Transplantation of an obesity-associated human gut microbiota to mice induces vascular dysfunction and glucose intolerance.

Recent preclinical data suggest that alterations in the gut microbiota may be an important factor linking obesity to vascular dysfunction, an early sign of cardiovascular disease. The purpose of this study was to begin translation of these preclinical data by examining whether vascular phenotypes in humans are transmissible through the gut microbiota. We hypothesized that germ-free mice colonized with gut microbiota from obese individuals would display diminished vascular function compared to germ-free mice receiving microbiota from lean individuals.

Lifelong voluntary aerobic exercise prevents age- and Western diet- induced vascular dysfunction, mitochondrial oxidative stress and inflammation in mice.

The results of the present study establish the temporal pattern of age-related vascular dysfunction across the adult lifespan in sedentary mice consuming a non-Western diet, and the underlying mechanisms The results demonstrate that consuming a Western diet accelerates and exacerbates vascular ageing across the lifespan in sedentary mice They also show that lifelong voluntary aerobic exercise has remarkable protective effects on vascular function throughout the lifespan, in the setting of ageing alone, as well as ageing compounded by Western diet consumption Overall, the results indicate that amelioration of mitochondrial oxidative stress and inflammation are key mechanisms underlying the voluntary aerobic exercise-associated preservation of vascular function across the lifespan in both the presence and absence of a Western dietary pattern ABSTRACT: Advancing age is the major risk factor for cardiovascular diseases, driven largely by vascular endothelial dysfunction (impaired endothelium-dependent dilatation, EDD) and aortic stiffening (increased aortic pulse wave velocity, aPWV). In humans, vascular ageing occurs in the presence of differences in diet and physical activity, but the interactive effects of these factors are unknown. We assessed carotid artery EDD and aPWV across the lifespan in mice consuming standard (normal) low-fat chow (NC) or a high-fat/high-sucrose Western diet (WD) in the absence (sedentary, SED) or presence (voluntary wheel running, VWR) of aerobic exercise.

Microbial metabolite indole-3-propionic acid supplementation does not protect mice from the cardiometabolic consequences of a Western diet.

Emerging evidence suggests that intestinal microbes regulate host physiology and cardiometabolic health, although the mechanism(s) by which they do so is unclear. Indoles are a group of compounds produced from bacterial metabolism of the amino acid tryptophan. In light of recent data suggesting broad physiological effects of indoles on host physiology, we examined whether indole-3-propionic acid (IPA) would protect mice from the cardiometabolic consequences of a Western diet.

Sodium Glucose Co-Transporter 2 Inhibition Does Not Favorably Modify the Physiological Responses to Dietary Counselling in Diabetes-Free, Sedentary Overweight and Obese Adult Humans.

Sedentary obesity is associated with increased risk of many cardio-metabolic diseases, including type 2 diabetes. Weight loss is therefore a desirable goal for sedentary adults with obesity. Weight loss is also a well-documented side effect of sodium glucose co-transporter 2 (SGLT2) inhibition, a pharmaceutical strategy for diabetes treatment.

Monounsaturated fatty acids protect against palmitate-induced lipoapoptosis in human umbilical vein endothelial cells.

Diets high in saturated fatty acids are linked to increased cardiovascular disease risk, whereas monounsaturated fatty acids have been associated with improved cardiovascular outcomes. Accordingly, cell culture studies have demonstrated that saturated fatty acids, particularly long chain saturated fatty acids such as palmitate, induce dysfunction and cell death in a variety of cell types, and monounsaturated fatty acids may confer protection against palmitate-mediated damage. The aim of the present study was to examine whether monounsaturated fatty acids could protect against palmitate-mediated cell death in endothelial cells, to determine if AMPK inactivation and activation (via compound C and AICAR, respectively) underlies both palmitate-induced damage and monounsaturated fatty acid-mediated protection, and to explore the role of ER stress in this context.

Gut microbiota regulates cardiac ischemic tolerance and aortic stiffness in obesity.

The gut microbiota has emerged as an important regulator of host physiology, with recent data suggesting a role in modulating cardiovascular health. The present study determined if gut microbial signatures could transfer cardiovascular risk phenotypes between lean and obese mice using cecal microbiota transplantation (CMT). Pooled cecal contents collected from obese leptin-deficient (Ob) mice or C57Bl/6j control (Con) mice were transplanted by oral gavage into cohorts of recipient Ob and Con mice maintained on identical low-fat diets for 8 wk ( = 9-11/group).

Suppression of the gut microbiome ameliorates age-related arterial dysfunction and oxidative stress in mice.

Key Points: Age-related arterial dysfunction, characterized by oxidative stress- and inflammation-mediated endothelial dysfunction and arterial stiffening, is the primary risk factor for cardiovascular diseases. To investigate whether age-related changes in the gut microbiome may mediate arterial dysfunction, we suppressed gut microbiota in young and old mice with a cocktail of broad-spectrum, poorly-absorbed antibiotics in drinking water for 3-4 weeks. In old mice, antibiotic treatment reversed endothelial dysfunction and arterial stiffening and attenuated vascular oxidative stress and inflammation.

SGLT2 inhibition via dapagliflozin improves generalized vascular dysfunction and alters the gut microbiota in type 2 diabetic mice.

Background: Type 2 diabetes (T2D) is associated with generalized vascular dysfunction characterized by increases in large artery stiffness, endothelial dysfunction, and vascular smooth muscle dysfunction. Sodium glucose cotransporter 2 inhibitors (SGLT2i) represent the most recently approved class of oral medications for the treatment of T2D, and have been shown to reduce cardiovascular and overall mortality. Although it is currently unclear how SGLT2i decrease cardiovascular risk, an improvement in vascular function is one potential mechanism.

The gut microbiota as a novel regulator of cardiovascular function and disease.

The gut microbiome has emerged as a critical regulator of human physiology. Deleterious changes to the composition or number of gut bacteria, commonly referred to as gut dysbiosis, has been linked to the development and progression of numerous diet-related diseases, including cardiovascular disease (CVD). Most CVD risk factors, including aging, obesity, certain dietary patterns, and a sedentary lifestyle, have been shown to induce gut dysbiosis.

Suppression of gut dysbiosis reverses Western diet-induced vascular dysfunction.

Vascular dysfunction represents a critical preclinical step in the development of cardiovascular disease. We examined the role of the gut microbiota in the development of obesity-related vascular dysfunction. Male C57BL/6J mice were fed either a standard diet (SD) ( n = 12) or Western diet (WD) ( n = 24) for 5 mo, after which time WD mice were randomized to receive either unsupplemented drinking water or water containing a broad-spectrum antibiotic cocktail (WD + Abx) ( n = 12/group) for 2 mo.

Mitochondria-targeted antioxidant therapy with MitoQ ameliorates aortic stiffening in old mice.

Aortic stiffening is a major independent risk factor for cardiovascular diseases, cognitive dysfunction, and other chronic disorders of aging. Mitochondria-derived reactive oxygen species are a key source of arterial oxidative stress, which may contribute to arterial stiffening by promoting adverse structural changes-including collagen overabundance and elastin degradation-and enhancing inflammation, but the potential for mitochondria-targeted therapeutic strategies to ameliorate aortic stiffening with primary aging is unknown. We assessed aortic stiffness [pulse-wave velocity (aPWV)], ex vivo aortic intrinsic mechanical properties [elastic modulus (EM) of collagen and elastin regions], and aortic protein expression in young (~6 mo) and old (~27 mo) male C57BL/6 mice consuming normal drinking water (YC and OC) or water containing mitochondria-targeted antioxidant MitoQ (250 µM; YMQ and OMQ) for 4 wk.

Tauroursodeoxycholic Acid Reduces Arterial Stiffness and Improves Endothelial Dysfunction in Type 2 Diabetic Mice.

Background/aims: Endoplasmic reticulum (ER) stress has emerged as a potential mechanism contributing to diabetes and its comorbidities. However, the importance of ER stress in diabetic vascular dysfunction is unclear. The purpose of this study was to examine the effects of the ER stress inhibitor, tauroursodeoxycholic acid (TUDCA), on arterial stiffness and endothelial dysfunction in type 2 diabetic mice.

Voluntary aerobic exercise increases arterial resilience and mitochondrial health with aging in mice.

Mitochondrial dysregulation and associated excessive reactive oxygen species (mtROS) production is a key source of oxidative stress in aging arteries that reduces baseline function and may influence resilience (ability to withstand stress). We hypothesized that voluntary aerobic exercise would increase arterial resilience in old mice. An acute mitochondrial stressor (rotenone) caused greater (further) impairment in peak carotid EDD in old (~27 mo.

Fuzhuan tea reverses arterial stiffening after modest weight gain in mice.

Objectives: The aim of this study was to examine the effects of a Western diet (WD) and supplementation with Fuzhuan tea on large artery stiffness, as determined by aortic pulse wave velocity (aPWV).

Methods: Mice were subjected to a standard diet (SD; n = 12) or WD (n = 10) for 7 mo, and were then separated to receive nonsupplemented drinking water (SD-W and WD-W) or water supplemented with Fuzhuan tea (SD-T and WD-T) (200 mg/kg daily); mice were then maintained on their respective diets for an additional 2 mo.

Results: After the initial 7-mo feeding period, WD elicited a modest and significantly greater increase in body weight than did SD (39.

Sodium nitrite supplementation improves motor function and skeletal muscle inflammatory profile in old male mice.

Aging is associated with motor declines that lead to functional limitations and disability, necessitating the development of therapies to slow or reverse these events. We tested the hypothesis that sodium nitrite supplementation attenuates declines in motor function in older C57BL/6 mice. Motor function was assessed using a battery of tests (grip strength, open-field distance, rota-rod endurance) in old animals (age 20-24 mo) at baseline and after 8 wk of sodium nitrite (old nitrite, n = 22, 50 mg/liter) or no treatment (old control, n = 40), and in young reference animals (3 mo, n = 87).