune pathways [x].
|Rituximab||Rituximab is used to treat certain types of cancer like non-Hodgkin lymphoma and chronic lymphocytic leukemia. It is also used to treat rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis, and pemphigus vulgaris.|
|TAVNEOS® (avacopan) is a non-steroidal targeted therapy that was designed to block a receptor involved inANCA-associated vasculitis.|