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Bugs & us: the role of the gut in autoimmunity.

Luckey D, Gomez A, Murray J, White B, Taneja V - Indian J. Med. Res. (2013)

Bottom Line: Genomic wide association studies have confirmed the HLA (human leukocyte antigen) class II genes as the strongest risk factor for predisposition to RA.Using transgenic mice expressing RA-associated and resistant HLA genes, we have developed a collagen-induced arthritis (CIA) model that shares similarities with human disease in sex-bias, autoantibody profile and phenotype.Studies in animal models underscore the impact of the gut flora in extra-intestinal diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Medicine, Division ofRheumatology, Mayo Clinic, Rochester, MN, 55905, USA.

ABSTRACT
Rheumatoid arthritis (RA) is a multifactorial disease and requires interaction between genetic and environmental factors for predisposition. The presence of bacterial DNA of the gut residing commensals in synovium as well as dysbiosis of certain commensal bacteria in faecal samples of RA patients as compared to controls suggest a significant role of the gut flora in pathogenesis of RA. The gut commensals are involved in host immune development and function suggesting they might be critical epigenetic factors modifying autoimmune diseases like RA. This raises the question if gut-derived commensal can be exploited to generate a biomarker profile along with genetic factors to define individuals at risk. Genomic wide association studies have confirmed the HLA (human leukocyte antigen) class II genes as the strongest risk factor for predisposition to RA. HLA-DQ8 and DRB1FNx010401 molecules predispose to develop arthritis while DRB1FNx010402 provides protection. Interaction between host genetic factors like major histocompatibility complex (MHC) and gut microbiota and its impact on the development of RA is difficult to study in humans due to high variability in the genetic factors and diet. Animal models provide a means to study the molecular basis of pathogenesis thereby providing a basis for developing therapeutic strategies. Using transgenic mice expressing RA-associated and resistant HLA genes, we have developed a collagen-induced arthritis (CIA) model that shares similarities with human disease in sex-bias, autoantibody profile and phenotype. Studies in transgenic mice suggest that arthritis-susceptibility may be associated with dysbiosis in the gut microbiome. Studies in animal models underscore the impact of the gut flora in extra-intestinal diseases. Exploring the role of gut microbes will significantly advance our understanding of RA pathogenesis and may further help develop strategies for mucosal modulation of RA.

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Relative abundance of OTUs in the faecal microbiomes of male and female *0401 and *0402 mice. (A) *0402 females show significantly higher relative abundances of Bifidobacterium-Parabacteroides OTUs while males harbour high levels of Barnesiella viscericola. (B) Bipartite interaction matrix plot showing the relationships between the main OTUs detected in male and female *0402 mice. (C) Male *0401 mice gut microbiome has higher frequency of Bifidobacteria compared to females. (D) Bipartite interaction matrix plot showing the relationships between the main OTUs detected and sex. The position, width and direction of the upper multicolor blocks and wedges show how abundant each OTU is in males or females. Source: Ref. 79.
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Figure 3: Relative abundance of OTUs in the faecal microbiomes of male and female *0401 and *0402 mice. (A) *0402 females show significantly higher relative abundances of Bifidobacterium-Parabacteroides OTUs while males harbour high levels of Barnesiella viscericola. (B) Bipartite interaction matrix plot showing the relationships between the main OTUs detected in male and female *0402 mice. (C) Male *0401 mice gut microbiome has higher frequency of Bifidobacteria compared to females. (D) Bipartite interaction matrix plot showing the relationships between the main OTUs detected and sex. The position, width and direction of the upper multicolor blocks and wedges show how abundant each OTU is in males or females. Source: Ref. 79.

Mentions: According to ANOSIM test there were significant differences in the bacterial community structures between male and female *0402 mice that were driven by specific bacteria. The OTUs distributions at the genus and phylum levels confirmed that the higher abundance of Actinobacteria (including Bifidobacterium) and Bacteroidetes, and lower levels of Firmicutes (including Allobaculum) in *0402 females drive the observed differences between sexes in *0402 mice. In contrast, the ANOSIM test for *0401 mice did not show differences in faecal microbiota sex-based suggesting arthritis-susceptible mice had lost the microbial dynamism required for immune regulation in mice. However, *0401 males showed a significantly higher abundance of B. pseudolongum compared to females79 (Fig. 3). These data suggest that a loss of the gut microbial dynamism in females may, in combination with the genetic factors, contribute to disease susceptibility. These studies also point out that sex hormones may have a significant role in modulation of the gut microbiome. In humans, men with RA do have higher levels of estrogen84, suggesting that host gut-hormonal axis may modulate immune response in favour of susceptibility in genetically susceptible individuals.


Bugs & us: the role of the gut in autoimmunity.

Luckey D, Gomez A, Murray J, White B, Taneja V - Indian J. Med. Res. (2013)

Relative abundance of OTUs in the faecal microbiomes of male and female *0401 and *0402 mice. (A) *0402 females show significantly higher relative abundances of Bifidobacterium-Parabacteroides OTUs while males harbour high levels of Barnesiella viscericola. (B) Bipartite interaction matrix plot showing the relationships between the main OTUs detected in male and female *0402 mice. (C) Male *0401 mice gut microbiome has higher frequency of Bifidobacteria compared to females. (D) Bipartite interaction matrix plot showing the relationships between the main OTUs detected and sex. The position, width and direction of the upper multicolor blocks and wedges show how abundant each OTU is in males or females. Source: Ref. 79.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928703&req=5

Figure 3: Relative abundance of OTUs in the faecal microbiomes of male and female *0401 and *0402 mice. (A) *0402 females show significantly higher relative abundances of Bifidobacterium-Parabacteroides OTUs while males harbour high levels of Barnesiella viscericola. (B) Bipartite interaction matrix plot showing the relationships between the main OTUs detected in male and female *0402 mice. (C) Male *0401 mice gut microbiome has higher frequency of Bifidobacteria compared to females. (D) Bipartite interaction matrix plot showing the relationships between the main OTUs detected and sex. The position, width and direction of the upper multicolor blocks and wedges show how abundant each OTU is in males or females. Source: Ref. 79.
Mentions: According to ANOSIM test there were significant differences in the bacterial community structures between male and female *0402 mice that were driven by specific bacteria. The OTUs distributions at the genus and phylum levels confirmed that the higher abundance of Actinobacteria (including Bifidobacterium) and Bacteroidetes, and lower levels of Firmicutes (including Allobaculum) in *0402 females drive the observed differences between sexes in *0402 mice. In contrast, the ANOSIM test for *0401 mice did not show differences in faecal microbiota sex-based suggesting arthritis-susceptible mice had lost the microbial dynamism required for immune regulation in mice. However, *0401 males showed a significantly higher abundance of B. pseudolongum compared to females79 (Fig. 3). These data suggest that a loss of the gut microbial dynamism in females may, in combination with the genetic factors, contribute to disease susceptibility. These studies also point out that sex hormones may have a significant role in modulation of the gut microbiome. In humans, men with RA do have higher levels of estrogen84, suggesting that host gut-hormonal axis may modulate immune response in favour of susceptibility in genetically susceptible individuals.

Bottom Line: Genomic wide association studies have confirmed the HLA (human leukocyte antigen) class II genes as the strongest risk factor for predisposition to RA.Using transgenic mice expressing RA-associated and resistant HLA genes, we have developed a collagen-induced arthritis (CIA) model that shares similarities with human disease in sex-bias, autoantibody profile and phenotype.Studies in animal models underscore the impact of the gut flora in extra-intestinal diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Medicine, Division ofRheumatology, Mayo Clinic, Rochester, MN, 55905, USA.

ABSTRACT
Rheumatoid arthritis (RA) is a multifactorial disease and requires interaction between genetic and environmental factors for predisposition. The presence of bacterial DNA of the gut residing commensals in synovium as well as dysbiosis of certain commensal bacteria in faecal samples of RA patients as compared to controls suggest a significant role of the gut flora in pathogenesis of RA. The gut commensals are involved in host immune development and function suggesting they might be critical epigenetic factors modifying autoimmune diseases like RA. This raises the question if gut-derived commensal can be exploited to generate a biomarker profile along with genetic factors to define individuals at risk. Genomic wide association studies have confirmed the HLA (human leukocyte antigen) class II genes as the strongest risk factor for predisposition to RA. HLA-DQ8 and DRB1FNx010401 molecules predispose to develop arthritis while DRB1FNx010402 provides protection. Interaction between host genetic factors like major histocompatibility complex (MHC) and gut microbiota and its impact on the development of RA is difficult to study in humans due to high variability in the genetic factors and diet. Animal models provide a means to study the molecular basis of pathogenesis thereby providing a basis for developing therapeutic strategies. Using transgenic mice expressing RA-associated and resistant HLA genes, we have developed a collagen-induced arthritis (CIA) model that shares similarities with human disease in sex-bias, autoantibody profile and phenotype. Studies in transgenic mice suggest that arthritis-susceptibility may be associated with dysbiosis in the gut microbiome. Studies in animal models underscore the impact of the gut flora in extra-intestinal diseases. Exploring the role of gut microbes will significantly advance our understanding of RA pathogenesis and may further help develop strategies for mucosal modulation of RA.

Show MeSH
Related in: MedlinePlus