ABSTRACT
Previously, we showed enhanced efficacy of oral immunotherapy (OIT) using fructo-oligosaccharides (FOS, prebiotics) added to the diet of cow's milk allergic mice indicated by a reduction in clinical symptoms and mast cell degranulation. Prebiotics are fermented by gut bacteria, affecting both bacterial composition and availability of metabolites (i.e. short-chain fatty acids (SCFA)). It is thus far unknown which microbial alterations are involved in successful outcomes of OIT with prebiotic supplementation for the treatment of food allergy. To explore potential changes in the microbiota composition and availability of SCFA induced by OIT+FOS. C3H/HeOuJ mice were sensitised and received OIT with or without a FOS supplemented diet. After three weeks, faecal samples were collected to analyse gut microbiota composition using 16S rRNA sequencing. SCFA concentrations were determined in cecum content. FOS supplementation in sensitised mice changed the overall microbial community structure in faecal samples compared to sensitised mice fed the control diet (P=0.03). In contrast, a high level of resemblance in bacterial community structure was observed between the non-sensitised control mice and the OIT+FOS treated mice. OIT mice showed an increased relative abundance of the dysbiosis-associated phylum Proteobacteria compared to the OIT+FOS mice. FOS supplementation increased the relative abundance of genus Allobaculum (Firmicutes), putative butyrate-producing bacteria. OIT+FOS reduced the abundances of the genera's unclassified Rikenellaceae (Bacteroidetes, putative pro-inflammatory bacteria) and unclassified Clostridiales (Firmicutes) compared to sensitised controls and increased the abundance of Lactobacillus (Firmicutes, putative beneficial bacteria) compared to FOS. OIT+FOS mice had increased butyric acid and propionic acid concentrations. OIT+FOS induced a microbial profile closely linked to non-allergic mice and increased concentrations of butyric acid and propionic acid. Future research should confirm whether there is a causal relationship between microbial modulation and the reduction in acute allergic symptoms induced by OIT+FOS.
Subject(s)
Food Hypersensitivity , Oligosaccharides , Prebiotics/administration & dosage , Animals , Bacteria/classification , Bacteria/genetics , Bacteria/isolation & purification , Butyrates/metabolism , Cecum/metabolism , Cecum/microbiology , Diet Therapy/methods , Fatty Acids, Volatile/metabolism , Feces/microbiology , Food Hypersensitivity/immunology , Food Hypersensitivity/microbiology , Food Hypersensitivity/therapy , Gastrointestinal Microbiome/drug effects , Immunotherapy/methods , Lactobacillus/isolation & purification , Mice , Mice, Inbred C3H , Microbiota/drug effects , Milk/adverse effects , Milk/metabolism , Oligosaccharides/administration & dosage , Oligosaccharides/pharmacology , Proteobacteria/isolation & purification , RNA, Ribosomal, 16S/geneticsABSTRACT
The mechanism of neurodegeneration in Parkinson's disease (PD) remains unknown but it has been hypothesised that the intestinal tract could be an initiating and contributing factor to the neurodegenerative processes. In PD patients as well as in animal models for PD, alpha-synuclein-positive enteric neurons in the colon and evidence of colonic inflammation have been demonstrated. Moreover, several studies reported pro-inflammatory bacterial dysbiosis in PD patients. Here, we report for the first time significant changes in the composition of caecum mucosal associated and luminal microbiota and the associated metabolic pathways in a rotenone-induced mouse model for PD. The mouse model for PD, induced by the pesticide rotenone, is associated with an imbalance in the gut microbiota, characterised by a significant decrease in the relative abundance of the beneficial commensal bacteria genus Bifidobacterium. Overall, intestinal bacterial dysbiosis might play an important role in both the disruption of intestinal epithelial integrity and intestinal inflammation, which could lead or contribute to the observed alpha-synuclein aggregation and PD pathology in the intestine and central nervous system in the oral rotenone mouse model of PD.
Subject(s)
Bacteria/isolation & purification , Gastrointestinal Microbiome , Parkinson Disease/microbiology , Animals , Bacteria/classification , Bacteria/genetics , Colon/microbiology , Disease Models, Animal , Humans , Intestines/microbiology , Male , Mice , Mice, Inbred C57BLABSTRACT
Toll-like receptor 9 (TLR9) agonists are being developed for treatment of colorectal and other cancers, yet the impact of these drugs on human intestines remains unknown. This, together with the fact that there are additional potential indications for TLR9 agonist therapy (e.g., autoimmune and infectious diseases), led us to investigate the impact of MGN1703 (Lefitolimod) on intestinal homeostasis and viral persistence in HIV-positive individuals. Colonic sigmoid biopsies were collected (baseline and week four) from 11 HIV+ individuals on suppressive antiretroviral therapy, who received MGN1703 (60 mg s.c.) twice weekly for 4 weeks in a single-arm, phase 1b/2a study. Within sigmoid mucosa, global transcriptomic analyses revealed 248 modulated genes (false discovery rate<0.05) including many type I interferon (IFN)-stimulated genes. MGN1703 increased the frequencies of cells exhibiting MX1 (P=0.001) and ISG15 (P=0.014) protein expression. No changes were observed in neutrophil infiltration (myeloperoxidase; P=0.97). No systematic effect on fecal microbiota structure was observed (analysis of similarity Global R=-0.105; P=0.929). TLR9 expression at baseline was inversely proportional to the change in integrated HIV DNA during MGN1703 treatment (P=0.020). In conclusion, MGN1703 induced a potent type I IFN response, without a concomitant general inflammatory response, in the intestines.
Subject(s)
Colon, Sigmoid/physiology , DNA/therapeutic use , Gastrointestinal Microbiome/drug effects , HIV Infections/immunology , HIV-1/physiology , Intestines/immunology , Toll-Like Receptor 9/agonists , Colon, Sigmoid/drug effects , Colon, Sigmoid/virology , Cytokines/genetics , Cytokines/metabolism , DNA, Viral/genetics , Female , Gene Expression Profiling , HIV Infections/drug therapy , Homeostasis , Humans , Immunity, Mucosal/drug effects , Interferon Type I/metabolism , Intestines/drug effects , Intestines/virology , Male , Myxovirus Resistance Proteins/genetics , Myxovirus Resistance Proteins/metabolism , Ubiquitins/genetics , Ubiquitins/metabolism , Viral Load/drug effectsABSTRACT
OBJECTIVE: To compare the effects of oral diazepam, lorazepam and alprazolam premedication on venous admixture. MATERIAL AND METHODS: One hundred fifty patients divided in three groups were included in the study. The venous admixture was determined using the ISO-shunt nomogram. The values obtained 90 minutes after administration of the drugs were compared with the values before the drug administration. The Student's t-test was applied to find out the significance. RESULTS: These were highly significant change in increase in venous admixture (Qs/Qt) in group I patients 90 minutes after premedication as compared to premedication values. There was statistically insignificant difference in venous admixture (Qs/Qt) in group II and group III patients 90 minutes after premedication as compared to premedication values. CONCLUSION: From the present study it can be concluded that 2 mg of oral lorozepam given 90 minutes before surgery to healthy patients have significant effects on venous admixture. However, the effects of alprazolam and diazepam had no significant effect on venous admixture.
