Objective
The HLA–B27/β2‐microglobulin (β2m)–transgenic (Tg) rat is a leading model of B27‐associated spondyloarthritis (SpA), and the disease is dependent on the presence of intestinal bacteria. ...Previous studies have shown that adult HLA–B27/β2m–Tg rats have an altered intestinal microbiota. This study sought to better define the age‐dependent changes to both mucosal immune function and dysbiosis in this rat model of SpA.
Methods
Intestinal contents were collected from wild‐type and HLA–B27/β2m–Tg rats postweaning (ages 3 and 6 weeks), at disease onset (age 10 weeks), and after the establishment of disease (ages ≥16 weeks). The microbial community structure was determined by 16S ribosomal RNA sequencing and quantitative reverse transcription–polymerase chain reaction (qRT‐PCR). Mucosal and systemic Th1, Th17, and Treg cell responses were analyzed by flow cytometry, as was the frequency of IgA‐coated intestinal bacteria. Intestinal expression of inflammatory cytokines and antimicrobial peptides (AMPs) was determined by qRT‐PCR.
Results
An inflammatory cytokine signature and elevated AMP expression during the postweaning period preceded the development of clinical bowel inflammation and dysbiosis in HLA–B27/β2m–Tg rats. An early and sustained expansion of the Th17 cell pool was specifically observed in the cecal and colonic mucosa of HLA–B27/β2m–Tg rats. Strongly elevated intestinal colonization of Akkermansia muciniphila and an increased frequency of IgA‐coated fecal bacteria were significantly associated with expression of HLA–B27 and arthritis development.
Conclusion
HLA–B27/β2m expression in this rat model renders the host hyperresponsive to microbial antigens from infancy. Early activation of innate immunity and expansion of a mucosal Th17 signature are soon followed by dysbiosis in HLA–B27/β2m–Tg animals. The pathologic processes of perturbed mucosal immunity and dysbiosis strongly merit further study in both prediseased and diseased populations of patients with SpA.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Acute anterior uveitis (AAU) and the spondyloarthritis (SpA) subtypes ankylosing spondylitis, reactive arthritis and psoriatic arthritis are among the inflammatory diseases affected by the biology of ...the intestinal microbiome. In this Review, the relationship between AAU, SpA and the microbiome is discussed, with a focus on the major SpA risk gene HLA-B*27 and how it is associated with both intestinal tolerance and the loss of ocular immune privilege that can accompany AAU. We provide four potential mechanisms to account for how dysbiosis, barrier function and immune response contribute to the development of ocular inflammation and the pathogenesis of AAU. Finally, potential therapeutic avenues to target the microbiota for the clinical management of AAU and SpA are outlined.
Although very high levels of interleukin (IL)-1β are present in the intestines of patients suffering from inflammatory bowel diseases (IBD), little is known about the contribution of IL-1β to ...intestinal pathology. Here, we used two complementary models of chronic intestinal inflammation to address the role of IL-1β in driving innate and adaptive pathology in the intestine. We show that IL-1β promotes innate immune pathology in Helicobacter hepaticus-triggered intestinal inflammation by augmenting the recruitment of granulocytes and the accumulation and activation of innate lymphoid cells (ILCs). Using a T cell transfer colitis model, we demonstrate a key role for T cell-specific IL-1 receptor (IL-1R) signals in the accumulation and survival of pathogenic CD4(+) T cells in the colon. Furthermore, we show that IL-1β promotes Th17 responses from CD4(+) T cells and ILCs in the intestine, and we describe synergistic interactions between IL-1β and IL-23 signals that sustain innate and adaptive inflammatory responses in the gut. These data identify multiple mechanisms through which IL-1β promotes intestinal pathology and suggest that targeting IL-1β may represent a useful therapeutic approach in IBD.
Inflammatory bowel disease (IBD) is characterized by dysregulated immune responses to the intestinal microbiota, and by chronic intestinal inflammation. Several recent studies demonstrate the ...importance of innate microbial recognition by immune and nonimmune cells in the gut. Paradoxically, either diminished or exacerbated innate immune signaling may trigger the breakdown of intestinal homeostasis, leading to IBD and colitis-associated cancer (CAC). This dichotomy may reflect divergent functional roles for immune sensing in intestinal epithelial cells and leukocytes, which may vary with distinct disease mechanisms.
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
Microbiome community composition plays an important role in human health, and while most research to date has focused on high-microbial-biomass communities, low-biomass communities are also ...important. However, contamination and technical noise make determining the true community signal difficult when biomass levels are low, and the influence of varying biomass on sequence processing methods has received little attention. Here, we benchmarked six methods that infer community composition from 16S rRNA sequence reads, using samples of varying biomass. We included two operational taxonomic unit (OTU) clustering algorithms, one entropy-based method, and three more-recent amplicon sequence variant (ASV) methods. We first compared inference results from high-biomass mock communities to assess baseline performance. We then benchmarked the methods on a dilution series made from a single mock community-samples that varied only in biomass. ASVs/OTUs inferred by each method were classified as representing expected community, technical noise, or contamination. With the high-biomass data, we found that the ASV methods had good sensitivity and precision, whereas the other methods suffered in one area or in both. Inferred contamination was present only in small proportions. With the dilution series, contamination represented an increasing proportion of the data from the inferred communities, regardless of the inference method used. However, correlation between inferred contaminants and sample biomass was strongest for the ASV methods and weakest for the OTU methods. Thus, no inference method on its own can distinguish true community sequences from contaminant sequences, but ASV methods provide the most accurate characterization of community and contaminants.
Microbial communities have important ramifications for human health, but determining their impact requires accurate characterization. Current technology makes microbiome sequence data more accessible than ever. However, popular software methods for analyzing these data are based on algorithms developed alongside older sequencing technology and smaller data sets and thus may not be adequate for modern, high-throughput data sets. Additionally, samples from environments where microbes are scarce present additional challenges to community characterization relative to high-biomass environments, an issue that is often ignored. We found that a new class of microbiome sequence processing tools, called amplicon sequence variant (ASV) methods, outperformed conventional methods. In samples representing low-biomass communities, where sample contamination becomes a significant confounding factor, the improved accuracy of ASV methods may allow more-robust computational identification of contaminants.
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.
The role of the gut and microbes in the pathogenesis of spondyloarthritis Asquith, Mark, Ph.D; Elewaut, Dirk, MD, Ph.D; Lin, Phoebe, MD, Ph.D ...
Baillière's best practice and research in clinical rheumatology/Baillière's best practice & research. Clinical rheumatology,
10/2014, Volume:
28, Issue:
5
Journal Article
Peer reviewed
Open access
Abstract The intestinal microbiota is firmly implicated not only in the pathogenesis of inflammatory bowel disease (IBD) but increasingly also in the development of inflammation at extraintestinal ...tissue sites. Significant clinical, genetic, immunological, and microbiological overlap exists between IBD and spondyloarthritis (SpA), which indicates that pathophysiological mechanisms are shared between these diseases and may center on the intestinal microbiota. Recently, culture-independent techniques have enabled the microbiota in health and disease to be described in increasing detail. Moreover, functional studies have identified myriad host effector and regulatory pathways that shape or are shaped by this microbial community. We consider the complex relationship between SpA pathogenesis and gut microbes, with a discussion of how manipulation of the gut microbiota itself may be a promising future target for SpA therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Purpose of Review
The microbiome is the term that describes the microbial ecosystem that cohabits an organism such as humans. The microbiome has been implicated in a long list of immune-mediated ...diseases which include rheumatoid arthritis, ankylosing spondylitis, and even gout. The mechanisms to account for this effect are multiple. The clinical implications from observations on the microbiome and disease are broad.
Recent Findings
A growing number of microbiota constituents such as
Prevotella copri
,
Porphyromonas gingivalis
, and
Collinsella
have been correlated or causally related to rheumatic disease. The microbiome has a marked effect on the immune system. Our understanding of immune pathways modulated by the microbiota such as the induction of T helper 17 (Th17) cells and secretory immunoglobulin A (IgA) responses to segmented filamentous bacteria continues to expand. In addition to the gut microbiome, bacterial communities of other sites such as the mouth, lung, and skin have also been associated with the pathogenesis of rheumatic diseases.
Summary
Strategies to alter the microbiome or to alter the immune activation from the microbiome might play a role in the future therapy for rheumatic diseases.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background & Aims Toll-like receptors (TLR) are innate immune receptors involved in recognition of the intestinal microflora; they are expressed by numerous cell types in the intestine, including ...epithelial cells, myeloid cells, and lymphocytes. Little is known about the relative contributions of TLR signaling in distinct cellular compartments to intestinal homeostasis. We aimed to define the roles of TLR signals in distinct cell types in the induction and regulation of chronic intestinal inflammation. Methods We assessed the roles of the shared TLR signaling adaptor protein, MyD88, in several complementary mouse models of inflammatory bowel disease, mediated by either innate or adaptive immune activation. MyD88-deficient mice and bone marrow chimeras were used to disrupt TLR signals selectively in distinct cellular compartments in the intestine. Results MyD88-dependent activation of myeloid cells was required for the development of chronic intestinal inflammation. By contrast, although epithelial cell MyD88 signals were required for host survival, they were insufficient to induce intestinal inflammation in the absence of an MyD88-competent myeloid compartment. MyD88 expression by T cells was not required for their pathogenic and regulatory functions in the intestine. Conclusions Cellular compartmentalization of MyD88 signals in the intestine allow the maintenance of host defense and prevent deleterious inflammatory responses.
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