The Effect of Antibiotics Treatment on the Maternal Immune Response and Gut Microbiome in Pregnant and Non-Pregnant Mice.

The gut microbiota are involved in adaptations of the maternal immune response to pregnancy. We therefore hypothesized that inducing gut dysbiosis during pregnancy alters the maternal immune response. Thus, pregnant mice received antibiotics from day 9 to day 16 to disturb the maternal gut microbiome. Feces were collected before, during and after antibiotic treatment, and microbiota were measured using 16S RNA sequencing. Mice were sacrificed at day 18 of pregnancy and intestinal (Peyer's patches (PP) and mesenteric lymph nodes (MLN)) and peripheral immune responses (blood and spleen) were measured using flow cytometry. Antibiotic treatment decreased fetal and placental weight. The bacterial count and the Shannon index were significantly decreased (Friedman, followed by Dunn's test, p < 0.05) and the bacterial genera abundance was significantly changed (Permanova, p < 0.05) following antibiotics treatment as compared with before treatment. Splenic Th1 cells and activated blood monocytes were increased, while Th2, Th17 and FoxP3/RoRgT double-positive cells in the PP and MLNs were decreased in pregnant antibiotics-treated mice as compared with untreated pregnant mice. In addition, intestinal dendritic cell subsets were affected by antibiotics. Correlation of immune cells with bacterial genera showed various correlations between immune cells in the PP, MLN and peripheral circulation (blood and spleen). We conclude the disturbed gut microbiota after antibiotics treatment disturbed the maternal immune response. This disturbed maternal immune response may affect fetal and placental weight.

Contribution of pathogenic T helper 1 and 17 cells to bursitis and tenosynovitis in polymyalgia rheumatica.

Background: Although polymyalgia rheumatica (PMR) is a very common rheumatic inflammatory disease, current insight into the pathobiology of PMR is limited and largely based on studies in blood. We investigated T helper 1 (TH1) and T helper 17 (TH17) cell responses in blood, synovial fluid and bursa tissue of patients with PMR. Materials and methods: Blood samples were collected from 18 patients with new-onset PMR and 32 healthy controls. Synovial fluid was aspirated from the inflamed shoulder bursae or biceps tendon sheath of 13 patients. Ultrasound-guided biopsies of the subacromial-subdeltoid (SASD) bursa were obtained from 11 patients. T cells were examined by flow cytometry, immunohistochemistry and immunofluorescence staining. Results: Besides an increase of TH17 (CD4+IL-17+IFN-γ-) cells and T cytotoxic 17 (TC17; CD8+IL-17+IFN-γ-) cells, no other major changes were noted in the circulating T cell compartment of patients with PMR. Absolute numbers of CD4+ and CD8+ T cells were similar in blood and synovial fluid of patients with PMR. Synovial fluid T cells showed an effector-memory (CD45RO+CCR7-) phenotype. Percentages of TH1 (CD4+IFN-γ+IL-17-) cells and TH1/TH17 (CD4+IFN-γ+IL-17+) cells, but not TH17 or TC17 cells, were increased in the synovial fluid. Bursa tissue biopsies contained a small number of T cells, which were mostly CD8 negative. The majority of bursa tissue T cells produced IFN-γ but not IL-17. For comparison, B cells were scarcely detected in the bursa tissue. Conclusion: Although the circulating TH17 cell pool is expanded in patients with PMR, our findings indicate that TH1 cells are involved in the inflammation of bursae and tendon sheaths in this condition. Our study points towards the TH1 cell pathway as a potential target for therapy in PMR.

Maternal obesity during pregnancy leads to derangements in one-carbon metabolism and the gut microbiota: implications for fetal development and offspring wellbeing.

A healthy diet before and during pregnancy is beneficial in acquiring essential B vitamins involved in 1-carbon metabolism, and in maintaining a healthy gut microbiota. Each play important roles in fetal development, immune-system remodeling, and pregnancy-nutrient acquisition. Evidence shows that there is a reciprocal interaction between the one-carbon metabolism and the gut microbiota given that dietary intake of B vitamins has been shown to influence the composition of the gut microbiota, and certain gut bacteria also synthesize B vitamins. This reciprocal interaction contributes to the individual's overall availability of B vitamins and, therefore, should be maintained in a healthy state during pregnancy. There is an emerging consensus that obese pregnant women often have derangements in 1-carbon metabolism and gut dysbiosis owing to high intake of nutritiously poor foods and a chronic systemic inflammatory state. For example, low folate and vitamin B12 in obese women coincide with the decreased presence of B vitamin-producing bacteria and increased presence of inflammatory-associated bacteria from approximately mid-pregnancy. These alterations are risk factors for adverse pregnancy outcomes, impaired fetal development, and disruption of fetal growth and microbiota formation, which may lead to potential long-term offspring metabolic and neurologic disorders. Therefore, preconceptional and pregnant obese women may benefit from dietary and lifestyle counseling to improve their dietary nutrient intake, and from monitoring their B vitamin levels and gut microbiome by blood tests and microbiota stool samples. In addition, there is evidence that some probiotic bacteria have folate biosynthetic capacity and could be used to treat gut dysbiosis. Thus, their use as an intervention strategy for obese women holds potential and should be further investigated. Currently, there are many knowledge gaps concerning the relationship between one-carbon metabolism and the gut microbiota, and future research should focus on intervention strategies to counteract B vitamin deficiencies and gut dysbiosis in obese pregnant women, commencing with the use of probiotic and prebiotic supplements.

A systematic analysis on the clinical safety and efficacy of onco-virotherapy.

Several onco-virotherapy candidates have been developed and clinically evaluated for the treatment of cancer, and several are approved for clinical use. In this systematic review we explored the clinical impact of onco-virotherapy compared to other cancer therapies by analyzing factors such as trial design, patient background, therapy design, delivery strategies, and study outcomes. For this purpose, we retrieved clinical studies from three platforms: ClinicalTrials.gov, PubMed, and EMBASE. We found that most studies were performed in patients with advanced and metastatic tumors, using a broad range of genetically engineered vectors and mainly administered intratumorally. Therapeutic safety was the most frequently assessed outcome, while relatively few studies focused on immunological antitumor responses. Moreover, only 59 out of 896 clinical studies were randomized controlled trials reporting comparative data. This systemic review thus reveals the need of more, and better controlled, clinical studies to increase our understanding on the application of onco-virotherapy either as a single treatment or in combination with other cancer immunotherapies.