The Potential Role of Butyrate in the Pathogenesis and Treatment of Autoimmune Rheumatic Diseases.

The gut microbiota is a complex ecosystem of microorganisms residing in the human gastrointestinal tract, playing a crucial role in various biological processes and overall health maintenance. Dysbiosis, an imbalance in the composition and function of the gut microbiota, is linked to systemic autoimmune diseases (SAD). Short-chain fatty acids (SCFAs), especially butyrate, produced by the gut microbiota through the fermentation of dietary fibers, play a significant role in immunomodulation and maintaining intestinal homeostasis. Butyrate is essential for colonocyte energy, anti-inflammatory responses, and maintaining intestinal barrier integrity. Studies show reduced butyrate-producing bacteria in SAD patients, suggesting that increasing butyrate levels could have therapeutic benefits. Butyrate's anti-inflammatory effects and its potential therapeutic role have been studied in rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, systemic sclerosis, and Behçet's disease. Despite promising in vitro and animal model results, human studies are limited, and the optimal strategies for modulating dysbiosis in SADs remain elusive. This review explores the current evidence on the immunoregulatory role of butyrate and its potential therapeutic effects in SAD.

Endometriosis, Pain, and Related Psychological Disorders: Unveiling the Interplay among the Microbiome, Inflammation, and Oxidative Stress as a Common Thread.

Endometriosis (EM), a chronic condition in endometrial tissue outside the uterus, affects around 10% of reproductive-age women, significantly affecting fertility. Its prevalence remains elusive due to the surgical confirmation needed for diagnosis. Manifesting with a range of symptoms, including dysmenorrhea, dyschezia, dysuria, dyspareunia, fatigue, and gastrointestinal discomfort, EM significantly impairs quality of life due to severe chronic pelvic pain (CPP). Psychological manifestations, notably depression and anxiety, frequently accompany the physical symptoms, with CPP serving as a key mediator. Pain stems from endometrial lesions, involving oxidative stress, neuroinflammation, angiogenesis, and sensitization processes. Microbial dysbiosis appears to be crucial in the inflammatory mechanisms underlying EM and associated CPP, as well as psychological symptoms. In this scenario, dietary interventions and nutritional supplements could help manage EM symptoms by targeting inflammation, oxidative stress, and the microbiome. Our manuscript starts by delving into the complex relationship between EM pain and psychological comorbidities. It subsequently addresses the emerging roles of the microbiome, inflammation, and oxidative stress as common links among these abovementioned conditions. Furthermore, the review explores how dietary and nutritional interventions may influence the composition and function of the microbiome, reduce inflammation and oxidative stress, alleviate pain, and potentially affect EM-associated psychological disorders.

Oral microbiota signatures associated with viremia and CD4 recovery in treatment-naïve HIV-1-infected patients.

PURPOSE: Few reports focused on the role of oral microbiome diversity in HIV infection. We characterized the microbiota-immunity axis in a cohort of treatment-naïve HIV-1-infected patients undergoing antiretroviral therapy (ART) focusing on the oral microbiome (OM) and immunological responsivity. METHODS: The sequencing of 16S rRNA V3-V4 hypervariable region was performed on salivary samples of 15 healthy control (HC) and 12 HIV + patients before starting ART and after reaching virological suppression. Then, we correlated the OM composition with serum cytokines and the Short Chain Fatty acids (SCFAs). RESULTS: The comparison between HIV patients and HC oral microbiota showed differences in the bacterial α-diversity and richness. We documented a negative correlation between oral Prevotella and intestinal valeric acid at before starting ART and a positive correlation between oral Veillonella and gut acetic acid after reaching virological suppression. Finally, an increase in the phylum Proteobacteria was observed comparing saliva samples of immunological responders (IRs) patients against immunological non-responders (INRs). CONCLUSIONS: For the first time, we described an increase in the oral pro-inflammatory Proteobacteria phylum in INRs compared to IRs. We provided more evidence that saliva could be a non-invasive and less expensive approach for research involving the oral cavity microbiome in HIV patients.

Comparison of ELISA with automated ECLIA for IL-6 determination in COVID-19 patients: An Italian real-life experience.

Objectives: Coronavirus disease 2019 (COVID-19) has a wide spectrum of clinical severity. A cytokine storm is associated with COVID-19 severity. Of these, IL-6 is significantly associated with higher mortality and is also a marker for predicting disease prognosis. IL-6 may act as a target for therapeutics and, a blockade of IL-6 function by Tocilizumab has been described as a treatment of the inflammatory process COVID-19-related. This study aims to describe our experience comparing two different methods, in detail Human IL-6 Instant ELISA and the Elecsys IL-6 based on ECLIA, for the IL-6 assessment. Design and methods: IL-6 levels from serum samples of 104 COVID-19 patients, admitted to the AOU Careggi (Hospital in Florence -Italy), were assessed by using the two above-mentioned methods, and the results were analysed through Passing-Bablok regression fit and Bland-Altman plot. Results: The regression exhibited a linear relation between the methods with a regression equation (y = - 0.13 + 0.63 x; 95 % C.I. intercept = - 0.13 to 4.55; 95 % C.I. slope = 1.03 to 1.26 with R2 = 0.89, p > 0.05), showing a positive slope. The agreement of the two methods reported a bias of -25.0 pg/mL. Thus, the two methods correlate but do not agree in terms of numeric results. Conclusions: The two assays showed good comparability. However, because of the extremely wide linear range of the ECLIA, its throughput and its capacity for immune profiling, it represents an interesting emerging technology in the immunology field.

Real-Life Comparison of Four JAK Inhibitors in Rheumatoid Arthritis (ELECTRA-i Study).

Background: Real-world evidence of the efficacy and adverse events of JAK inhibitor treatment (Tofacitinib, Baricitinib, Upadacitinib, and Filgotinib) in rheumatoid arthritis is still limited. Methods: We studied 115 patients from the Rheumatology Unit of S. Giovanni di Dio Hospital affected by D2T-RA, according to the 2010 EULAR criteria. Out of the 115 patients, 17 had been treated with Baricitinib 8 mg/daily, 32 with Filgotinib 200 mg/daily, 21 with Tofacitinib 10 mg/daily, and 45 with Upadacitinib 15 mg/daily. We evaluated the clinical response after 3, 6, and 12 months of treatment and the follow-up from September 2022 to September 2023. All patients were evaluated according to the number of tender joints (NTJs), number of swollen joints (NSJs), visual analog scale (VAS), global assessment (GA), health assessment questionnaire (HAQ), Disease Activity Score (DAS28), and CDAI. Furthermore, laboratory parameters of efficacy and tolerability were evaluated. Results: All treatments demonstrated a statistically significant decrease in the DAS28 and CDAI scores, tender and swollen joint counts, VAS, HAQ, and patient global assessment (PGA) after 3, 6, and 12 months of treatment. All treatments showed similar behavior, and statistically significant decreases in circulating calprotectin, TNFα, and IL-6 were observed for all drugs after 12 months of treatment. In addition, soluble urokinase plasminogen activator receptor (suPAR) values showed significant differences at baseline and after 12 months of treatment for Filgotinib: 4.87 ± 4.53 vs. 3.61 ± 0.9 (0.009) and Upadacitinib: 6.64 ± 7.12 vs. 4.06 ± 3.61 (0.0003), while no statistically significant differences were found for Baricitinib: 3.4 ± 0.1 vs. 3.78 ± 0.1 and Tofacitinib: 3.95 ± 1.77 vs. 2.58 ± 0.1. The TC/HDL-C ratio (atherogenic index) showed significant differences when comparing Baricitinib vs. Filgotinib (0.0012), Filgotinib vs. Tofacitinib (0.0095), and Filgotinib vs. Upadacitinib (0.0001); furthermore, the LDL-C/HDL-C ratio in the Filgotinib group did not change (2.37 ± 0.45 vs. 2.35 ± 2.13 (NS)) after 12 months of treatment. Venous Thrombotic Events (VTEs) and major adverse cardiovascular events (MACEs) accounted for 1% of adverse events after treatment with Baricitinib. Herpes zoster reactivation accounted for 1% of adverse events after treatment with Filgotinib and Tofacitinib, while non-melanoma skin cancer (NMSC) accounted for 1% of adverse events after Upadacitinib treatment. Conclusions: Our real-world data from patients with RA show differences in some laboratory parameters and in the impact of lipid metabolism in JAK inhibitor treatment.

The differential crosstalk of the skin-gut microbiome axis as a new emerging actor in systemic sclerosis.

OBJECTIVES: We characterized the microbiota in SSc, focusing on the skin-oral-gut axis and the serum and faecal free fatty acid (FFA) profile. METHODS: Twenty-five SSc patients with ACA or anti-Scl70 autoantibodies were enrolled. The microbiota of faecal, saliva and superficial epidermal samples was assessed through next-generation sequencing analysis. GC-MS was used to quantify faecal and serum FFAs. Gastrointestinal symptoms were investigated with the University of California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument (UCLA GIT-2.0) questionnaire. RESULTS: The ACA+ and anti-Scl70+ groups displayed different cutaneous and faecal microbiota profiles. The classes of cutaneous Sphingobacteriia and Alphaproteobacteria, the faecal phylum Lentisphaerae, the levels of the classes Lentisphaeria and Opitutae, and the genus NA-Acidaminococcaceae were significantly higher in faecal samples from the ACA+ patients than in samples from the anti-Scl70+ patients. The cutaneous Sphingobacteria and the faecal Lentisphaerae were significantly correlated (rho = 0.42; P = 0.03). A significant increase in faecal propionic acid was observed in ACA+ patients. Moreover, all levels of faecal medium-chain FFAs and hexanoic acids were significantly higher in the ACA+ group than in the anti-Scl70+ group (P < 0.05 and P < 0.001, respectively). In the ACA+ group, the analysis of the serum FFA levels showed an increasing trend in valeric acid. CONCLUSION: Different microbiota signatures and FFA profiles were found for the two groups of patients. Despite being in different body districts, the cutaneous Sphingobacteria and faecal Lentisphaerae appear interdependent.

Different Biomarkers of Response to Treatment with Selective Jak-1 Inhibitors in Rheumatoid Arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a systemic autoimmune disease that causes progressive joint damage. The Janus kinase (JAK) inhibitors (JAK-I) represent a new therapeutic option for RA patients, blocking the intracellular JAK-STAT pathway. Today, no studies have been conducted to determine whether new biomarkers could better reflect disease activity in patients treated with JAK-I than traditional disease activity indicators. Thus, the aim of our study was to determine additional disease activity biomarkers in RA patients receiving selective JAK-1 inhibitors. METHODS: we enrolled 57 patients with RA: 34 patients were treated with Upadacitinib (UPA) and 23 patients with Filgotinib (FIL). All patients were evaluated for clinimetry with DAS28 and Crohn's Disease Activity Index (CDAI), number of tender and swollen joints, Visual Analogic Scale (VAS), Physician Global Assessment (PhGA), and Health Assessment Questionnaire (HAQ), at baseline and at the 12th week of treatment. Lymphocyte subpopulations, complete blood count, erythrocyte sedimentation rate (ESR), C-Reactive Protein (CRP), anti-cyclic citrullinated peptide antibodies (APCA), rheumatoid factor (RF) IgM, interleukin 6 (IL-6), circulating calprotectin (cCLP), tumor necrosis factor α (TNFα), soluble urokinase Plasminogen Activator Receptor (suPAR), complement functional activity were measured at baseline and after the 12th week of treatment. RESULTS: in both groups of patients, we documented a significant reduction in the clinimetric parameters DAS28, CDAI, number of tender joints, number of swollen joints, VAS, PhGA, and HAQ. Moreover, significant differences were reported for laboratory parameters of ESR, CRP, IL-6, suPAR, cCLP, and PLT/L ratio in both groups. However, no difference was demonstrated between the two groups for changes in renal, hepatic, and lipid parameters. CONCLUSIONS: the suPAR and cCLP levels may lead towards a different therapeutic choice between UPA and FIL, with the expression of two different RA pathophenotypes directing FIL towards a lymphocyte-poor form and UPA towards a myeloid form of RA.

Corrigendum: Characterization of the "gut microbiota-immunity axis" and microbial lipid metabolites in atrophic and potential celiac disease.

[This corrects the article DOI: 10.3389/fmicb.2022.886008.].

Oral and fecal microbiota perturbance in cocaine users: Can rTMS-induced cocaine abstinence support eubiosis restoration?

The effects of cocaine on microbiota have been scarcely explored. Here, we investigated the gut (GM) and oral (OM) microbiota composition of cocaine use disorder (CUD) patients and the effects of repetitive transcranial magnetic stimulation (rTMS). 16S rRNA sequencing was used to characterize GM and OM, whereas PICRUST2 assessed functional changes in microbial communities, and gas-chromatography was used to evaluate fecal short and medium chain fatty acids. CUD patients reported a significant decrease in alpha diversity and modification of the abundances of several taxa in both GM and OM. Furthermore, many predicted metabolic pathways were differentially expressed in CUD patients' stool and saliva samples, as well as reduced levels of butyric acid that appear restored to normal amounts after rTMS treatment. In conclusion, CUD patients showed a profound dysbiotic fecal and oral microbiota composition and function and rTMS-induced cocaine abstinence determined the restoration of eubiotic microbiota.