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The TLR9 agonist MGN1703 triggers a potent type I interferon response in the sigmoid colon.
Krarup, AR, Abdel-Mohsen, M, Schleimann, MH, Vibholm, L, Engen, PA, Dige, A, Wittig, B, Schmidt, M, Green, SJ, Naqib, A, et al
Mucosal immunology. 2018;(2):449-461
Abstract
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.
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A multicenter, randomized controlled comparison of three renutrition strategies for the management of moderate acute malnutrition among children aged from 6 to 24 months (the MALINEA project).
Vray, M, Hedible, BG, Adam, P, Tondeur, L, Manirazika, A, Randremanana, R, Mainassara, H, Briend, A, Artaud, C, von Platen, C, et al
Trials. 2018;(1):666
Abstract
BACKGROUND The aim of this open-label, randomized controlled trial conducted in four African countries (Madagascar, Niger, Central African Republic, and Senegal) is to compare three strategies of renutrition for moderate acute malnutrition (MAM) in children based on modulation of the gut microbiota with enriched flours alone, enriched flours with prebiotics or enriched flours coupled with antibiotic treatment. METHODS To be included, children aged between 6 months and 2 years are preselected based on mid-upper-arm circumference (MUAC) and are included based on a weight-for-height Z-score (WHZ) between - 3 and - 2 standard deviations (SD). As per current protocols, children receive renutrition treatment for 12 weeks and are assessed weekly to determine improvement. The primary endpoint is recovery, defined by a WHZ ≥ - 1.5 SD after 12 weeks of treatment. Data collected include clinical and socioeconomic characteristics, side effects, compliance and tolerance to interventions. Metagenomic analysis of gut microbiota is conducted at inclusion, 3 months, and 6 months. The cognitive development of children is evaluated in Senegal using only the Developmental Milestones Checklist II (DMC II) questionnaire at inclusion and at 3, 6, and 9 months. The data will be correlated with renutrition efficacy and metagenomic data. DISCUSSION This study will provide new insights for the treatment of MAM, as well as original data on the modulation of gut microbiota during the renutrition process to support (or not) the microbiota hypothesis of malnutrition. TRIAL REGISTRATION ClinicalTrials.gov, ID: NCT03474276 Last update 28 May 2018.
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3.
[Diet and microbiota. Impact on health].
Álvarez-Calatayud, G, Guarner, F, Requena, T, Marcos, A
Nutricion hospitalaria. 2018;(Spec No6):11-15
Abstract
months of life, reaching the state of mature microbiota when the child is around two years old. Even so, diet, lifestyle, antibiotic consumption or the aging process will determine changes in its composition and, as a consequence, the possibility of suffering chronic non-communicable diseases. Currently, there is sufficient scientific evidence to strengthen the importance of diet for the establishment, structure and functional activity of the gut microbiota, as well as many studies that demonstrate the role of diet in certain diseases through its effects on microbial communities of the gut. Modulation of the gut microbiota through dietary intervention is an emerging therapeutic and preventive strategy for many conditions. Probiotics and prebiotics may also be effective for restoration of beneficial bacteria and microbiota diversity capable to shift from disease to health promoting states.
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Methodological considerations for the identification of choline and carnitine-degrading bacteria in the gut.
Jameson, E, Quareshy, M, Chen, Y
Methods (San Diego, Calif.). 2018;:42-48
Abstract
The bacterial formation of trimethylamine (TMA) has been linked to cardiovascular disease. This review focuses on the methods employed to investigate the identity of the bacteria responsible for the formation of TMA from dietary choline and carnitine in the human gut. Recent studies have revealed the metabolic pathways responsible for bacterial TMA production, primarily the anaerobic glycyl radical-containing, choline-TMA lyase, CutC and the aerobic carnitine monooxygenase, CntA. Identification of these enzymes has enabled bioinformatics approaches to screen both human-associated bacterial isolate genomes and whole gut metagenomes to determine which bacteria are responsible for TMA formation in the human gut. We centre on several key methodological aspects for identifying the TMA-producing bacteria and report how these pathways can be identified in human gut microbiota through bioinformatics analysis of available bacterial genomes and gut metagenomes.
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5.
The effect of drinking water pH on the human gut microbiota and glucose regulation: results of a randomized controlled cross-over intervention.
Hansen, TH, Thomassen, MT, Madsen, ML, Kern, T, Bak, EG, Kashani, A, Allin, KH, Hansen, T, Pedersen, O
Scientific reports. 2018;(1):16626
Abstract
Studies in rodent models have shown that alterations in drinking water pH affect both the composition of the gut microbiota and host glucose regulation. To explore a potential impact of electrochemically reduced alkaline (pH ≈ 9) versus neutral (pH ≈ 7) drinking water (2 L/day) on human intestinal microbiota and host glucose metabolism we conducted a randomized, non-blinded, cross-over study (two 2-week intervention periods, separated by a 3-week wash-out) in 29 healthy, non-smoking Danish men, aged 18 to 35 years, with a body mass index between 20.0 to 27.0 kg m-2. Volunteers were ineligible if they had previously had abdominal surgery, had not been weight stabile for at least two months, had received antibiotic treatment within 2 months, or had a habitual consumption of caloric or artificially sweetened beverages in excess of 1 L/week or an average intake of alcohol in excess of 7 units/week. Microbial DNA was extracted from faecal samples collected at four time points, before and after each intervention, and subjected to 16S rRNA gene amplicon sequencing (Illumina MiSeq, V4 region). Glycaemic regulation was evaluated by means of an oral glucose tolerance test.No differential effect of alkaline versus neutral drinking water was observed for the primary outcome, overall gut microbiota diversity as represented by Shannon's index. Similarly, neither a differential effect on microbiota richness or community structure was observed. Nor did we observe a differential effect on the abundance of individual operational taxonomic units (OTUs) or genera. However, analyses of within period effects revealed a significant (false discovery rate ≤5%) increase in the relative abundance of 9 OTUs assigned to order Clostridiales, family Ruminococcaceae, genus Bacteroides, and species Prevotella copri, indicating a potential effect of quantitative or qualitative changes in habitual drinking habits. An increase in the concentration of plasma glucose at 30 minutes and the incremental area under the curve of plasma glucose from 0 30 and 0 120 minutes, respectively, was observed when comparing the alkaline to the neutral intervention. However, results did not withstand correction for multiplicity. In contrast to what has been reported in rodents, a change in drinking water pH had no impact on the composition of the gut microbiota or glucose regulation in young male adults. The study is registered at www.clinicaltrials.gov (NCT02917616).
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Microbiota in obesity: interactions with enteroendocrine, immune and central nervous systems.
Mulders, RJ, de Git, KCG, Schéle, E, Dickson, SL, Sanz, Y, Adan, RAH
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2018;(4):435-451
Abstract
Western diets, with high consumption of simple sugars and saturated fats, contribute to the rise in the prevalence of obesity. It now seems clear that high-fat diets cause obesity, at least in part, by modifying the composition and function of the microorganisms that colonize in the gastrointestinal tract, the microbiota. The exact pathways by which intestinal microbiota contribute to obesity remain largely unknown. High-fat diet-induced alterations in intestinal microbiota have been suggested to increase energy extraction, intestinal permeability and systemic inflammation while decreasing the capability to generate obesity-suppressing short-chain fatty acids. Moreover, by increasing systemic inflammation, microglial activation and affecting vagal nerve activity, 'obese microbiota' indirectly influence hypothalamic gene expression and promote overeating. Because the potential of intestinal microbiota to induce obesity has been recognized, multiple ways to modify its composition and function are being investigated to provide novel preventive and therapeutic strategies against diet-induced obesity.
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7.
[Role of prebiotics and probiotics in the functionality of the microbiota in the patients receiving enteral nutrition].
Ballesteros Pomar, MD, González Arnaiz, E
Nutricion hospitalaria. 2018;(Spec no2):18-26
Abstract
Set of resident microorganisms in our body that are responsible for the absorption of nutrients and the maintenance of health is named microbiota. The microbiota´s role is protective, trophic and metabolic. Different groups of microbiota intestinal name enterotypes, each one of them are in relation to specific dietary habits. The absence of enteral stimulation affects both epithelial and GALT and the development of the microbiota. This situation modifies the immune system´s interaction, with a less competitive exclusion of more pathogenic bacteria, which can promote infections. These changes are likely reversible when supplementation with enteral nutrition is used. Dietary fibre and probiotics, to be fermented by colonic microbiota produce gases and short-chain fatty acids causing an acid pH in the large intestine which hinders the growth of pathogenic microorganisms. The administration of probiotic with enteral nutrition in critically ill patients was associated with lower rates of infection with no effect on mortality, average stay, or diarrhea. Also proposed as a strategy to reduce infectious complications in elective surgery and to reduce the time of tolerance of enteral feeding in preterm or low birth weight. In acute pancreatitis, it has been suggested a possible role of probiotics to restore intestinal integrity, but more safety studies are needed. There are isolated cases of bacteremia, sepsis or endocarditis usually in immunocompromised patients. Yet the benefits appear to be greater than the risks.
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8.
Gut microbiota functions: metabolism of nutrients and other food components.
Rowland, I, Gibson, G, Heinken, A, Scott, K, Swann, J, Thiele, I, Tuohy, K
European journal of nutrition. 2018;(1):1-24
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Abstract
The diverse microbial community that inhabits the human gut has an extensive metabolic repertoire that is distinct from, but complements the activity of mammalian enzymes in the liver and gut mucosa and includes functions essential for host digestion. As such, the gut microbiota is a key factor in shaping the biochemical profile of the diet and, therefore, its impact on host health and disease. The important role that the gut microbiota appears to play in human metabolism and health has stimulated research into the identification of specific microorganisms involved in different processes, and the elucidation of metabolic pathways, particularly those associated with metabolism of dietary components and some host-generated substances. In the first part of the review, we discuss the main gut microorganisms, particularly bacteria, and microbial pathways associated with the metabolism of dietary carbohydrates (to short chain fatty acids and gases), proteins, plant polyphenols, bile acids, and vitamins. The second part of the review focuses on the methodologies, existing and novel, that can be employed to explore gut microbial pathways of metabolism. These include mathematical models, omics techniques, isolated microbes, and enzyme assays.
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9.
Probiotics drive gut microbiome triggering emotional brain signatures.
Bagga, D, Reichert, JL, Koschutnig, K, Aigner, CS, Holzer, P, Koskinen, K, Moissl-Eichinger, C, Schöpf, V
Gut microbes. 2018;(6):486-496
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Abstract
Experimental manipulation of the gut microbiome was found to modify emotional and cognitive behavior, neurotransmitter expression and brain function in rodents, but corresponding human data remain scarce. The present double-blind, placebo-controlled randomised study aimed at investigating the effects of 4 weeks' probiotic administration on behavior, brain function and gut microbial composition in healthy volunteers. Forty-five healthy participants divided equally into three groups (probiotic, placebo and no intervention) underwent functional MRI (emotional decision-making and emotional recognition memory tasks). In addition, stool samples were collected to investigate the gut microbial composition. Probiotic administration for 4 weeks was associated with changes in brain activation patterns in response to emotional memory and emotional decision-making tasks, which were also accompanied by subtle shifts in gut microbiome profile. Microbiome composition mirrored self-reported behavioral measures and memory performance. This is the first study reporting a distinct influence of probiotic administration at behavioral, neural, and microbiome levels at the same time in healthy volunteers. The findings provide a basis for future investigations into the role of the gut microbiota and potential therapeutic application of probiotics.
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How to predict and improve prognosis of food allergy.
Dahdah, L, Pecora, V, Riccardi, C, Fierro, V, Valluzzi, R, Mennini, M
Current opinion in allergy and clinical immunology. 2018;(3):228-233
Abstract
PURPOSE OF REVIEW The prevalence of food allergy is increasing. More children are being diagnosed with food allergies, and it is taking longer to outgrow them, among those who develop tolerance. The aim of this review is to draw the profile of the persistent food allergic, so that prevention strategies can be developed and active treatment set up. RECENT FINDINGS Many determinants are involved in food allergy prognosis: ethnicity and sex, type of food, innate immune system, eliciting dose, sensitization status and other biomarkers determination, gut microbiome composition, and the presence of comorbidities. Once identified, a persistent food allergy could be conveyed to active treatments, such as oral immunotherapy or the use of biologics, always taking into account their experimental nature. SUMMARY A better understanding of prognostic factors and phenotypes of food allergy is crucial in decision-making when it comes to food allergy prevention and management. A good classification of the allergic patient allows to determine the degree of exclusion diets and the timing of the reintroduction of avoided food when possible. In the cases of persistent and severe food allergy, many promising interventions are emerging which could improve prognosis and quality of care.