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Project description:The development of neutralizing FVIII antibodies is the most serious complication of hemophilia A treatment. The currently known patient- and treatment-related risk factors for inhibitor development do not accurately predict this adverse event in all patients. The composition of the gut microbiota has been shown to influence immune-mediated diseases at distant anatomical sites (eg, lungs, brain, and joints). We demonstrate that a disrupted gut microbiota can be created in a mouse model of hemophilia A using a broad-spectrum antibiotic. Under controlled conditions, this sustained dysbiosis was associated with an increase in splenic B cells and the development of higher titer, FVIII-specific immunoglobulin G antibodies after FVIII challenge. Splenic and mesenteric lymph node cytokines, T cells, and dendritic cells were unaffected before administration of FVIII. However, the immune transcriptome of both aforementioned secondary lymphoid organs was significantly modified. Short-chain fatty acids (SCFAs), which are immunomodulatory microbial metabolites, were depleted in cecal contents of the dysbiotic mice. Furthermore, supplementation of the drinking water with butyrate, the most immunologically active SCFA, successfully achieved attenuation of the FVIII immune response. Collectively, data from this exploratory study suggest that the composition of the gut microbiota alters the FVIII immune response via the action of specific microbial metabolites on the immune cell transcriptome and that oral supplementation with butyrate effectively reduces the FVIII immune response.
| S-EPMC7322952 | biostudies-literature
Project description:Gut dysbiosis modulates the immune response to factor VIIII in murine hemophilia A
| PRJNA575698 | ENA
Project description:Inhibitors of factor VIII (FVIII) remain the most challenging complication of FVIII protein replacement therapy in hemophilia A (HA). Understanding the mechanisms that guide FVIII-specific B cell development could help identify therapeutic targets. The B cell-activating factor (BAFF) cytokine family is a key regulator of B cell differentiation in normal homeostasis and immune disorders. Thus, we used patient samples and mouse models to investigate the potential role of BAFF in modulating FVIII inhibitors. BAFF levels were elevated in pediatric and adult HA inhibitor patients and decreased to levels similar to those of noninhibitor controls after successful immune tolerance induction (ITI). Moreover, elevations in BAFF levels were seen in patients who failed to achieve FVIII tolerance with anti-CD20 antibody-mediated B cell depletion. In naive HA mice, prophylactic anti-BAFF antibody therapy prior to FVIII immunization prevented inhibitor formation and this tolerance was maintained despite FVIII exposure after immune reconstitution. In preimmunized HA mice, combination therapy with anti-CD20 and anti-BAFF antibodies dramatically reduced FVIII inhibitors via inhibition of FVIII-specific plasma cells. Our data suggest that BAFF may regulate the generation and maintenance of FVIII inhibitors and/or anti-FVIII B cells. Finally, anti-CD20/anti-BAFF combination therapy may be clinically useful for ITI.
| S-EPMC8262462 | biostudies-literature
Project description:The influence of the gut microbiota on traumatic brain injury (TBI) is presently unknown. This knowledge gap is of paramount clinical significance as TBI patients are highly susceptible to alterations in the gut microbiota by antibiotic exposure. Antibiotic-induced gut microbial dysbiosis established prior to TBI significantly worsened neuronal loss and reduced microglia activation in the injured hippocampus with concomitant changes in fear memory response. Importantly, antibiotic exposure for 1 week after TBI reduced cortical infiltration of Ly6Chigh monocytes, increased microglial pro-inflammatory markers, and decreased T lymphocyte infiltration, which persisted through 1 month post-injury. Moreover, microbial dysbiosis was associated with reduced neurogenesis in the dentate gyrus 1 week after TBI. By 3 months after injury (11 weeks after discontinuation of the antibiotics), we observed increased microglial proliferation, increased hippocampal neuronal loss, and modulation of fear memory response. These data demonstrate that antibiotic-induced gut microbial dysbiosis after TBI impacts neuroinflammation, neurogenesis, and fear memory and implicate gut microbial modulation as a potential therapeutic intervention for TBI.
| S-EPMC7944629 | biostudies-literature
Project description:The microbiome is essential for host health, and perturbations resulting from antibiotic use can lead to dysbiosis and disease. Diet can be a powerful modulator of microbiome composition and function, with the potential to mitigate the negative effects of antibiotic use. Thus, it is necessary to study the impacts of diet and drug interactions on the gut microbiome. Coffee is a commonly consumed beverage containing many compounds that have the potential to affect the microbiome, including caffeine, polyphenols, and fiber. We supplemented mice with caffeinated and decaffeinated coffee in conjunction with amoxicillin, and used 16S rRNA amplicon sequencing of fecal samples to investigate changes in diversity and composition of the murine fecal microbiome. We found that antibiotics, regardless of coffee supplementation, caused significant disruption to the murine fecal microbiome, enriching for Proteobacteria, Verrucomicrobia, and Bacteroidetes, but reducing Firmicutes. While we found that coffee alone did not have a significant impact on the composition of the fecal microbiome, coffee supplementation did significantly affect relative abundance metrics in mice treated with amoxicillin. After caffeinated coffee supplementation, mice treated with amoxicillin showed a smaller increase in Proteobacteria, specifically of the family Burkholderiaceae. Correspondingly we found that in vitro, Burkholderia cepacia was highly resistant to amoxicillin, and that it was inhibited by concentrations of caffeine and caffeinated coffee comparable to levels of caffeine in murine ceca. Overall, this work shows that coffee, and possibly the caffeine component, can impact both the microbiome and microbiome members during antibiotic exposure.
| S-EPMC8278525 | biostudies-literature
Project description:A mutual interplay exists between adaptive immune system and gut microbiota. Altered gut microbial ecosystems are associated with the metabolic syndrome, occurring in most obese individuals. However, it is unknown why 10-25% of obese individuals are metabolically healthy, while normal weight individuals can develop inflammation and atherosclerosis. We modeled these specific metabolic conditions in mice fed with a chow diet, an obesogenic but not inflammatory diet-mimicking healthy obesity, or Paigen diet-mimicking inflammation in the lean subjects. We analyzed a range of markers and cytokines in the aorta, heart, abdominal fat, liver and spleen, and metagenomics analyses were performed on stool samples. T lymphocytes infiltration was found in the aorta and in the liver upon both diets, however a significant increase in CD4+ and CD8+ cells was found only in the heart of Paigen-fed animals, paralleled by increased expression of IL-1, IL-4, IL-6, IL-17, and IFN-γ. Bacteroidia, Deltaproteobacteria, and Verrucomicrobia dominated in mice fed Paigen diet, while Gammaproteobacteria, Delataproteobacteria, and Erysipelotrichia were more abundant in obese mice. Mice reproducing human metabolic exceptions displayed gut microbiota phylogenetically distinct from normal diet-fed mice, and correlated with specific adaptive immune responses. Diet composition thus has a pervasive role in co-regulating adaptive immunity and the diversity of microbiota.
| S-EPMC5479914 | biostudies-other
Project description:MethodThis study included 74 Chinese male patients with HCC. They were divided into early (n = 19), intermediate (n = 37), and terminal (n = 18) groups, referred to as Barcelona Clinic Liver Cancer stage 0+A, B, and C+D, respectively. Paired fecal and plasma samples were collected. Microbial composition and profiles were analyzed by 16S rRNA gene sequencing. The levels of gut damage marker (regenerating islet-derived protein 3α (REG3α)) and microbial translocation markers (soluble CD14 (sCD14), lipopolysaccharide-binding protein (LBP), peptidoglycan recognition proteins (PGRPs)) were determined in plasma samples of patients by ELISA. Twenty plasma cytokine and chemokines were determined by Luminex.ResultsIn early, intermediate, and terminal groups, the abundance of the Bifidobacteriaceae family decreased significantly (3.52%, 1.55%, and 0.56%, respectively, P = 0.003), while the abundance of the Enterococcaceae family increased significantly (1.6%, 2.9%, and 13.4%, respectively, P = 0.022). Levels of REG3α and sCD14 were markedly elevated only in the terminal group compared with the early (P = 0.025 and P = 0.048) and intermediate groups (P = 0.023 and P = 0.046). The level of LBP significantly increased in the intermediate (P = 0.035) and terminal (P = 0.025) groups compared with the early group. The PGRP levels were elevated only in the terminal group compared with the early group (P = 0.018). The ratio of Enterococcaceae to Bifidobacteriaceae was significantly associated with the levels of REG3α, LBP, sCD14, and PGRPs. With HCC progression, increased levels of inflammatory cytokines accompanied by a T cell-immunosuppressive response and microbial translocation were observed.ConclusionGut microbiota compositional and functional shift, together with elevated gut damage and microbial translocation, may promote HCC development by stimulating inflammatory response and suppressing T cell response.
| S-EPMC8551979 | biostudies-literature
Project description:Inflammatory bowel diseases (IBD) are associated with functional inhibition of epithelial Na+/H+ exchange. In mice, a selective disruption of NHE3 (Slc9a3), a major apical Na+/H+ exchanger, also promotes IBD-like symptoms and gut microbial dysbiosis. We hypothesized that disruption of Na+/H+ exchange is necessary for the development of dysbiosis, which promotes an exacerbated mucosal inflammatory response. Therefore, we performed a temporal analysis of gut microbiota composition, and mucosal immune response to adoptive T cell transfer was evaluated in Rag2-/- and NHE3-/-/Rag2-/- (DKO) mice with and without broad-spectrum antibiotics. Microbiome (16S profiling), colonic histology, T cell and neutrophil infiltration, mucosal inflammatory tone, and epithelial permeability were analyzed. In adoptive T cell transfer colitis model, Slc9a3 status was the most significant determinant of gut microbial community. In DKO mice, NHE3-deficiency and dysbiosis were associated with dramatically accelerated and exacerbated disease, with rapid body weight loss, increased mucosal T cell and neutrophil influx, increased mucosal cytokine expression, increased permeability, and expansion of CD25-FoxP3+ Tregs; this enhanced susceptibility was alleviated by oral broad-spectrum antibiotics. Based on these results and our previous work, we postulate that epithelial electrolyte homeostasis is an important modulator in the progression of colitis, acting through remodeling of the gut microbial community.
| S-EPMC4822813 | biostudies-other
Project description:The role of dietary fiber in chronic inflammatory disorders has been explored, but very little is known about its benefits in acute inflammation. Previously, we have demonstrated that dietary cellulose supplementation confers protection in a murine model of sepsis by promoting the growth of the gut microbiota that are linked to metabolic health. The survival benefit is associated with a decrease in serum concentration of proinflammatory cytokines, reduced neutrophil infiltration in the lungs, and diminished hepatic inflammation. Here, we aim to understand if the benefit of manipulating the gut microbiome exerts a broader "systemic" influence on the immune system in a lethal murine endotoxemia model. We hypothesize that mice-fed high-fiber cellulose (HF) diet will demonstrate a reduction in activated macrophages and dendritic cells (DCs) and a concomitant increase in the suppressive capacity of T-regulatory cells (Tregs) toward T cells responsiveness. We characterized the immunological profile and activation status of macrophages, DCs, and T cells in mice on HF diet that were then subjected to endotoxemia. Supplementation with HF diet decreased the number and activation of splenic macrophages and DCs in mice after LPS administration. Similarly, HF diet amplified the suppressive function of Tregs and induced anergy in T cells as compared with mice on a regular diet. Our data suggest that the use of HF diet can be a simple, yet effective tool that decreases the hepatic DNA-binding activity of NF-κB leading to a reduction in proinflammatory cytokine response in a murine endotoxemia model.
| S-EPMC6222003 | biostudies-literature
Project description:The gut microbiota is a well-known prognostic factor and a modulator of treatment sensitivity in patients with cancers treated with immune checkpoint inhibitors. However, data on hepatocellular carcinoma (HCC) are lacking. This study aimed to evaluate the prognostic role of the gut microbiota and changes produced by immunotherapy on the intestinal environment in patients with cirrhosis and HCC. Eleven patients treated with Tremelimumab and/or Durvalumab were included in the analysis. All study participants underwent gut microbiota profiling, quantification of fecal calprotectin, serum levels of zonulin-1, lipopolysaccharide binding protein (LBP), and programmed death-ligand 1 (PD-L1) at baseline and at each treatment cycle until the third cycle, then every three cycles until treatment discontinuation or last visit. The 6 patients who achieved disease control (DC) showed lower pretreatment fecal calprotectin (median, 12.5; interquartile range [IQR], 5-29 vs. median, 116; IQR, 59-129 µg/g; P = 0.047) and PD-L1 serum levels (median, 0.08; IQR, 0.07-0.09 vs. median, 1.04; IQR, 0.17-1.95 ng/mL; P = 0.02) than nonresponders. The relative abundance of Akkermansia (log2 fold change [FC], 2.72; adjusted P [Padj] = 0.012) was increased, whereas that of Enterobacteriaceae (log2 FC, -2.34; Padj = 0.04) was reduced in the DC group. During treatment, fecal calprotectin showed a temporal evolution opposite to the Akkermansia to Enterobacteriaceae ratio and gut microbiota alpha diversity, but similar to zonulin-1 and LBP. Bifidobacterium had a stable behavior in patients with a long follow-up, while Akkermansia was more variable. Akkermansia and Bifidobacterium showed similar temporal patterns and causative relationships with Prevotella, Veillonella, Ruminococcus, Roseburia, Lachnospira, Faecalibacterium, and Clostridium. Conclusion: A favorable composition of the gut microbiota and low intestinal inflammation are associated with achieving DC. The intestinal environment changes dynamically during therapy.
| S-EPMC9134810 | biostudies-literature