Impact of selenium on the intestinal microbiome-eCBome axis in the context of diet-related metabolic health in mice.

Dietary micronutrients act at the intestinal level, thereby influencing microbial communities, the host endocannabinoidome, and immune and anti-oxidative response. Selenium (Se) is a trace element with several health benefits. Indeed, Se plays an important role in the regulation of enzymes with antioxidative and anti-inflammatory activity as well as indicators of the level of oxidative stress, which, together with chronic low-grade inflammation, is associated to obesity. To understand how Se variations affect diet-related metabolic health, we fed female and male mice for 28 days with Se-depleted or Se-enriched diets combined with low- and high-fat/sucrose diets. We quantified the plasma and intestinal endocannabinoidome, profiled the gut microbiota, and measured intestinal gene expression related to the immune and the antioxidant responses in the intestinal microenvironment. Overall, we show that intestinal segment-specific microbiota alterations occur following high-fat or low-fat diets enriched or depleted in Se, concomitantly with modifications of circulating endocannabinoidome mediators and changes in cytokine and antioxidant enzyme expression. Specifically, Se enrichment was associated with increased circulating plasma levels of 2-docosahexaenoyl-glycerol (2-DHG), a mediator with putative beneficial actions on metabolism and inflammation. Others eCBome mediators also responded to the diets. Concomitantly, changes in gut microbiota were observed in Se-enriched diets following a high-fat diet, including an increase in the relative abundance of Peptostreptococcaceae and Lactobacillaceae. With respect to the intestinal immune response and anti-oxidative gene expression, we observed a decrease in the expression of proinflammatory genes Il1ß and Tnfα in high-fat Se-enriched diets in caecum, while in ileum an increase in the expression levels of the antioxidant gene Gpx4 was observed following Se depletion. The sex of the animal influenced the response to the diet of both the gut microbiota and endocannabinoid mediators. These results identify Se as a regulator of the gut microbiome and endocannabinoidome in conjunction with high-fat diet, and might be relevant to the development of new nutritional strategies to improve metabolic health and chronic low-grade inflammation associated to metabolic disorders.

Influence of diet on acute endocannabinoidome mediator levels post exercise in active women, a crossover randomized study.

The extended endocannabinoid system, also termed endocannabinoidome, participates in multiple metabolic functions in health and disease. Physical activity can both have an acute and chronic impact on endocannabinoid mediators, as does diet. In this crossover randomized controlled study, we investigated the influence of diet on the peripheral response to acute maximal aerobic exercise in a sample of active adult women (n = 7) with no underlying metabolic conditions. We compared the impact of 7-day standardized Mediterranean diet (MedDiet) and control diet inspired by Canadian macronutrient intake (CanDiet) on endocannabinoidome and short-chain fatty acid metabolites post maximal aerobic exercise. Overall, plasmatic endocannabinoids, their congeners and some polyunsaturated fatty acids increased significantly post maximal aerobic exercise upon cessation of exercise and recovered their initial values within 1 h after exercise. Most N-acylethanolamines and polyunsaturated fatty acids increased directly after exercise when the participants had consumed the MedDiet, but not when they had consumed the CanDiet. This impact was different for monoacylglycerol endocannabinoid congeners, which in most cases reacted similarly to acute exercise while on the MedDiet or the CanDiet. Fecal microbiota was only minimally affected by the diet in this cohort. This study demonstrates that endocannabinoidome mediators respond to acute maximal aerobic exercise in a way that is dependent on the diet consumed in the week prior to exercise.

Innovaciones en la terapia antimicrobiana / Innovations in antimicrobial therapy

Resumen La resistencia microbiana ha llevado a la búsqueda de innovadoras alternativas para su contención y dentro de las más promisorias están el uso de péptidos sintéticos, no sólo por sus características intrínsecas antimicrobianas, sino por las interacciones sinérgicas y antagónicas que presenta con otros mediadores inmunológicos. Estas propiedades han permitido crear péptidos sintéticos reguladores de defensa innata que representan un nuevo enfoque inmunomodulador para el tratamiento de infecciones; sin embargo, sólo los diseñados con alto score antimicrobiano, han demostrado eficacia en estudios clínicos de Fase 3. Debido a su amplio espectro de actividad, un único péptido puede actuar contra bacterias Gram negativas, Gram positivas, hongos, e incluso virus y parásitos, aumentando el interés por investigar estas dinámicas moléculas. Por otra parte, se encuentra el sistema CRISPR, para la edición de genomas bacterianos, permitirá reducir su actividad virulenta y diseñar antimicrobianos basados en nucleasas CRISPR-Cas 9 programables contra dianas específicas, las que representan un promisorio camino en el estudio de nuevas alternativas con alto potencial para eliminar la resistencia a antibióticos de bacterias altamente patógenas. Asimismo, se aborda la terapia con fagos, referida a la acción de virus que infectan bacterias, usados solos o en cocteles para aumentar el espectro de acción de estos, aprovechando su abundancia en la naturaleza, ya que se ha considerado que cada bacteria tiene un virus específico que podría emplearse como potente agente antibacteriano. Finalmente, mientras se usen como principal medio de contención solo tratamientos convencionales antimicrobianos, incluso de manera oportuna y acertada, la microevolución en las bacterias se asegurará de seguir su curso.

Abstract Microbial resistance has led to the search for innovative alternatives to contain it. One of the most promising ones is the use of peptides, not only due to their intrinsically antimicrobial characteristics, but also due to the synergistic and antagonistic interactions they present with other immunological mediators. These properties have enabled the creation of innate immune regulatory peptides, which represent a new immunomodulatory approach to treat infections. However, despite multiple attempts tested, only the designed with a high antimicrobial score have demonstrated effectiveness in phase three clinical trials. Yet, given their exceptionally wide spectrum of activity, a single peptide can have activity against Gram-negative bacterial, Gram-positive bacterial, fungi and even viruses and parasites, increasing the interest in researching these dynamic molecules. Furthermore, the CRISPR system enables the editing of bacterial genomes, which would make it possible to reduce their virulent activity and design antimicrobials based on programmable CRISPR-Cas 9 nucleases against specific targets. This system represent a promising path in the study of new alternatives with high potential to eliminate antibiotic resistance of highly pathogenic bacteria. Likewise, phage therapy, that is, the action of viruses that infect bacteria, used alone or in cocktails to increase their spectrum of action, taking advantage of their abundance in nature, given that it has been considered that each bacterium has a specific virus that it could be used as a potent antibacterial agent. Finally, as long as conventional antimicrobial treatments continue to be used as the main means of containment, even when they are used correctly, the microevolution of bacteria will be itself sure to continue its own path.