Objective
To investigate whether HLA–B27–mediated experimental spondyloarthritis (SpA) is associated with a common gut microbial signature, in order to identify potential drivers of pathogenesis.
...Methods
The effects of HLA–B27 on 3 genetic backgrounds, dark agouti (DA), Lewis, and Fischer, were compared, using wild‐type littermates and HLA–B7–transgenic Lewis rats as controls. Cecum and colon tissue specimens or contents were collected from the rats at 2, 3–4, and 6–8 months of age, and histologic analysis was performed to assess inflammation, RNA sequencing was used to determine gene expression differences, and 16S ribosomal RNA gene sequencing was used to determine microbiota differences.
Results
Both HLA–B27–transgenic Lewis rats and HLA–B27–transgenic Fischer rats developed gut inflammation, while DA rats were resistant to the effects of HLA–B27, and HLA–B7–transgenic rats were not affected. Immune dysregulation was similar in affected Lewis and Fischer rats and was dominated by activation of interleukin‐23 (IL‐23)/IL‐17, interferon, tumor necrosis factor, and IL‐1 cytokines and pathways in the colon and cecum, while DA rats exhibited low‐level cytokine dysregulation without inflammation. Gut microbial changes in HLA–B27–transgenic rats were strikingly divergent on the 3 different host genetic backgrounds, including different patterns of dysbiosis in HLA–B27–transgenic Lewis and HLA–B27–transgenic Fischer rat strains, with some overlap. Interestingly, DA rats lacked segmented filamentous bacteria that promote CD4+ Th17 cell development, which may explain their resistance to disease.
Conclusion
The effects of HLA–B27 on gut microbiota and dysbiosis in SpA are highly dependent on the host genetic background and/or environment, despite convergence of dysregulated immune pathways. These results implicate an ecological model of dysbiosis, with the effects of multiple microbes contributing to the aberrant immune response, rather than a single or small number of microbes driving pathogenesis.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
PURPOSE OF REVIEWMicrobial dysbiosis in the gut is emerging as a common component in various inflammatory disorders including spondyloarthritis (SpA). The depth of this influence has begun to be ...realized with next-generation sequencing of the gut microbiome providing unbiased assessment of previously uncharted bacterial populations.
RECENT FINDINGSDecreased numbers of Firmicutes, a major phyla of gut commensals, especially the species Faecalibacterium prausnitzii and Clostridium leptum have been found in various inflammatory disorders including SpA and inflammatory bowel disease (IBD), and could be an important link between SpA and gut inflammation. Multiple studies in ankylosing spondylitis, psoriatic arthritis, juvenile SpA, and animal models of SpA are revealing common bacterial associations among these diseases as well as IBD.
SUMMARYWe are beginning to appreciate the complex relationship between the gut microbiome and host immune regulation and dysregulation in health and disease. Potentially important differences have been revealed in SpA, but cause and effect relationships remain far from established. Many critical questions remain to be answered before we can apply new knowledge to improve therapeutics in SpA.
Spondyloarthritis (SpA) is a group of immune mediated inflammatory diseases with a strong association to the major histocompatibility (MHC) class I molecule, HLA-B27. Although the association between ...HLA-B27 and AS has been known for almost 50 years, the mechanisms underlying disease pathogenesis are elusive. Over the years, three hypotheses have been proposed to explain HLA-B27 and disease association: 1) HLA B27 presents arthritogenic peptides and thus creates a pathological immune response; 2) HLA-B27 misfolding causes endoplasmic reticulum (ER) stress which activates the unfolded protein response (UPR); 3) HLA-B27 dimerizes on the cell surface and acts as a target for natural killer (NK) cells. None of these hypotheses explains SpA pathogenesis completely. Evidence supports the hypothesis that HLA-B27-related diseases have a microbial pathogenesis. In animal models of various SpAs, a germ-free environment abrogates disease development and colonizing these animals with gut commensal microbes can restore disease manifestations. The depth of microbial influence on SpA development has been realized due to our ability to characterize microbial communities in the gut using next-generation sequencing approaches. In this review, we will discuss various putative pathobionts in the pathogenesis of HLA-B27-associated diseases. We pursue whether a single pathobiont or a disruption of microbial community and function is associated with HLA-B27-related diseases. Furthermore, rather than a specific pathobiont, metabolic functions of various disease-associated microbes might be key. While the use of germ-free models of SpA have facilitated understanding the role of microbes in disease development, future studies with animal models that mimic diverse microbial communities instead of mono-colonization are indispensable. We discuss the causal mechanisms underlying disease pathogenesis including the role of these pathobionts on mucin degradation, mucosal adherence, and gut epithelial barrier disruption and inflammation. Finally, we review the various uses of microbes as therapeutic modalities including pre/probiotics, diet, microbial metabolites and fecal microbiota transplant. Unravelling these complex host-microbe interactions will lead to the development of new targets/therapies for alleviation of SpA and other HLA-B27 associated diseases.
The HLA-B27 gene is a major risk factor for clinical diseases including ankylosing spondylitis, acute anterior uveitis, reactive arthritis, and psoriatic arthritis, but its mechanism of risk ...enhancement is not completely understood. The gut microbiome has recently been shown to influence several HLA-linked diseases. However, the role of HLA-B27 in shaping the gut microbiome has not been previously investigated. In this study, we characterize the differences in the gut microbiota mediated by the presence of the HLA-B27 gene. We identified differences in the cecal microbiota of Lewis rats transgenic for HLA-B27 and human β2-microglobulin (hβ2m), compared with wild-type Lewis rats, using biome representational in situ karyotyping (BRISK) and 16S rRNA gene sequencing. 16S sequencing revealed significant differences between transgenic animals and wild type animals by principal coordinates analysis. Further analysis of the data set revealed an increase in Prevotella spp. and a decrease in Rikenellaceae relative abundance in the transgenic animals compared to the wild type animals. By BRISK analysis, species-specific differences included an increase in Bacteroides vulgatus abundance in HLA-B27/hβ2m and hβ2m compared to wild type rats. The finding that HLA-B27 is associated with altered cecal microbiota has not been shown before and can potentially provide a better understanding of the clinical diseases associated with this gene.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Axial spondyloarthritis (axSpA) is a chronic, immune‐mediated disease characterized by inflammatory axial skeleton involvement and extra‐musculoskeletal manifestations. The continuum of axSpA ranges ...from nonradiographic axSpA (nr‐axSpA) to ankylosing spondylitis, also known as radiographic axSpA; the latter is defined by definitive radiographic sacroiliitis. Human leukocyte antigen B27 (HLA‐B27) is a genetic marker strongly associated with axSpA; it aids in the diagnosis of axSpA, and its absence leads to delay in diagnosis. For HLA‐B27‐negative patients, disease pathogenesis is poorly understood, signs and symptoms are frequently underrecognized, and diagnosis and treatment are commonly delayed. The proportion of HLA‐B27‐negative patients may be higher among non‐White patients and those with nr‐axSpA, who can face additional diagnostic challenges related to lack of definitive radiographic sacroiliitis. In this narrative review, we discuss the role of HLA‐B27 in the diagnosis and pathogenesis of axSpA and highlight various pathways and genes that may be related to axSpA pathogenesis in HLA‐B27‐negative patients. We also emphasize the need to characterize gut microbial communities in these patients. Adequate understanding of clinical and pathological features underlying HLA‐B27‐negative patients with axSpA will improve diagnosis, treatment, and outcomes for this complex inflammatory disease.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Antioxidant enzymes play a significant role in eliminating toxic levels of reactive oxygen species (ROS), generated during stress from living cells. In the present study, two different antioxidant ...enzymes namely copper-zinc superoxide dismutase derived from Potentilla astrisanguinea (PaSOD) and ascorbate peroxidase (RaAPX) from Rheum austral both of which are high altitude cold niche area plants of Himalaya were cloned and simultaneously over-expressed in Arabidopsis thaliana to alleviate cold stress. It was found that the transgenic plants over-expressing both the genes were more tolerant to cold stress than either of the single gene expressing transgenic plants during growth and development. In both single (PaSOD, RaAPX) and double (PaSOD + RaAPX) transgenic plants higher levels of total antioxidant enzyme activities, chlorophyll content, total soluble sugars, proline content and lower levels of ROS, ion leakage were recorded when compared to the WT during cold stress (4°C), besides increase in yield. In the present study, Confocal and SEM analysis in conjunction with qPCR data on the expression pattern of lignin biosynthetic pathway genes revealed that the cold stress tolerance of the transgenic plants might be because of the peroxide induced up-regulation of lignin by antioxidant genes mediated triggering.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
HLA-B27 is a major risk factor for spondyloarthritis (SpA), yet the underlying mechanisms remain unclear. HLA-B27 misfolding-induced IL-23, which is mediated by endoplasmic reticulum (ER) stress has ...been hypothesized to drive SpA pathogenesis. Expression of HLA-B27 and human β
m (hβ
m) in rats (HLA-B27-Tg) recapitulates key SpA features including gut inflammation. Here we determined whether deleting the transcription factor CHOP (Ddit3-/-), which mediates ER-stress induced IL-23, affects gut inflammation in HLA-B27-Tg animals. ER stress-mediated Il23a overexpression was abolished in CHOP-deficient macrophages. Although CHOP-deficiency also reduced Il23a expression in immune cells isolated from the colon of B27+ rats, Il17a levels were not affected, and gut inflammation was not reduced. Rather, transcriptome analysis revealed increased expression of pro-inflammatory genes, including Il1a, Ifng and Tnf in HLA-B27-Tg colon tissue in the absence of CHOP, which was accompanied by higher histological Z-scores. RNAScope localized Il17a mRNA to the lamina propria of the HLA-B27-Tg rats and revealed similar co-localization with Cd3e (CD3) in the presence and absence of CHOP. This demonstrates that CHOP-deficiency does not improve, but rather exacerbates gut inflammation in HLA-B27-Tg rats, indicating that HLA-B27 is not promoting gut disease through ER stress-induced IL-23. Hence, CHOP may protect rats from more severe HLA-B27-induced gut inflammation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The gut microbiota plays a pivotal role in regulating host immunity, and dysregulation of this interaction is implicated in autoimmune and inflammatory diseases, including spondyloarthritis (SpA). ...This review explores microbial dysbiosis and altered metabolic function observed in various forms of SpA, such as ankylosing spondylitis (AS), psoriatic arthritis (PsA), acute anterior uveitis (AAU), and SpA-associated gut inflammation. Studies on animal models and clinical samples highlight the association between gut microbial dysbiosis, metabolic perturbations and immune dysregulation in SpA pathogenesis. These studies have received impetus through next-generation sequencing methods, which have enabled the characterization of gut microbial composition and function, and host gene expression. Microbial/metabolomic studies have revealed potential biomarkers and therapeutic targets, such as short-chain fatty acids, and tryptophan metabolites, offering insights into disease mechanisms and treatment approaches. Further studies on microbial function and its modulation of the immune response have uncovered molecular mechanisms underlying various SpA. Understanding the complex interplay between microbial community structure and function holds promise for improved diagnosis and management of SpA and other autoimmune disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Axial spondyloarthritis (axSpA) is an inflammatory arthritis involving the spine and the sacroiliac joint with extra-articular manifestations in the eye, gut, and skin. The intestinal microbiota has ...been implicated as a central environmental component in the pathogenesis of various types of spondyloarthritis including axSpA. Additionally, alterations in the oral microbiota have been shown in various rheumatological conditions, such as rheumatoid arthritis (RA). Therefore, the aim of this study was to investigate whether axSpA patients have an altered immunoglobulin A (IgA) response in the gut and oral microbial communities. We performed 16S rRNA gene (16S) sequencing on IgA positive (IgA
+
) and IgA negative (IgA
-
) fractions (IgA-SEQ) from feces (n=17 axSpA; n=14 healthy) and saliva (n=14 axSpA; n=12 healthy), as well as on IgA-unsorted fecal and salivary samples. PICRUSt2 was used to predict microbial metabolic potential in axSpA patients and healthy controls (HCs). IgA-SEQ analyses revealed enrichment of several microbes in the fecal (
Akkermansia
,
Ruminococcaceae
,
Lachnospira
) and salivary (
Prevotellaceae
,
Actinobacillus
) microbiome in axSpA patients as compared with HCs. Fecal microbiome from axSpA patients showed a tendency towards increased alpha diversity in IgA
+
fraction and decreased diversity in IgA
-
fraction in comparison with HCs, while the salivary microbiome exhibits a significant decrease in alpha diversity in both IgA
+
and IgA
-
fractions. Increased IgA coating of
Clostridiales Family XIII
in feces correlated with disease severity. Inferred metagenomic analysis suggests perturbation of metabolites and metabolic pathways for inflammation (oxidative stress, amino acid degradation) and metabolism (propanoate and butanoate) in axSpA patients. Analyses of fecal and salivary microbes from axSpA patients reveal distinct populations of immunoreactive microbes compared to HCs using the IgA-SEQ approach. These bacteria were not identified by comparing their relative abundance alone. Predictive metagenomic analysis revealed perturbation of metabolites/metabolic pathways in axSpA patients. Future studies on these immunoreactive microbes may lead to better understanding of the functional role of IgA in maintaining microbial structure and human health.
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