The gut commensal Blautia maintains colonic mucus function under low-fiber consumption through secretion of short-chain fatty acids.

Beneficial gut bacteria are indispensable for developing colonic mucus and fully establishing its protective function against intestinal microorganisms. Low-fiber diet consumption alters the gut bacterial configuration and disturbs this microbe-mucus interaction, but the specific bacteria and microbial metabolites responsible for maintaining mucus function remain poorly understood. By using human-to-mouse microbiota transplantation and ex vivo analysis of colonic mucus function, we here show as a proof-of-concept that individuals who increase their daily dietary fiber intake can improve the capacity of their gut microbiota to prevent diet-mediated mucus defects. Mucus growth, a critical feature of intact colonic mucus, correlated with the abundance of the gut commensal Blautia, and supplementation of Blautia coccoides to mice confirmed its mucus-stimulating capacity. Mechanistically, B. coccoides stimulated mucus growth through the production of the short-chain fatty acids propionate and acetate via activation of the short-chain fatty acid receptor Ffar2, which could serve as a new target to restore mucus growth during mucus-associated lifestyle diseases.

Intestinal α-Defensins Play a Minor Role in Modulating the Small Intestinal Microbiota Composition as Compared to Diet.

The intestinal microbiota is at the interface between the host and its environment and thus under constant exposure to host-derived and external modulators. While diet is considered to be an important external factor modulating microbiota composition, intestinal defensins, one of the major classes of antimicrobial peptides, have been described as key host effectors that shape the gut microbial community. However, since dietary compounds can affect defensin expression, thereby indirectly modulating the intestinal microbiota, their individual contribution to shaping gut microbiota composition remains to be defined. To disentangle the complex interaction among diet, defensins, and small-intestinal microbiota, we fed wild-type (WT) mice and mice lacking functionally active α-defensins (Mmp7-/- mice) either a control diet or a Western-style diet (WSD) that is rich in saturated fat and simple carbohydrates but low in dietary fiber. 16S rDNA sequencing and robust statistical analyses identified that bacterial composition was strongly affected by diet while defensins had only a minor impact. These findings were independent of sample location, with consistent results between the lumen and mucosa of the jejunum and ileum, in both mouse genotypes. However, distinct microbial taxa were also modulated by α-defensins, which was supported by differential antimicrobial activity of ileal protein extracts. As the combination of WSD and defensin deficiency exacerbated glucose metabolism, we conclude that defensins only have a fine-tuning role in shaping the small-intestinal bacterial composition and might instead be important in protecting the host against the development of diet-induced metabolic dysfunction. IMPORTANCE Alterations in the gut microbial community composition are associated with many diseases, and therefore identifying factors that shape the microbial community under homeostatic and diseased conditions may contribute to the development of strategies to correct a dysbiotic microbiota. Here, we demonstrate that a Western-style diet, as an extrinsic parameter, had a stronger impact on shaping the small intestinal bacterial composition than intestinal defensins, as an intrinsic parameter. While defensins have been previously shown to modulate bacterial composition in young mice, our study supplements these findings by showing that defensins may be less important in adult mice that harbor a mature microbial community. Nevertheless, we observed that defensins did affect the abundance of distinct bacterial taxa in adult mice and protected the host from aggravated diet-induced glucose impairments. Consequently, our study uncovers a new angle on the role of intestinal defensins in the development of metabolic diseases in adult mice.

Muc2-dependent microbial colonization of the jejunal mucus layer is diet sensitive and confers local resistance to enteric pathogen infection.

Intestinal mucus barriers normally prevent microbial infections but are sensitive to diet-dependent changes in the luminal environment. Here we demonstrate that mice fed a Western-style diet (WSD) suffer regiospecific failure of the mucus barrier in the small intestinal jejunum caused by diet-induced mucus aggregation. Mucus barrier disruption due to either WSD exposure or chromosomal Muc2 deletion results in collapse of the commensal jejunal microbiota, which in turn sensitizes mice to atypical jejunal colonization by the enteric pathogen Citrobacter rodentium. We illustrate the jejunal mucus layer as a microbial habitat, and link the regiospecific mucus dependency of the microbiota to distinctive properties of the jejunal niche. Together, our data demonstrate a symbiotic mucus-microbiota relationship that normally prevents jejunal pathogen colonization, but is highly sensitive to disruption by exposure to a WSD.

Intravenous Administration Errors Intercepted by Smart Infusion Technology in an Adult Intensive Care Unit.

OBJECTIVES: The aim of the study was to investigate the efficacy of intravenous (IV) smart pumps with drug libraries and dose error reduction system (DERS) to intercept programming errors entailing high risk for patients in an adult intensive care unit (ICU). METHODS: A 2-year retrospective study was conducted in the adult ICU of the Hospital Juárez de México in Mexico City to evaluate the impact of IV smart pump/DERS (Hospira MedNet) technology implementation. We conducted a descriptive analysis of the reports generated by the system's software from April 2014 through May 2016. Our study focused on the upper hard limit alerts and used the systems' variance reports and IV Medication Harm Index methodology to determine the severity of the averted overdoses for medications with the highest number of edits. RESULTS: The system monitored 124,229 infusion programs and averted on 36,942 deviations of the preset safe limits. Upper hard limit alerts accounted for 26.4% of pump reprogramming events. One hundred sixty-six significant administration errors were intercepted and prevented, and IV Medication Harm Index analysis identified 83 of them as highest-risk averted overdoses with insulin accounting for 51.8% of those. The rate of compliance with the safety software during the study period was 69.8%. CONCLUSIONS: Our study contributes additional evidence of the impact of IV smart pump/DERS technology. These pumps effectively intercepted severe infusion errors and significantly prevented adverse drug events related to dosing. Our results support the implementation of this technology in ICUs as a minimum safety standard and could help drive an IV infusion safety initiative in Mexico.

Does an Apple a Day Also Keep the Microbes Away? The Interplay Between Diet, Microbiota, and Host Defense Peptides at the Intestinal Mucosal Barrier.

A crucial mechanism of intestinal defense includes the production and secretion of host defense peptides (HDPs). HDPs control pathogens and commensals at the intestinal interface by direct killing, by sequestering vital ions, or by causing bacterial cells to aggregate in the mucus layer. Accordingly, the combined activity of various HDPs neutralizes gut bacteria before reaching the mucosa and thus helps to maintain the homeostatic balance between the host and its microbes at the mucosal barrier. Defects in the mucosal barrier have been associated with various diseases that are on the rise in the Western world. These include metabolic diseases, such as obesity and type 2 diabetes, and inflammatory intestinal disorders, including ulcerative colitis and Crohn's disease, the two major entities of inflammatory bowel disease. While the etiology of these diseases is multifactorial, highly processed Western-style diet (WSD) that is rich in carbohydrates and fat and low in dietary fiber content, is considered to be a contributing lifestyle factor. As such, WSD does not only profoundly affect the resident microbes in the intestine, but can also directly alter HDP function, thereby potentially contributing to intestinal mucosal barrier dysfunction. In this review we aim to decipher the complex interaction between diet, microbiota, and HDPs. We discuss how HDP expression can be modulated by specific microbes and their metabolites as well as by dietary factors, including fibers, lipids, polyphenols and vitamins. We identify several dietary compounds that lead to reduced HDP function, but also factors that stimulate HDP production in the intestine. Furthermore, we argue that the effect of HDPs against commensal bacteria has been understudied when compared to pathogens, and that local environmental conditions also need to be considered. In addition, we discuss the known molecular mechanisms behind HDP modulation. We believe that a better understanding of the diet-microbiota-HDP interdependence will provide insights into factors underlying modern diseases and will help to identify potential dietary interventions or probiotic supplementation that can promote HDP-mediated intestinal barrier function in the Western gut.

Mutations that increase expression of the EmrAB-TolC efflux pump confer increased resistance to nitroxoline in Escherichia coli.

OBJECTIVES: To determine the mechanism of resistance to the antibiotic nitroxoline in Escherichia coli. METHODS: Spontaneous nitroxoline-resistant mutants were selected at different concentrations of nitroxoline. WGS and strain reconstruction were used to define the genetic basis for the resistance. The mechanistic basis of resistance was determined by quantitative PCR (qPCR) and by overexpression of target genes. Fitness costs of the resistance mutations and cross-resistance to other antibiotics were also determined. RESULTS: Mutations in the transcriptional repressor emrR conferred low-level resistance to nitroxoline [nitroxoline MIC (MICNOX)=16 mg/L] by increasing the expression of the emrA and emrB genes of the EmrAB-TolC efflux pump. These resistant mutants showed no fitness reduction and displayed cross-resistance to nalidixic acid. Second-step mutants with higher-level resistance (MICNOX=32-64 mg/L) had mutations in the emrR gene, together with either a 50 kb amplification, a mutation in the gene marA, or an IS upstream of the lon gene. The latter mutations resulted in higher-level nitroxoline resistance due to increased expression of the tolC gene, which was confirmed by overexpressing tolC from an inducible plasmid in a low-level resistance mutant. Furthermore, the emrR mutations conferred a small increase in resistance to nitrofurantoin only when combined with an nfsAB double-knockout mutation. However, nitrofurantoin-resistant nfsAB mutants showed no cross-resistance to nitroxoline. CONCLUSIONS: Mutations in different genes causing increased expression of the EmrAB-TolC pump lead to an increased resistance to nitroxoline. The structurally similar antibiotics nitroxoline and nitrofurantoin appear to have different modes of action and resistance mechanisms.

Revealing the Virulence Potential of Clinical and Environmental Aspergillus fumigatus Isolates Using Whole-Genome Sequencing.

Aspergillus fumigatus is considered a common causative agent of human fungal infections. A restricted number of virulence factors have been described, and none of them lead to a differentiation in the virulence level among different strains. Variations in the virulence phenotype depending on the isolate origin, measured as survival percentage in animal infection models, have been previously reported. In this study, we analyzed the whole-genome sequence of A. fumigatus isolates from clinical and environmental origins to determine their virulence genetic content. The sample included four isolates sequenced at the University Medical Center Groningen (UMCG), three clinical (two of them isolated from the same patient) and the experimental strain B5233, and the draft genomes of one reference strain, two environmental and two clinical isolates obtained from a public database. The fungal genomes were screened for the presence of virulence-related genes (VRGs) using an in-house database of 244 genes related to thermotolerance, resistance to immune responses, cell wall formation, nutrient uptake, signaling and regulation, and production of toxins and secondary metabolites and allergens. In addition, we performed a variant calling analysis to compare the isolates sequenced at the UMCG and investigated their genetic relatedness using the TRESP (Tandem Repeats located within Exons of Surface Protein coding genes) genotyping method. We neither observed a difference in the virulence genetic content between the clinical isolates causing an invasive infection and a colonizing clinical isolate nor between isolates from the clinical and environmental origin. The four novel A. fumigatus sequences had a different TRESP genotype and a total number of genetic variants ranging from 48,590 to 68,352. In addition, a comparative genomics analysis showed the presence of single nucleotide polymorphisms in VRGs and repetitive genetic elements located next to VRG groups, which could influence the regulation of these genes. In conclusion, our genomic analysis revealed a high genetic diversity between environmental and clinical A. fumigatus isolates, as well as between clinical isolates from the same patient, indicating an infection with a mixed-population in the latter case. However, all isolates had a similar virulence genetic content, demonstrating their pathogenic potential at least at the genomic level.

Impact of Implementing Smart Infusion Pumps in an Intensive Care Unit in Mexico: A Pre-Post Cost Analysis Based on Intravenous Solutions Consumption.

Background: The use of smart pump technology has shown to be profitable in the intensive care unit (ICU) because it avoids costs from prevented medication errors and allows for savings on disposables and medications by establishing standardized concentrations and dosing units. Objective: The objective of the study is to evaluate the economic impact of the implementation of smart infusion pumps in the consumption of intravenous (IV) solutions in an ICU. Methods: A retrospective observational study was conducted with a pre-post design. The study occurred in the adult ICU of the Hospital Juárez de México. The pattern of consumption of IV solutions (sodium chloride 9%, Hartmann's solution, dextrose 5% and 10%, sodium chloride 0.9% with dextrose 5%) was analyzed preimplementation and postimplementation of 50 Plum A+™ pumps with Hospira MedNet™ security software. Using the TreeAge Pro 2016 software, deterministic and probabilistic analyses were carried out (10 000 Monte Carlo simulations) to confirm the robustness of the annual consumption comparison and the associated expenses before and after implementing smart technology. Results: The implementation of the smart pumps reduced the annual consumption of IV solutions to 8994 units (18%) and 3649 liters (22.3%). In the first year, MXN$55 850.97 were saved. From an institutional perspective and with a probability of 0.63, the use of MedNet™ technology proved to be a lower cost alternative (17.1% saved) with respect to the conventional infusion systems. Conclusion: The implementation of smart infusion pumps allows savings, specifically for the IV solutions used in ICU.