Compositional and functional aberrance of the gut microbiota in treatment-naïve patients with primary Sjögren's syndrome.

OBJECTIVES: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: The gut microbiota in treatment-naïve pSS patients was disturbed and shared significant similarity with that in SLE patients.

Compositional and functional aberrance of the gut microbiota in treatment naïve patients with primary Sjögren's syndrome.

OBJECTIVES: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: The gut microbiota in treatment naïve pSS patients was disturbed and shared significant similarity with that in SLE patients.

[Fecal Microbiota Transplantation:Traditional Chinese Medicine Meets Western Medicine].

Fecal microbiota transplantation (FMT) is a therapy of transplanting the functional flora from the feces of a healthy donor into the gastrointestinal tract of a patient to reconstruct the normal flora.The application of FMT in western medicine dates from the 1950s.After decades of development,the efficacy of FMT has been proven in a variety of diseases.The record of FMT in traditional Chinese medicine (TCM) dates early from the 3rd century A.D.,and relevant theories have been recorded in many TCM works in the past dynasties.FMT as a therapy that has been written into guidelines has been accepted by some countries and regions such as the United States and the United Kingdom in the treatment of Clostridium difficile infection,and its clinical indications are expanding.TCM and western medicine,with different medical thoughts,meet in the application of FMT.Exploring a normative and effective FMT procedure reflects not only the patient-centered principle but also the mutual promotion of TCM and western medicine.

Gut Microbiota in Lupus: a Butterfly Effect?

PURPOSE OF REVIEW: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that typically displays chronic inflammatory tissue damage and miscellaneous circulatory autoantibodies, as well as distinctive type 1 interferon signatures. The etiology of SLE is unclear and currently is attributed to genetic predisposition and environmental triggers. Gut microbiota has recently been considered a critical environmental pathogenic factor in immune-related disorders, and studies are ongoing to uncover the key pathogens and the imputative mechanisms. Fundamental advancements on the role of the microbiota in SLE pathology have been achieved in recent years and are summarized in this review. RECENT FINDINGS: Recent findings suggested that gut commensals could propagate autoimmunity via molecular mimicry in which ortholog-carrying microbes cross-activate autoreactive T/B cells and trigger the response against host autoantigens, or via bystander activation by stimulating antigen-presenting cells that present autoantigens and enhancing the expression of co-stimulatory molecules and cytokines, thus leading to the loss of self-tolerance and the production of autoantibodies. Additionally, the break of gut barrier and the translocation of gut commensals to inner organs can trigger immune dysregulation and inappropriate systemic inflammation. All these microbiota-mediated mechanisms could contribute to lupus immunopathogenesis and promote disease development in susceptible individuals. Evidence of the causative role of disturbed gut microbiome in SLE is still limited, and the related molecular mechanisms and pathways are largely elusive. However, the modification of gut microbiota, such as pathobiont vaccine, special diet, restricted consortium transplantation, as well as regulatory metabolites supplementation, might be promising strategies for lupus prophylaxis and treatment.

Metagenomic profiling of the pro-inflammatory gut microbiota in ankylosing spondylitis.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Enhanced Propulsion of Urease-Powered Micromotors by Multilayered Assembly of Ureases on Janus Magnetic Microparticles.

Enzyme-powered micro/nanomotors propelled by biocompatible fuels generally show a weak propulsive force, which greatly limits their applications in complex biological environments. Herein, we have developed a novel and versatile approach to significantly enhance the propulsion of enzyme-powered micromotors by multilayered assembly of enzymes. As an example, multilayers of biotinylated ureases (BU) were asymmetrically immobilized on biotinylated Janus Au/magnetic microparticles (MMPs) with the assistance of streptavidin (SA). When the mass ratio of BU into SA and the amount of BU used in the assembly process are increased, the amount of urease immobilized on the biotinylated Janus Au/MMPs increased monotonously while the migration speed of the micromotor was augmented gradually until a saturated value. The as-optimized micromotors can be self-propelled with an average speed up to about 21.5 ± 0.8 µm/s at physiological urea concentrations (10 mM), which is five times faster than that of the monolayered counterparts and two times faster than that of the previously reported values. Owing to the enhanced thrust, the micromotors can move in liquids with viscosities similar to that of blood. In addition, with the inherent magnetic property of MMPs, the micromotors can exhibit fast magnetic separation and controllable motion direction by external magnetic fields. Our results provide a new pathway for designing high-efficient enzyme-powered micro/nanomotors and thereby promote their biomedical applications.

Integration of microbiome and epigenome to decipher the pathogenesis of autoimmune diseases.

The interaction between genetic predisposition and environmental factors are of great significance in the pathogenesis and development of autoimmune diseases (AIDs). The human mucosa is the most frequent site that interacts with the exterior environment, and commensal microbiota at the gut and other human mucosal cavities play a crucial role in the regulation of immune system. Growing evidence has shown that the compositional and functional changes of mucosal microbiota are closely related to AIDs. Gut dysbiosis not only influence the expression level of Toll-like receptors (TLRs) of antigen presenting cells, but also contribute to Th17/Treg imbalance. Epigenetic modifications triggered by environmental factors is an important mechanism that leads to altered gene expression. Researches addressing the role of DNA methylation, histone modification and non-coding RNA in AIDs have been increasing in recent years. Furthermore, studies showed that human microbiota and their metabolites can regulate immune cells and cytokines via epigenomic modifications. For example, short-chain fatty acids (SCFAs) produced by gut microbiota promote the differentiation of naïve T cell into Treg by suppressing histone deacetylases (HDACs). Therefore, we propose that dysbiosis and resulting metabolites may cause aberrant immune responses via epigenetic modifications, and lead to AIDs. With the development of high-throughput sequencing, metagenome analysis has been applied to investigate the dysbiosis in AIDs patients. We have tested the fecal, dental and salivary samples from treatment-naïve rheumatoid arthritis (RA) individuals by metagenomic shotgun sequencing and a metagenome-wide association study. Dysbiosis was detected in the gut and oral microbiomes of RA patients, but it was partially restored after treatment. We also found functional changes of microbiota and molecular mimicry of human antigens in RA individuals. By integrating the analysis of multi-omics of microbiome and epigenome, we could explore the interaction between human immune system and microbiota, and thereby unmasking specific and more sensitive biomarkers as well as potential therapeutic targets. Future studies aiming at the crosstalk between human dysbiosis and epigenetic modifications and their influences on AIDs will facilitate our understanding and better managing of these debilitating AIDs.

Epigenetic programming mediates abnormal gut microbiota and disease susceptibility in offspring with prenatal dexamethasone exposure.

Prenatal dexamethasone exposure (PDE) can lead to increased susceptibility to various diseases in adult offspring, but its effect on gut microbiota composition and the relationship with disease susceptibility remains unclear. In this study, we find sex-differential changes in the gut microbiota of 6-month-old infants with prenatal dexamethasone therapy (PDT) that persisted in female infants up to 2.5 years of age with altered bile acid metabolism. PDE female offspring rats show abnormal colonization and composition of gut microbiota and increased susceptibility to cholestatic liver injury. The aberrant gut microbiota colonization in the PDE offspring can be attributed to the inhibited Muc2 expression caused by decreased CDX2 expression before and after birth. Integrating animal and cell experiments, we further confirm that dexamethasone could inhibit Muc2 expression by activating GR/HDAC11 signaling and regulating CDX2 epigenetic modification. This study interprets abnormal gut microbiota and disease susceptibility in PDT offspring from intrauterine intestinal dysplasia.

Numerical Simulation on Laser Shock Peening of B4C-TiB2 Composite Ceramics.

The introduction of residual stresses using laser shock peening (LSP) is an effective means of improving the mechanical properties of ceramics. Numerical simulations offer greater convenience and efficiency than in-lab experiments when testing the effects of different processing techniques on residual stress distribution. In this work, a B4C-TiB2 ceramic model based on the extended Drucker-Prager model was established to investigate the effects of laser power density, the number of impacts and laser spot overlapping rate on the residual stress distribution, and the reliability of the simulation method was verified by experimental data. The following results are obtained: increasing the laser power density and the number of impacts can increase the surface residual compressive stress and reduce the depth of the residual compressive stress; the presence of multiple impacts will significantly reduce the depth of the residual compressive stress layer; with the increase in the laser spot overlapping rate, the compressive residual stress in the processed area gradually increases and is more uniformly distributed; the best processing effect can be achieved by using a spot overlapping rate of 50%.

Impact of targeted therapies on the risk of cardiovascular events in patients with psoriasis and psoriatic arthritis: A systematic review and aggregate data meta-analysis of randomized controlled trials.

OBJECTIVE: We aimed to investigate the effect of targeted therapies on cardiovascular risk in psoriasis (PsO) and psoriatic arthritis (PsA) via a meta-analysis of randomized controlled trials (RCTs). METHODS: Pubmed, Embase, Cochrane Library, and Scopus were searched for RCTs reporting targeted therapies in patients with PsO/PsA published until 28 October 2021. The primary and secondary outcomes included the relationship between targeted therapies and all cardiovascular events (CVEs), major adverse cardiovascular events (MACEs), myocardial infarction (MI), heart failure, and stroke in PsO/PsA. The outcome risk ratios (RRs) were calculated using the Mantel-Haenszel fixed-effect method. RESULTS: A total of 81 articles involving 88 RCTs were included. There was no statistically significant difference regarding the occurrence of all CVEs for all targeted therapies (RR = 1.03, 95% CI 0.74-1.43, P = .85) compared to placebo in PsO/PsA. No statistically significant difference existed between drugs and placebo in patients with PsA on all CVEs (RR = 0.81, 95% CI 0.48-1.36, P = .43). Surprisingly, the incidence of all CVEs was higher in the low dosage group compared to the high dosage group of all targeted therapies (RR = 1.97, 95% CI 1.19-3.27, P = .008) and prominently anti-interleukin-17 agent (RR = 2.20, 95% CI 1.05-4.58, P = .04). CONCLUSION: Current targeted therapies are not associated with the risk of CVEs. Based on the existing evidence, we reported here that a dosage reduction of targeted therapies was not recommended.

Disturbed gut virome with potent interferonogenic property in systemic lupus erythematosus.

Accumulating evidence suggests an essential role of disturbed gut microbiota in the etiopathogenesis of systemic lupus erythematosus (SLE), but it remains unclear as to gut virome. In this study, fecal virus-like particles (VLPs) isolated from 76 non-treated SLE patients and 75 healthy controls were subjected to gut virome profiling. The proportion of bacteriophages was significantly elevated in the SLE gut, and the altered viral taxa were correlated with clinical parameters. Gut virome and bacteriome were closely associated with each other in SLE patients. The combination of gut viral and bacterial markers displayed better performance in distinguishing SLE patients from healthy controls. Further, VLPs from non-treated SLE patients promoted interferon-α production in an epithelial cell line and human immune cells. Intriguingly, the interferon-stimulatory capacity diminished in VLPs from post-treated SLE patients. Our findings may shed novel insights into SLE pathogenesis. Further in-depth understanding of gut virome might help develop future biomarkers and therapeutics for SLE patients.

Microbiota-indole 3-propionic acid-brain axis mediates abnormal synaptic pruning of hippocampal microglia and susceptibility to ASD in IUGR offspring.

BACKGROUND: Autism spectrum disorder (ASD) has been associated with intrauterine growth restriction (IUGR), but the underlying mechanisms are unclear. RESULTS: We found that the IUGR rat model induced by prenatal caffeine exposure (PCE) showed ASD-like symptoms, accompanied by altered gut microbiota and reduced production of indole 3-propionic acid (IPA), a microbiota-specific metabolite and a ligand of aryl hydrocarbon receptor (AHR). IUGR children also had a reduced serum IPA level consistent with the animal model. We demonstrated that the dysregulated IPA/AHR/NF-κB signaling caused by disturbed gut microbiota mediated the hippocampal microglia hyperactivation and neuronal synapse over-pruning in the PCE-induced IUGR rats. Moreover, postnatal IPA supplementation restored the ASD-like symptoms and the underlying hippocampal lesions in the IUGR rats. CONCLUSIONS: This study suggests that the microbiota-IPA-brain axis regulates ASD susceptibility in PCE-induced IUGR offspring, and supplementation of microbiota-derived IPA might be a promising interventional strategy for ASD with a fetal origin. Video Abstract.

Immune cell dysregulation as a mediator of fibrosis in systemic sclerosis.

Systemic sclerosis (SSc) is a destructive connective tissue disease characterized by dysregulation of the immune system and fibrosis in the skin and internal organs. The pathogenesis of SSc is complex and remains to be determined. So far, limited specific disease-modifying treatments are available for the effective control of fibrosis in patients with SSc. Studies from the past few years hint at the importance of immune dysfunctions, including the dysregulation of innate and adaptive immune cells, as well as the aberrant secretion of inflammatory and fibrotic cytokines, in the pathogenesis of SSc fibrosis. In this Review, we summarize the most pertinent findings concerning the involvement of dysregulated immune responses in fibrosis of the skin and lungs in SSc and highlight the current and potential immune-based targets for SSc therapeutics.

Development of a Diagnostic Model Focusing on Esophageal Dysmotility in Patients with Systemic Sclerosis.

OBJECTIVE: Esophageal dysmotility is a common and neglected complication of systemic sclerosis (SSc) associated with poor prognosis, while the assessment remains a challenge. We aimed to develop a diagnostic model for esophageal dysmotility in SSc patients that provides individualized risk estimates. METHODS: Seventy-five SSc patients who underwent high-resolution manometry (HRM) were included in the study. Esophageal widest diameter (WED) was measured on a chest CT scan. Esophageal parameters between patients with and without esophageal dysmotility were compared. Multivariate logistic regression analysis and Least Absolute Shrinkage and Selection Operator (LASSO) regression were used to fit the model. The diagnostic model was evaluated by discrimination and calibration. Internal validation was estimated using the enhanced bootstrap method with 1000 repetitions. RESULTS: Sixty-one systemic sclerosis patients (81.3%) were diagnosed with esophageal dysmotility according to the Chicago Classification v 3.0. The diagnostic model for evaluating the probability of esophageal dysmotility integrated clinical and imaging features, including disease duration, ILD, and WED. The model displayed good discrimination with an area under the curve (AUC) of 0.923 (95% CI: 0.837-1.000), a Brier score of 0.083, and good calibration. A high AUC value of 0.911 could still be achieved in the internal validation. CONCLUSION: The diagnostic model, which combines the disease duration, ILD, and imaging feature (WED), is an effective and noninvasive method for predicting esophageal dysmotility in SSc patients.

An Autoimmunogenic and Proinflammatory Profile Defined by the Gut Microbiota of Patients With Untreated Systemic Lupus Erythematosus.

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.

The Gut Microbiota: Emerging Evidence in Autoimmune Diseases.

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.