The pathogenesis of autoimmune diseases (AIDs) is not only attributed to genetic susceptibilities but also environmental factors, among which, disturbed gut microbiota has attracted increasing ...attention. Compositional and functional changes of gut microbiota have been reported in various AIDs, and increasing evidence suggests that disturbed gut microbiota contributes to their immunopathogenesis. The accepted mechanisms include abnormal microbial translocation, molecular mimicry, and dysregulation of both local and systemic immunity. Studies have also suggested microbiota-based classification models and therapeutic interventions for patients with AIDs. Further in-depth mechanistic studies on microbiota–autoimmunity interplay in AIDs are urgently needed and underway to explore novel and precise diagnostic biomarkers and develop disease and patient-tailored therapeutic strategies.
The compositional and functional changes of gut microbiota have been implicated in various autoimmune diseases (AIDs) by high-throughput techniques such as metagenomic sequencing.Correlation studies in humans and interventional studies in animal models have suggested that disturbed gut microbiota is involved in the immunopathogenesis of AIDs.The mechanisms of disturbed gut microbiota include abnormal microbial translocation, molecular mimicry, and dysregulation of both local and systemic immunity.In-depth deciphering of gut microbiota will help us to develop new microbiota-based assessments and interventions for patients with AIDs, which can help with their diagnosis, prognosis and treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective
Changes in gut microbiota have been linked to systemic lupus erythematosus (SLE), but knowledge is limited. Our study aimed to provide an in‐depth understanding of the contribution of gut ...microbiota to the immunopathogenesis of SLE.
Methods
Fecal metagenomes from 117 patients with untreated SLE and 52 SLE patients posttreatment were aligned with 115 matched healthy controls and analyzed by whole‐genome profiling. For comparison, we assessed the fecal metagenome of MRL/lpr mice. The oral microbiota origin of the gut species that existed in SLE patients was documented by single‐nucleotide polymorphism–based strain‐level analyses. Functional validation assays were performed to demonstrate the molecular mimicry of newly found microbial peptides.
Results
Gut microbiota from individuals with SLE displayed significant differences in microbial composition and function compared to healthy controls. Certain species, including the Clostridium species ATCC BAA‐442 as well as Atopobium rimae, Shuttleworthia satelles, Actinomyces massiliensis, Bacteroides fragilis, and Clostridium leptum, were enriched in SLE gut microbiota and reduced after treatment. Enhanced lipopolysaccharide biosynthesis aligned with reduced branched chain amino acid biosynthesis was observed in the gut of SLE patients. The findings in mice were consistent with our findings in human subjects. Interestingly, some species with an oral microbiota origin were enriched in the gut of SLE patients. Functional validation assays demonstrated the proinflammatory capacities of some microbial peptides derived from SLE‐enriched species.
Conclusion
This study provides detailed information on the microbiota of untreated patients with SLE, including their functional signatures, similarities with murine counterparts, oral origin, and the definition of autoantigen‐mimicking peptides. Our data demonstrate that microbiome‐altering approaches may offer valuable adjuvant therapies in SLE.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Gut dysbiosis has been reported implicated in ankylosing spondylitis (AS), a common chronic inflammatory disease mainly affects sacroiliac joints and spine. Utilizing deep sequencing on the feces of ...untreated AS patients, our study aimed at providing an in-depth understanding of AS gut microbiota.
We analyzed the fecal metagenome of 85 untreated AS patients and 62 healthy controls by metagenomic shotgun sequencing, and 23 post-treatment feces of those AS patients were collected for comparison. Comparative analyses among different cohorts including AS, rheumatoid arthritis and Behcet's disease were performed to uncover some common signatures related to inflammatory arthritis. Molecular mimicry of a microbial peptide was also demonstrated by ELISpot assay.
We identified AS-enriched species including Bacteroides coprophilus, Parabacteroides distasonis, Eubacterium siraeum, Acidaminococcus fermentans and Prevotella copri. Pathway analysis revealed increased oxidative phosphorylation, lipopolysaccharide biosynthesis and glycosaminoglycan degradation in AS gut microbiota. Microbial signatures of AS gut selected by random forest model showed high distinguishing accuracy. Some common signatures related to autoimmunity, such as Bacteroides fragilis and type III secretion system (T3SS), were also found. Finally, in vitro experiments demonstrated an increased amount of IFN-γ producing cells triggered by a bacterial peptide of AS-enriched species, mimicking type II collagen.
These findings collectively indicate that gut microbiota was perturbed in untreated AS patients with diagnostic potential, and some AS-enriched species might be triggers of autoimmunity by molecular mimicry. Additionally, different inflammatory arthritis shared some common microbial signatures.
•Gut microbiota was perturbed in untreated ankylosing spondylitis patients.•Distinctive species and pathways were found and correlated with clinical indices.•A diagnostic classifier was made based on differently expressed gut microbes.•Common gut microbial signatures of inflammatory arthritis were revealed.•A microbial peptide can trigger IFN-γ secretion by mimicking type II collagen.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To investigate the compositional and functional characteristics of the gut microbiota in primary Sjögren's syndrome (pSS) and compare them with those in systemic lupus erythematosus (SLE).
Stool ...samples from 78 treatment-naïve pSS patients and 78 matched healthy controls were detected by shotgun metagenomic sequencing and compared with those from 49 treatment-naïve SLE patients. The virulence loads and mimotopes of the gut microbiota were also assessed by sequence alignment.
The gut microbiota of treatment-naïve pSS patients had lower richness and evenness and showed a different community distribution than that of healthy controls. The microbial species enriched in the pSS-associated gut microbiota included Lactobacillus salivarius, Bacteroides fragilis, Ruminococcus gnavus, Clostridium bartlettii, Clostridium bolteae, Veillonella parvula, and Streptococcus parasanguinis. Lactobacillus salivarius was the most discriminating species in the pSS patients, especially in those with interstitial lung disease (ILD). Among the differentiating microbial pathways, the superpathway of l-phenylalanine biosynthesis was also further enriched in pSS complicated with ILD. There were more virulence genes carried by the gut microbiota in pSS patients, most of which encoded peritrichous flagella, fimbriae, or curli fimbriae, three types of bacterial surface organelles involved in bacterial colonization and invasion. Five microbial peptides with the potential to mimic pSS-related autoepitopes were also enriched in the pSS gut. SLE and pSS shared significant gut microbial traits, including community distribution, altered microbial taxonomy and pathways, and enriched virulence genes. However, Ruminococcus torques was depleted in pSS patients but enriched in SLE patients compared to healthy controls.
The gut microbiota in treatment-naïve pSS patients was disturbed and shared significant similarity with that in SLE patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To investigate the compositional and functional characteristics of the gut microbiota in primary Sjögren's syndrome (pSS) and compare them with those in systemic lupus erythematosus (SLE).
Stool ...samples from 78 treatment naïve pSS patients and 78 matched healthy controls were detected by shotgun metagenomic sequencing and compared with those from 49 treatment naïve SLE patients. The virulence loads and mimotopes of the gut microbiota were also assessed by sequence alignment.
The gut microbiota of treatment naïve pSS patients had lower richness and evenness and showed a different community distribution than that of healthy controls. The microbial species enriched in the pSS-associated gut microbiota included Lactobacillus salivarius, Bacteroides fragilis, Ruminococcus gnavus, Clostridium bartlettii, Clostridium bolteae, Veillonella parvula, and Streptococcus parasanguinis. Lactobacillus salivarius was the most discriminating species in the pSS patients, especially in those with interstitial lung disease (ILD). Among the differentiating microbial pathways, the superpathway of l-phenylalanine biosynthesis was also further enriched in pSS complicated with ILD. There were more virulence genes carried by the gut microbiota in pSS patients, most of which encoded peritrichous flagella, fimbriae, or curli fimbriae, three types of bacterial surface organelles involved in bacterial colonization and invasion. Five microbial peptides with the potential to mimic pSS-related autoepitopes were also enriched in the pSS gut. SLE and pSS shared significant gut microbial traits, including the community distribution, altered microbial taxonomy and pathways, and enriched virulence genes. However, Ruminococcus torques was depleted in pSS patients but enriched in SLE patients compared to that in healthy controls.
The gut microbiota in treatment naïve pSS patients was disturbed and shared significant similarity with that in SLE patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
One of the key issues with decentralized online multi-player games is ensuring fairness of game play despite different network latencies. One approach is to follow a "lock step" scheme that prevents ...any player from acting upon a message until that message is received by all the players. We present a fair synchronization protocol (FSP) that enforces fairness and is more efficient than a lock-step scheme. The basic FSP protocol is susceptible to cheating. Therefore, we add a cheat prevention mechanism as an enhancement. We implement the enhanced protocol, the cheat proof protocol (CPP), in a simple game environment and deploy it on the PlanetLab. The results indicate that the CPP is effective in enforcing fairness while preventing cheating.
One of the key issues with online multiplayer games is game play fairness. In both centralized and decentralized architectures the ordering of command messages from clients for execution is an ...important issue that impacts fairness and response time of game play. Recently, a fair-ordered message exchange protocol (FMEP), based on "reaction" times was proposed to order command messages for a client-server model. This thesis presents a cheat controlled protocol (CCP) that can be used to control cheating in the FMEP. We examined the performance of the CCP by emulating wide-area game play scenarios on the Planet-Lab. The results from the experiments indicate that the CCP is able to dramatically reduce the cheating opportunities that exist for clients. On the other hand, for the decentralized (distributed) model, one approach is to follow a "lock step" scheme that prevents any client from acting upon a message until that message is received by all clients. In this thesis, we present a fair synchronization protocol (FSP) that enforces fairness and is more efficient than the lock-step scheme. The basic FSP is susceptible to cheating. Therefore, we added a cheat prevention mechanism as an enhancement. We implemented the enhanced protocol, the Cheat Proof Protocol (CPP), on the Planet-Lab and studied the performance under the same game play scenarios used for the CCP. The results indicate that the CPP is effective in enforcing fairness and cheat prevention.
One of the key issues with online multiplayer games is game play fairness. In both centralized and decentralized architectures the ordering of command messages from clients for execution is an ...important issue that impacts fairness and response time of game play. Recently, a fair-ordered message exchange protocol (FMEP), based on "reaction" times was proposed to order command messages for a client-server model. This thesis presents a cheat controlled protocol (CCP) that can be used to control cheating in the FMEP. We examined the performance of the CCP by emulating wide-area game play scenarios on the Planet-Lab. The results from the experiments indicate that the CCP is able to dramatically reduce the cheating opportunities that exist for clients. On the other hand, for the decentralized (distributed) model, one approach is to follow a "lock step" scheme that prevents any client from acting upon a message until that message is received by all clients. In this thesis, we present a fair synchronization protocol (FSP) that enforces fairness and is more efficient than the lock-step scheme. The basic FSP is susceptible to cheating. Therefore, we added a cheat prevention mechanism as an enhancement. We implemented the enhanced protocol, the Cheat Proof Protocol (CPP), on the Planet-Lab and studied the performance under the same game play scenarios used for the CCP. The results indicate that the CPP is effective in enforcing fairness and cheat prevention.
Obesity-induced secretory disorder of adipose tissue-derived factors is important for cardiac damage. However, whether platelet-derived growth factor-D (PDGF-D), a newly identified adipokine, ...regulates cardiac remodeling in angiotensin II (AngII)-infused obese mice is unclear. Here, we found obesity induced PDGF-D expression in adipose tissue as well as more severe cardiac remodeling compared with control lean mice after AngII infusion. Adipocyte-specific PDGF-D knockout attenuated hypertensive cardiac remodeling in obese mice. Consistently, adipocyte-specific PDGF-D overexpression transgenic mice (PA-Tg) showed exacerbated cardiac remodeling after AngII infusion without high-fat diet treatment. Mechanistic studies indicated that AngII-stimulated macrophages produce urokinase plasminogen activator (uPA) that activates PDGF-D by splicing full-length PDGF-D into the active PDGF-DD. Moreover, bone marrow-specific uPA knockdown decreased active PDGF-DD levels in the heart and improved cardiac remodeling in HFD hypertensive mice. Together, our data provide for the first time a new interaction pattern between macrophage and adipocyte: that macrophage-derived uPA activates adipocyte-secreted PDGF-D, which finally accelerates AngII-induced cardiac remodeling in obese mice.
