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Published on: February 2, 2018
Gut dysbiosis modulates the immune response to factor VIII in murine hemophilia A
Julie Tarrant1, Matthew Cormier1, Kate Nesbitt1
1Department of Pathology and Molecular Medicine, Richardson Laboratory, Queen's University, Kingston, ON, Canada.
Abstract:
The development of neutralizing FVIII antibodies is the most serious complication of hemophilia A treatment. The currently known patient- and treatment-related risk factors for inhibitor development do not accurately predict this adverse event in all patients. The composition of the gut microbiota has been shown to influence immune-mediated diseases at distant anatomical sites (eg, lungs, brain, and joints). We demonstrate that a disrupted gut microbiota can be created in a mouse model of hemophilia A using a broad-spectrum antibiotic. Under controlled conditions, this sustained dysbiosis was associated with an increase in splenic B cells and the development of higher titer, FVIII-specific immunoglobulin G antibodies after FVIII challenge. Splenic and mesenteric lymph node cytokines, T cells, and dendritic cells were unaffected before administration of FVIII. However, the immune transcriptome of both aforementioned secondary lymphoid organs was significantly modified. Short-chain fatty acids (SCFAs), which are immunomodulatory microbial metabolites, were depleted in cecal contents of the dysbiotic mice. Furthermore, supplementation of the drinking water with butyrate, the most immunologically active SCFA, successfully achieved attenuation of the FVIII immune response. Collectively, data from this exploratory study suggest that the composition of the gut microbiota alters the FVIII immune response via the action of specific microbial metabolites on the immune cell transcriptome and that oral supplementation with butyrate effectively reduces the FVIII immune response.
Insights
Disrupting gut microbiota in hemophilia A mice increased FVIII antibodies. Supplementing with butyrate, a microbial metabolite, reduced this immune response, suggesting a link between gut health and treatment complications.
Area of Science:
- Immunology
- Microbiome research
- Hematology
Background:
- Neutralizing Factor VIII (FVIII) antibodies are a major complication in hemophilia A treatment.
- Existing risk factors do not fully predict inhibitor development.
- Gut microbiota composition influences immune responses in various diseases.
Purpose of the Study:
- To investigate the impact of gut dysbiosis on FVIII immune responses in a mouse model of hemophilia A.
- To explore the role of microbial metabolites, specifically short-chain fatty acids (SCFAs), in modulating these responses.
- To assess the therapeutic potential of butyrate supplementation.
Main Methods:
- Induced gut dysbiosis in hemophilia A mice using broad-spectrum antibiotics.
- Challenged mice with FVIII and analyzed immune cell populations and cytokine profiles.
- Examined the immune cell transcriptome in lymphoid organs.
- Measured SCFA levels in cecal contents.
- Administered butyrate supplementation to assess its effect on the immune response.
Main Results:
- Sustained gut dysbiosis led to increased splenic B cells and higher FVIII-specific IgG antibody titers.
- Immune transcriptomes of secondary lymphoid organs were significantly altered in dysbiotic mice.
- Depletion of SCFAs, particularly butyrate, was observed in dysbiotic mice.
- Butyrate supplementation attenuated the FVIII immune response.
Conclusions:
- Gut microbiota composition significantly influences the FVIII immune response.
- Microbial metabolites like SCFAs play a role in modulating immune responses via the immune cell transcriptome.
- Oral butyrate supplementation shows promise in reducing FVIII immune responses in hemophilia A.
