Role of the gut microbiota in the control of cardio-metabolic risk

An altered blood lipid profile and a suboptimal diet are among the main modifiable risk factors of cardiovascular diseases (CVDs), which remain the number one cause of death worldwide. Type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) promote endothelial dysfunction, an early key biomarker of CVD and atherosclerosis-related clinical events, that lead to microcirculation damage. Increasing evidence shows that gut microbes regulate host physiological and metabolic pathways, namely by producing bioactive metabolites (e.g. bile acids [BAs]). This PhD thesis is a proof-of-concept of the involvement of the gut microbiota in the nutritional and pharmacological control of cardio-metabolic risk in mice. Our first experimental data reveal that widely prescribed hypolipidemic drugs (i.e. simvastatin and ezetimibe) are able to modulate microbial composition in murine model by changing the relative abundance of the Lactobacillus genus. Furthermore, these changes are associated with modified expression of genes coding for cholesterol-homeostasis in the liver and jejunum. During the second phase of the thesis, we develop a model of endothelial dysfunction in small resistance arteries (mesenteric arteries) associated with the NAFLD phenotype. Deficiency in n-3 polyunsaturated fatty acids (PUFAs) is a nutritional characteristic of the Western diet. We knew that wild-type mice fed an n-3 PUFA-depleted diet develop the “hepatic phenotype” of NAFLD in mice. The same n-3 PUFA-depleted diet given to Apolipoprotein E knock-out (Apoe-/-) mice for 12 weeks accelerates the process of endothelial dysfunction, decreases nitrosylated-hemoglobin (Hb-NO) levels and induces hepatic steatosis, independently of obesity, fat intake or inflammation. In the last part of the thesis, we describe, in this model, the impact of gut microbiota modulation by inulin-type fructans (ITFs), considered to be prebiotics. We highlight that ITF supplementation for two weeks is able to improve endothelial function in small resistance arteries (i.e. mesenteric arteries) and plaque-prone vessels (i.e. carotid arteries) isolated from n-3 PUFA-depleted Apoe-/- mice by activating the NOS/NO pathway and restoring Hb-NO levels. ITFs profoundly modulate microbial composition in favor of NO-producing bacteria (e.g. those from the Enterobacteriaceae family or the Bifidobacterium genus) and in disfavor of bacteria involved in secondary BA synthesis (e.g. those from the Lachnospiraceae or Ruminococcaceae families). Modifying the composition of the gut microbiota changes its ability to produce bacterial metabolites, as indicated by increased primary and free BA concentration and higher GLP-1 production, both of which can directly or indirectly activate the NOS/NO pathway by enhancing eNOS phosphorylation. This PhD thesis is the starting point for future clinical trials studying the role of gut microbes in the control of cardio-metabolic risk through prebiotic-based intervention.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 201

Interventions to improve appropriateness of laboratory testing in the intensive care unit: a narrative review

Healthcare expenses are increasing, as is the utilization of laboratory resources. Despite this, between 20% and 40% of requested tests are deemed inappropriate. Improper use of laboratory resources leads to unwanted consequences such as hospital-acquired anemia, infections, increased costs, staff workload and patient stress and discomfort. The most unfavorable consequences result from unnecessary follow-up tests and treatments (overuse) and missed or delayed diagnoses (underuse). In this context, several interventions have been carried out to improve the appropriateness of laboratory testing. To date, there have been few published assessments of interventions specific to the intensive care unit. We reviewed the literature for interventions implemented in the ICU to improve the appropriateness of laboratory testing. We searched literature from 2008 to 2023 in PubMed, Embase, Scopus, and Google Scholar databases between April and June 2023. Five intervention categories were identified: education and guidance (E&G), audit and feedback, gatekeeping, computerized physician order entry (including reshaping of ordering panels), and multifaceted interventions (MFI). We included a sixth category exploring the potential role of artificial intelligence and machine learning (AI/ML)-based assisting tools in such interventions. E&G-based interventions and MFI are the most frequently used approaches. MFI is the most effective type of intervention, and shows the strongest persistence of effect over time. AI/ML-based tools may offer valuable assistance to the improvement of appropriate laboratory testing in the near future. Patient safety outcomes are not impaired by interventions to reduce inappropriate testing. The literature focuses mainly on reducing overuse of laboratory tests, with only one intervention mentioning underuse. We highlight an overall poor quality of methodological design and reporting and argue for standardization of intervention methods. Collaboration between clinicians and laboratory staff is key to improve appropriate laboratory utilization. This article offers practical guidance for optimizing the effectiveness of an intervention protocol designed to limit inappropriate use of laboratory resources

Ezetimibe and simvastatin modulate gut microbiota and expression of genes related to cholesterol metabolism

AIMS: Hypolipidemic drugs are prescribed in the most of cases for the treatment of cardiovascular diseases. Several studies have showed that the gut microbiota is able to regulate the host cholesterol metabolism. This study aimed to investigate the potential impact of hypolipidemic drugs on the gut microbiota in mice, and to correlate it to the regulation of cholesterol metabolism. MAIN METHODS: Male C57Bl/6J mice were divided into four groups fed either a control diet alone (CT), or supplemented with simvastatin (0.1% w/w, Zocor®, MSD), or ezetimibe (0.021% w/w, Ezetrol®, MSD) or a combination of simvastatin and ezetimibe (0.1% and 0.021%, respectively) for one week. KEY FINDINGS: The combination of ezetimibe and simvastatin is required to observe a drop in cholesterolemia, linked to a huge activation of hepatic SREBP-2 and the consequent increased expression of genes involved in LDL cholesterol uptake and cholesterol synthesis. The gut microbiota analysis revealed no change in total bacteria, and in major Gram positive and Gram negative bacteria, but a selective significant increase in Lactobacillus spp. in mice treated with the ezetimibe and a decrease by the combination. The changes in lactobacilli level observed in ezetimibe or combination treated-mice are negatively correlated to expression of genes related to cholesterol metabolism. SIGNIFICANCE: The present study showed that ezetimibe taken alone is able to modify the composition of gut microbiota in favor of Lactobacillus spp. These results suggest that members of the genus Lactobacillus play an important role in cholesterol metabolism, even in normocholesterolemic mouse model

0396 : Prebiotics supplementation improves the endothelial dysfunction induced by a nutritional deficiency in n-3 polyunsaturated fatty acids (PUFA)

Nutritional disorders are associated with a high risk of developing cardiovascular diseases, endothelial dysfunction being an early key marker. We have demonstrated that metabolic alterations induced by a nutritional depletion in n-3 PUFA are improved by a supplementation in prebiotics (non-digestible fructans). The present work focusses on the impact of prebiotics on the endothelial dysfunction induced by the n-3 PUFA depletion in ApoE–/– mice model. C57Bl/6J (WT) and ApoE–/– (KO) mice were fed a n-3 PUFA depleted-diet (DEF) for 12 weeks. For the last fifteen days, mice were or not supplemented with prebiotics (PRE). The vascular morphology and function were evaluated in first, second and third order mesenteric arteries by histology and wire myograph. Micro-arteries from KO DEF PRE mice develop an increased basal tone and present a larger vessel diameter, compared to vessels from non-supplemented mice. The PRE supplementation in KO DEF mice leads to an increased media thickness in first order mesenteric arteries, this is even higher in the second order branch, in comparison to non-supplemented mice. KO DEF PRE micro-arteries contract significantly more in response to a KCl challenge than vessels from non-supplemented mice. As expected micro-arteries from KO DEF mice present an endothelial dysfunction after 12 weeks of n-3 PUFA depletion with a significant decrease of endothelial-dependent relaxation in comparison to WT DEF arteries. The PRE supplementation is able to improve the endothelial function by restoring the endothelial-dependent relaxation in arteries from KO DEF mice. We point out fructan-type prebiotics as a potential therapeutic tool in endothelial dysfunction. Our results argue in favor of an outward muscular remodeling in mesenteric arteries, leading to an increased blood flow and a better vascular reactivity. The results on endothelial function evoke an important implication of the nitric oxide pathway in this phenomenon

Physical stability of an IV mixture of morphine and clonidine in syringe

BACKGROUND AND AIM Clonidine is frequently combined to opioids for the management of chronic pain. The aim of this study was to evaluate the physical stability of this combination at high and low concentrations in polypropylene syringes at 5±3°C and at 22±3°C. METHODS Five syringes with low concentration of clonidine (0.003 mg/mL) and morphine hydrochloride (0.417 mg/mL) and five syringes with high concentration of clonidine (0.032 mg/mL)and morphine hydrochloride (4.286 mg/mL) were evaluated. The turbidity, the pH and the crystal formation were controlled after the production and until 72h post-production. RESULTS No changes in color or appearance of opacity or turbidity were observed. Spectrophotometric measurements (at 350, 410 and 550 nm) and pH were not affected. The microscopic analysis did not detect any aggregate or crystal formation. DISCUSSION AND CONCLUSION The mixture of clonidine and morphine hydrochloride at low and high concentrations is physically stable for at least 72 hours post-production at 5±3°C and at 22±3°C. These results paved the way for a subsequent chemical stability study

Forecasting cross-border malaria case number: towards an early warning system to support malaria elimination plans

International audienceMalaria elimination, one of the Sustainable Development Goals of the United Nation, is challenged by cross-border context specificities. At the French Guiana-Brazil border, a system was developed to harmonized epidemiological data providing by the two countries. This study evaluates the feasibility of using such harmonized data to build a cross-border early warning system. To this end, the study compared ARI-MAX and LSTM approaches. Time-lagged meteorological data were introduced to improve the forecasts. LSTM outperformed ARIMAX, with a 10 to 39% decrease of Mean Absolute and Root Means Square Errors, and better predicted low case numbers. Meteorological data improved significantly model predictions, by considering time-lags from 3 to 7 weeks compatible with the knowledge found in the literature. This study demonstrated the feasibility of building a cross-border malaria early warning system, that would significantly contribute to malaria control and elimination

Lack of anti-inflammatory effect of coenzyme Q10 supplementation in the liver of rodents after lipopolysaccharide challenge

Background & aims : Sepsis is characterized by a systemic dysregulated inflammatory response and oxidative stress. A large body of evidence supports a key role of mitochondrial dysfunction during the various phases of sepsis (early and late-phase of sepsis-associated multiorgan failure). Coenzyme Q10 (CoQ10) is a key cofactor in the mitochondrial and respiratory chain, and is depleted in septic shock patients. However its effect on acute sepsis remains unexplored. The reduced form of CoQ10 (Qx) has been shown to lessen pro-inflammatory response in macrophages or fibroblasts in culture. The aim of the study is to investigate the effect of Qx on hepatic inflammation in models of acute LPS-induced inflammation. Methods : We have conducted 2 experiments: one in vitro using rat precision-cut liver slices (PCLS) incubated with LPS and Qx, and one in vivo experiment using mice fed with Qx for 2 weeks and killed 1 h after LPS administration. Results : LPS challenge induced hepatic inflammatory stress both in vitro and in vivo (increased TNFα, nitrite and PGE2 release and/or expression). Incubation of PCLS with Qx fails to modulate hepatic inflammatory stress. Furthermore, Qx supplementation is not able to counteract hepatic LPS-induced acute inflammation in vivo. Conclusion : Coenzyme Q10 is not able to counteract LPS-induced hepatic acute inflammation

Chitin-glucan and pomegranate polyphenols improve endothelial dysfunction.

The vascular dysfunction is the primary event in the occurrence of cardio-vascular risk, and no treatment exists until now. We tested for the first time the hypothesis that chitin-glucan (CG) - an insoluble fibre with prebiotic properties- and polyphenol-rich pomegranate peel extract (PPE) can improve endothelial and inflammatory disorders in a mouse model of cardiovascular disease (CVD), namely by modulating the gut microbiota. Male Apolipoprotein E knock-out (ApoE-/-) mice fed a high fat (HF) diet developed a significant endothelial dysfunction attested by atherosclerotic plaques and increasing abundance of caveolin-1 in aorta. The supplementation with CG + PPE in the HF diet reduced inflammatory markers both in the liver and in the visceral adipose tissue together with a reduction of hepatic triglycerides. In addition, it increased the activating form of endothelial NO-synthase in mesenteric arteries and the heme-nitrosylated haemoglobin (Hb-NO) blood levels as compared with HF fed ApoE-/- mice, suggesting a higher capacity of mesenteric arteries to produce nitric oxide (NO). This study allows to pinpoint gut bacteria, namely Lactobacillus and Alistipes, that could be implicated in the management of endothelial and inflammatory dysfunctions associated with CVD, and to unravel the role of nutrition in the modulation of those bacteria