Modulation of Inflammatory Arthritis in Mice by Gut Microbiota Through Mucosal Inflammation and Autoantibody Generation

Jubair, Widian; Hendrickson, Jason D.; Severs, Erin; Schulz, Hanna M.; Adhikari, Sumitra; Ir, Diana; Pagan, Jose D.; Anthony, Robert M.; Robertson, Charles E.; Frank, Daniel N.; Banda, Nirmal K.; Kuhn, Kristine A.

doi:10.1002/art.40490

Cited by 136 publications

(140 citation statements)

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“…Our data also show that zonulin-dependent increase of intestinal permeability essentially results from microbial dysbiosis initiated by the arthritogenic combination of auto-antigen and adjuvant. This finding is in accordance with a previous study showing that adjuvant alone was not sufficient to initiate mucosal inflammation 39 . In support of the role of microbial dysbiosis, stool transfer was sufficient to initiate intestinal barrier changes in germ-free mice.…”

Section: Discussionsupporting

confidence: 94%

“…A ltered intestinal microbiota composition, termed "dysbiosis", is associated with autoimmune diseases, particularly type 1 diabetes 1 , multiple sclerosis 2 , systemic lupus erythematosus 3 and rheumatoid arthritis (RA) 4,5 . Several findings support the hypothesis that the onset of RA is linked to the intestinal microbiota, for example that cell wall fragments from various intestinal bacteria have been found to be arthritogenic 6,7 , some drugs used to treat arthritis have antimicrobial effects (chloroquine, sulfasalazine and minocycline) [8][9][10] and the restoration of eubiosis in arthritis patients showing clinical improvement 7,11 .…”

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confidence: 99%

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Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis

et al. 2020

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Gut microbial dysbiosis is associated with the development of autoimmune disease, but the mechanisms by which microbial dysbiosis affects the transition from asymptomatic autoimmunity to inflammatory disease are incompletely characterized. Here, we identify intestinal barrier integrity as an important checkpoint in translating autoimmunity to inflammation. Zonulin family peptide (zonulin), a potent regulator for intestinal tight junctions, is highly expressed in autoimmune mice and humans and can be used to predict transition from autoimmunity to inflammatory arthritis. Increased serum zonulin levels are accompanied by a leaky intestinal barrier, dysbiosis and inflammation. Restoration of the intestinal barrier in the pre-phase of arthritis using butyrate or a cannabinoid type 1 receptor agonist inhibits the development of arthritis. Moreover, treatment with the zonulin antagonist larazotide acetate, which specifically increases intestinal barrier integrity, effectively reduces arthritis onset. These data identify a preventive approach for the onset of autoimmune disease by specifically targeting impaired intestinal barrier function.

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Section: Discussionsupporting

confidence: 94%

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confidence: 99%

Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis

et al. 2020

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“…We have also demonstrated that dysbiosis is an early feature of disease in HLA-B27transgenic rats, preceding the onset of clinical disease in the gut or joints (23). Similarly, gut dysbiosis has been demonstrated in RA (24,25), and animal models of RA such as collagen-induced arthritis have been shown to be influenced by the gut microbiome (26,27). In these studies, it is difficult to distinguish the potential effects of the gut microbiome on the disease from the effects of immunologic processes in the intestinal wall or the effects of treatments on the intestinal microbiome.…”

Section: Introductionmentioning

confidence: 54%

HLA alleles associated with risk of ankylosing spondylitis and rheumatoid arthritis influence the gut microbiome

Asquith

Sternes

Costello

et al. 2019

Preprint

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Objective. HLA alleles affect susceptibility to more than 100 diseases, but the mechanisms that account for these genotype-disease associations are largely unknown. HLA alleles strongly influence predisposition to ankylosing spondylitis (AS) and rheumatoid arthritis (RA). Both AS and RA patients have discrete intestinal and fecal microbiome signatures. Whether these changes are the cause or consequence of the diseases themselves is unclear. To distinguish these possibilities, we examined the effect of HLA-B27 and HLA-DRB1 RA risk alleles on the composition of the intestinal microbiome in healthy individuals.Methods. Five hundred sixty-eight stool and biopsy samples from 6 intestinal sites were collected from 107 healthy unrelated subjects, and stool samples were collected from 696 twin pairs from the TwinsUK cohort. Microbiome profiling was performed using sequencing of the 16S ribosomal RNA bacterial marker gene. All subjects were genotyped using the Illumina CoreExome SNP microarray, and HLA genotypes were imputed from these data.Results. Associations were observed between the overall microbial composition and both the HLA-B27 genotype and the HLA-DRB1 RA risk allele (P = 0.0002 and P = 0.00001, respectively). These associations were replicated using the stool samples from the TwinsUK cohort (P = 0.023 and P = 0.033, respectively).Conclusion. This study shows that the changes in intestinal microbiome composition seen in AS and RA are at least partially due to effects of HLA-B27 and HLA-DRB1 on the gut microbiome. These findings support the hypothesis that HLA alleles operate to cause or increase the risk of these diseases through interaction with the intestinal microbiome and suggest that therapies targeting the microbiome may be effective in preventing or treating these diseases.

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“…We have also demonstrated that dysbiosis is an early feature of disease in HLA–B27–transgenic rats, preceding the onset of clinical disease in the gut or joints . Similarly, gut dysbiosis has been demonstrated in RA , and animal models of RA such as collagen‐induced arthritis have been shown to be influenced by the gut microbiome . In these studies, it is difficult to distinguish the potential effects of the gut microbiome on the disease from the effects of immunologic processes in the intestinal wall or the effects of treatments on the intestinal microbiome.…”

Section: Introductionmentioning

confidence: 99%

HLA Alleles Associated With Risk of Ankylosing Spondylitis and Rheumatoid Arthritis Influence the Gut Microbiome

Asquith¹,

Sternes

Costello

et al. 2019

Arthritis & Rheumatology

135

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Objective HLA alleles affect susceptibility to more than 100 diseases, but the mechanisms that account for these genotype–disease associations are largely unknown. HLA alleles strongly influence predisposition to ankylosing spondylitis (AS) and rheumatoid arthritis (RA). Both AS and RA patients have discrete intestinal and fecal microbiome signatures. Whether these changes are the cause or consequence of the diseases themselves is unclear. To distinguish these possibilities, we examined the effect of HLA–B27 and HLA–DRB1 RA risk alleles on the composition of the intestinal microbiome in healthy individuals. Methods Five hundred sixty‐eight stool and biopsy samples from 6 intestinal sites were collected from 107 healthy unrelated subjects, and stool samples were collected from 696 twin pairs from the TwinsUK cohort. Microbiome profiling was performed using sequencing of the 16S ribosomal RNA bacterial marker gene. All subjects were genotyped using the Illumina CoreExome SNP microarray, and HLA genotypes were imputed from these data. Results Associations were observed between the overall microbial composition and both the HLA–B27 genotype and the HLA–DRB1 RA risk allele (P = 0.0002 and P = 0.00001, respectively). These associations were replicated using the stool samples from the TwinsUK cohort (P = 0.023 and P = 0.033, respectively). Conclusion This study shows that the changes in intestinal microbiome composition seen in AS and RA are at least partially due to effects of HLA‐B27 and HLA–DRB1 on the gut microbiome. These findings support the hypothesis that HLA alleles operate to cause or increase the risk of these diseases through interaction with the intestinal microbiome and suggest that therapies targeting the microbiome may be effective in preventing or treating these diseases.

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Modulation of Inflammatory Arthritis in Mice by Gut Microbiota Through Mucosal Inflammation and Autoantibody Generation

Abstract: These data support a model in which intestinal dysbiosis triggers mucosal immune responses that stimulate T and B cells that are key for the development of inflammatory arthritis.

Cited by 136 publications

References 50 publications

Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis

Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis

HLA alleles associated with risk of ankylosing spondylitis and rheumatoid arthritis influence the gut microbiome

HLA Alleles Associated With Risk of Ankylosing Spondylitis and Rheumatoid Arthritis Influence the Gut Microbiome

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