RESUMEN
BACKGROUND: The metabolic disturbances of obesity can be mitigated by strategies modulating the gut microbiota. In this study, we sought to identify whether innate or adaptive immunity mediates the beneficial metabolic effects of the human intestinal bacterium Bacteroides uniformis CECT 7771 in obesity. METHODS: We evaluated the effects of orally administered B. uniformis on energy homeostasis, intestinal immunity, hormone levels, and gut microbiota in wild-type and Rag1-deficient mice with diet-induced obesity. We also assessed whether B. uniformis needed to be viable to exert its beneficial effects in obesity and to directly induce immunoregulatory effects. RESULTS: The administration of B. uniformis to obese mice improved glucose tolerance and insulin secretion, restored the caloric intake suppression after an oral glucose challenge, and reduced hyperglycemia. The pre- and post-prandial glucose-related benefits were associated with restoration of the anti-inflammatory tone mediated by type 2 macrophages and regulatory T cells (Tregs) in the lamina propria of the small intestine. Contrastingly, B. uniformis administration failed to improve glucose tolerance in obese Rag1-/- mice, but prevented the increased body weight gain and adiposity. Overall, the beneficial effects seemed to be independent of enteroendocrine effects and of major changes in gut microbiota composition. B. uniformis directly induced Tregs generation from naïve CD4+ T cells in vitro and was not required to be viable to improve glucose homeostasis but its viability was necessary to prevent body weight gain in diet-induced obese wild-type mice. CONCLUSIONS: Here we demonstrate that B. uniformis modulates the energy homeostasis in diet-induced obese mice through different mechanisms. The bacterium improves oral glucose tolerance by adaptive immunity-dependent mechanisms that do not require cell viability and prevents body weight gain by adaptive immunity-independent mechanisms which require cell viability. Video Abstract.
Asunto(s)
Inmunidad Adaptativa , Bacteroides , Microbioma Gastrointestinal , Obesidad , Aumento de Peso , Animales , Ratones , Obesidad/inmunología , Obesidad/microbiología , Dieta Alta en Grasa/efectos adversos , Ratones Obesos , Linfocitos T Reguladores/inmunología , Ratones Endogámicos C57BL , Masculino , Humanos , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Probióticos/administración & dosificación , Ratones Noqueados , Glucosa/metabolismoRESUMEN
Listeria monocytogenes, a contaminant of raw milk, includes hypervirulent clonal complexes (CC) like CC1, CC4, and CC6, highly overrepresented in dairy products when compared to other food types. Whether their higher prevalence in dairy products is the consequence of a growth advantage in this food remains unknown. We examined growth kinetics of five L. monocytogenes isolates (CC1, CC4, CC6, CC9, and CC121) at 37 and 4 °C in ultra-high temperature (UHT) milk and raw milk. At 4 °C, hypovirulent CC9 and CC121 isolates exhibit better growth parameters in UHT milk compared to the hypervirulent CC1, CC4, and CC6 isolates. CC9 isolate in raw milk at 4 °C exhibited the fastest growth and the highest final concentrations. In contrast, hypervirulent isolates (CC1, CC4, and CC6) displayed better growth rates in UHT milk at 37 °C, the mammalian host temperature. Proteomic analysis of representative hyper- (CC1) and hypovirulent (CC9) isolates showed that they respond to milk cues differently with CC-specific traits. Proteins related to metabolism (such as LysA or different phosphotransferase systems), and stress response were upregulated in both isolates during growth in UHT milk. Our results show that there is a Listeria CC-specific and a Listeria CC-common response to the milk environment. These findings shed light on the overrepresentation of hypervirulent L. monocytogenes isolates in dairy products, suggesting that CC1 and CC4 overrepresentation in dairy products made of raw milk may arise from contamination during or after milking at the farm and discard an advantage of hypervirulent isolates in milk products when stored at refrigeration temperatures.
RESUMEN
Recent evidence suggests a role of sensory neurons expressing the sodium channel Nav1.8 on the energy homeostasis control. Using a murine diphtheria toxin ablation strategy and ad libitum and time-restricted feeding regimens of control or high-fat high-sugar diets, here we further explore the function of these neurons on food intake and on the regulation of gastrointestinal elements transmitting immune and nutrient sensing.The Nav1.8+ neuron ablation increases food intake in ad libitum and time-restricted feeding, and exacerbates daily body weight variations. Mice lacking Nav1.8+ neurons show impaired prandial regulation of gut hormone secretion and gut microbiota composition, and altered intestinal immunity.Our study demonstrates that Nav1.8+ neurons are required to control food intake and daily body weight changes, as well as to maintain physiological enteroendocrine and immune responses and the rhythmicity of the gut microbiota, which highlights the potential of Nav1.8+ neurons to restore energy balance in metabolic disorders.
Asunto(s)
Microbioma Gastrointestinal , Animales , Ratones , Peso Corporal , Dieta Alta en Grasa , Ingestión de Alimentos/fisiología , Microbioma Gastrointestinal/fisiología , Células Receptoras Sensoriales/metabolismoRESUMEN
SCOPE: Sensory neurons expressing the sodium channel Nav1.8 contain a repertoire of receptors for nutrient, hormonal, and inflammatory ligands. However, their function in key regulators of energy homeostasis control is not well understood and is completely unexplored in females. METHODS AND RESULTS: Mice lacking neurons expressing the sodium channel Nav1.8 were generated using an ablation strategy based on cre recombinase-mediated expression of diphtheria toxin fragment A (DTA) (Nav1.8-cre/DTA mice) to investigate whether these neurons modulate body weight, food intake, gut hormone secretion, gastrointestinal transit, and glucose tolerance in response to nutrient challenges in a sex-dependent manner. Male Nav1.8-cre/DTA mice show resistance to gain weight in response to high-fat high-sugar diet (HFHSD), whereas females lacking Nav1.8+ neurons have improved oral glucose tolerance accompanied by higher insulin levels and attenuated glucagon secretion after an oral glucose load. Female Nav1.8-cre/DTA mice also show higher fasting and postprandial glucagon like peptide-1 (GLP-1) levels with an increased number of GLP-1-positive cells. Finally, ablation of Nav1.8-expressing neurons accelerates the gastrointestinal transit in female mice under HFHSD. CONCLUSION: This data demonstrates sex-dependent differences in the Nav1.8-mediated regulation of energy metabolism, and provides new insights that may help in the design of sex-specific neuromodulation therapies for metabolic disorders induced by diets rich in fats and simple sugars.
Asunto(s)
Péptido 1 Similar al Glucagón , Glucosa , Ratones , Masculino , Femenino , Animales , Péptido 1 Similar al Glucagón/genética , Péptido 1 Similar al Glucagón/metabolismo , Ratones Obesos , Glucosa/metabolismo , Células Receptoras Sensoriales/metabolismo , Dieta Alta en Grasa/efectos adversos , Obesidad/metabolismo , Homeostasis , Canales de Sodio , Insulina/metabolismo , Glucemia/metabolismoRESUMEN
BACKGROUND: Listeriosis is a severe foodborne infection caused by Listeria monocytogenes, an important foodborne pathogen of animals and humans. Listeriosis is a rare disease in cats. OBJECTIVE: To describe the clinical, diagnostic imaging, histological, and microbiological features of L. monocytogenes-associated mesenteric lymphadenitis in a cat. ANIMALS: Listeria monocytogenes-associated mesenteric lymphadenitis was confirmed in a cat by histology and microbiology. RESULTS: Two distinct isolates of L. monocytogenes were cultured from the affected mesenteric lymph node and whole genome sequencing was performed. CONCLUSION AND CLINICAL IMPORTANCE: This report should alert veterinary clinicians and microbiologists to the syndrome, which may have implications for health and food safety in animals and humans.
Asunto(s)
Enfermedades de los Gatos , Listeria monocytogenes , Listeriosis , Linfadenitis Mesentérica , Humanos , Gatos , Animales , Listeria monocytogenes/genética , Linfadenitis Mesentérica/genética , Linfadenitis Mesentérica/veterinaria , Microbiología de Alimentos , Listeriosis/veterinaria , Listeriosis/microbiología , GenómicaRESUMEN
Food addiction (FA) is characterized by behavioral and neurochemical changes linked to loss of food intake control. Gut microbiota may influence appetite and food intake via endocrine and neural routes. The gut microbiota is known to impact homeostatic energy mechanisms, but its role in regulating the reward system is less certain. We show that the administration of Bacteroides uniformis CECT 7771 (B. uniformis) in a rat FA model impacts on the brain reward response, ameliorating binge eating and decreasing anxiety-like behavior. These effects are mediated, at least in part, by changes in the levels of dopamine, serotonin, and noradrenaline in the nucleus accumbens and in the expression of dopamine D1 and D2 receptors in the prefrontal cortex and intestine. B. uniformis reverses the fasting-induced microbiota changes and increases the abundance of species linked to healthy metabolotypes. Our data indicate that microbiota-based interventions might help to control compulsive overeating by modulating the reward response.
Asunto(s)
Ansiedad/metabolismo , Bacteroides/metabolismo , Trastorno por Atracón/metabolismo , Encéfalo/metabolismo , Microbioma Gastrointestinal/fisiología , Recompensa , Animales , Ansiedad/terapia , Bacteroides/aislamiento & purificación , Trastorno por Atracón/terapia , Humanos , Recién Nacido , Masculino , Microdiálisis/métodos , Ratas , Ratas Endogámicas WKYRESUMEN
Obesity currently represents a major societal and health challenge worldwide. Its prevalence has reached epidemic proportions and trends continue to rise, reflecting the need for more effective preventive measures. Hypothalamic circuits that control energy homeostasis in response to food intake are interesting targets for body-weight management, for example, through interventions that reinforce the gut-to-brain nutrient signalling, whose malfunction contributes to obesity. Gut microbiota-diet interactions might interfere in nutrient sensing and signalling from the gut to the brain, where the information is processed to control energy homeostasis. This gut microbiota-brain crosstalk is mediated by metabolites, mainly short chain fatty acids, secondary bile acids or amino acids-derived metabolites and subcellular bacterial components. These activate gut-endocrine and/or neural-mediated pathways or pass to systemic circulation and then reach the brain. Feeding time and dietary composition are the main drivers of the gut microbiota structure and function. Therefore, aberrant feeding patterns or unhealthy diets might alter gut microbiota-diet interactions and modify nutrient availability and/or microbial ligands transmitting information from the gut to the brain in response to food intake, thus impairing energy homeostasis. Herein, we update the scientific evidence supporting that gut microbiota is a source of novel dietary and non-dietary biological products that may beneficially regulate gut-to-brain communication and, thus, improve metabolic health. Additionally, we evaluate how the feeding time and dietary composition modulate the gut microbiota and, thereby, the intraluminal availability of these biological products with potential effects on energy homeostasis. The review also identifies knowledge gaps and the advances required to clinically apply microbiome-based strategies to improve the gut-brain axis function and, thus, combat obesity.
Asunto(s)
Encéfalo/fisiología , Metabolismo Energético , Microbioma Gastrointestinal/fisiología , Tracto Gastrointestinal/fisiología , Homeostasis , Microbiota/fisiología , Ritmo Circadiano , Dieta , Susceptibilidad a Enfermedades , Ingestión de Alimentos , Conducta Alimentaria , Humanos , Micronutrientes , Nutrientes , Obesidad/etiología , Obesidad/metabolismoRESUMEN
Impaired glucose homeostasis in obesity is mitigated by enhancing the glucoregulatory actions of glucagon-like peptide 1 (GLP-1), and thus, strategies that improve GLP-1 sensitivity and secretion have therapeutic potential for the treatment of type 2 diabetes. This study shows that Holdemanella biformis, isolated from the feces of a metabolically healthy volunteer, ameliorates hyperglycemia, improves oral glucose tolerance and restores gluconeogenesis and insulin signaling in the liver of obese mice. These effects were associated with the ability of H. biformis to restore GLP-1 levels, enhancing GLP-1 neural signaling in the proximal and distal small intestine and GLP-1 sensitivity of vagal sensory neurons, and to modify the cecal abundance of unsaturated fatty acids and the bacterial species associated with metabolic health. Our findings overall suggest the potential use of H biformis in the management of type 2 diabetes in obesity to optimize the sensitivity and function of the GLP-1 system, through direct and indirect mechanisms.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/microbiología , Firmicutes/fisiología , Péptido 1 Similar al Glucagón/metabolismo , Ratones Obesos/metabolismo , Ratones Obesos/microbiología , Animales , Glucemia/metabolismo , Modelos Animales de Enfermedad , Gluconeogénesis/fisiología , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa/métodos , Hiperglucemia/metabolismo , Insulina/metabolismo , Ratones , Ratones Endogámicos C57BL , Obesidad/metabolismo , Obesidad/microbiologíaRESUMEN
This study investigated the immune mechanisms whereby administration of Bacteroides uniformis CECT 7771 reduces metabolic dysfunction in obesity. C57BL/6 adult male mice were fed a standard diet or a Western diet high in fat and fructose, supplemented or not with B. uniformis CECT 7771 for 14 weeks. B. uniformis CECT 7771 reduced body weight gain, plasma cholesterol, triglyceride, glucose, and leptin levels; and improved oral glucose tolerance in obese mice. Moreover, B. uniformis CECT 7771 modulated the gut microbiota and immune alterations associated with obesity, increasing Tregs and reducing B cells, total macrophages and the M1/M2 ratio in both the gut and epididymal adipose tissue (EAT) of obese mice. B. uniformis CECT 7771 also increased the concentration of the anti-inflammatory cytokine IL-10 in the gut, EAT and peripheral blood, and protective cytokines TSLP and IL-33, involved in Treg induction and type 2 innate lymphoid cells activation, in the EAT. It also restored the obesity-reduced TLR5 expression in the ileum and EAT. The findings indicate that the administration of a human intestinal bacterium with immunoregulatory properties on the intestinal mucosa helps reverse the immuno-metabolic dysfunction caused by a Western diet acting over the gut-adipose tissue axis.
Asunto(s)
Infecciones por Bacteroides/metabolismo , Infecciones por Bacteroides/microbiología , Bacteroides/fisiología , Gastroenteritis/metabolismo , Gastroenteritis/microbiología , Transducción de Señal , Receptor Toll-Like 5/metabolismo , Inmunidad Adaptativa , Tejido Adiposo/metabolismo , Animales , Infecciones por Bacteroides/patología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Metabolismo Energético , Gastroenteritis/patología , Microbioma Gastrointestinal , Inmunidad Innata , Mediadores de Inflamación/metabolismo , Ratones , Ratones Obesos , FenotipoRESUMEN
Obesity has reached epidemic proportions and is associated with chronic-low-grade inflammation and metabolic morbidities. Energy-dense diets and a sedentary lifestyle are determinants of obesity. The gut microbiome is a novel biological factor involved in obesity via interactions with the host and the diet. The gut microbiome act as a synergistic force protecting or aggravating the effects of the diet on the metabolic phenotype. The role of the microbiome in the regulation of intestinal and systemic immunity is one of the mechanisms by which it contributes to the host's response to the diet and to the pathophysiology of diet-induced obesity. Here, we review the mechanisms whereby "obesogenic" diets and the microbiome impact immunity, locally and systemically, focusing on the consequences in the gut-adipose tissue axis. We also review the structural and microbial metabolites that influence immunity and how advances in this field could help design microbiome-informed strategies to tackle obesity-related disorders more effectively.
Asunto(s)
Microbioma Gastrointestinal , Enfermedades Metabólicas , Dieta , Humanos , Factores Inmunológicos , Enfermedades Metabólicas/etiología , ObesidadRESUMEN
Gut microbiota represents a therapeutic target for obesity. We hypothesize that B. uniformis CECT 7771 combined with wheat bran extract (WBE), its preferred carbon source, may exert superior anti-obesity effects. We performed a 17-week intervention in diet-induced obese mice receiving either B. uniformis, WBE, or their combination to identify interactions and independent actions on metabolism and immunity. B. uniformis combined with WBE was the most effective intervention, curbing weight gain and adiposity, while exerting more modest effects separately. The combination restored insulin-dependent metabolic routes in fat and liver, although the bacterium was the primary driver for improving whole-body glucose disposal. Moreover, B. uniformis-combined with WBE caused the highest increases in butyrate and restored the proportion of induced intraepithelial lymphocytes and type-3 innate lymphoid cells in the intestinal epithelium. Thus, strengthening the first line of immune defense against unhealthy diets and associated dysbiosis in the intestine. This intervention also attenuated the altered IL22 signaling and liver inflammation. Our study shows opportunities for employing B. uniformis, combined with WBE, to aid in the treatment of obesity.
Asunto(s)
Bacteroides , Fibras de la Dieta , Obesidad/dietoterapia , Tejido Adiposo/metabolismo , Animales , Ciego/metabolismo , Ciego/microbiología , Dieta Alta en Grasa/efectos adversos , Epidídimo/metabolismo , Ácidos Grasos/metabolismo , Microbioma Gastrointestinal , Inflamación , Insulina/metabolismo , Interleucinas/metabolismo , Mucosa Intestinal/inmunología , Hígado/metabolismo , Linfocitos/metabolismo , Masculino , Ratones , Obesidad/etiología , Obesidad/inmunología , Obesidad/metabolismo , Transducción de Señal , Termogénesis , Aumento de Peso , Interleucina-22RESUMEN
Cross-sectional studies conducted with obese and control subjects have suggested associations between gut microbiota alterations and obesity, but the links with specific disease phenotypes and proofs of causality are still scarce. The present study aimed to profile the gut microbiota of lean and obese children with and without insulin resistance to characterize associations with specific obesity-related complications and understand the role played in metabolic inflammation. Through massive sequencing of 16S rRNA gene amplicons and data analysis using a novel permutation approach, we have detected decreased incidence of Blautia species, especially Blautia luti and B. wexlerae, in the gut microbiota of obese children, which was even more pronounced in cases with both obesity and insulin resistance. There was also a parallel increase in proinflammatory cytokines and chemokines (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], and monocyte chemoattractant protein 1 [MCP-1]) in feces of obese children compared to those of lean ones. B. luti and B. wexlerae were also shown to exert an anti-inflammatory effect in peripheral blood mononuclear cell cultures in vitro, compared to non-obesity-associated species. We suggest that the depletion of B. luti and B. wexlerae species in the gut ecosystem may occur in cases of obesity and contribute to metabolic inflammation leading to insulin resistance.IMPORTANCE Child obesity constitutes a risk factor for developing insulin resistance which, if sustained, could lead to more severe conditions like type 2 diabetes (T2D) in adulthood. Our study identified previously unknown species whose depletion (Blautia luti and Blautia wexlerae) is associated with insulin resistance in obese individuals. Our results also indicate that these bacterial species might help to reduce inflammation causally linked to obesity-related complications. Childhood is considered a window of opportunity to tackle obesity. These new findings provide, therefore, valuable information for the future design of microbiota-based strategies for the early prevention of obesity-related complications.
RESUMEN
Obesity continues to be one of the major public health problems due to its high prevalence and co-morbidities. Common co-morbidities not only include cardiometabolic disorders but also mood and cognitive disorders. Obese subjects often show deficits in memory, learning and executive functions compared to normal weight subjects. Epidemiological studies also indicate that obesity is associated with a higher risk of developing depression and anxiety, and vice versa. These associations between pathologies that presumably have different etiologies suggest shared pathological mechanisms. Gut microbiota is a mediating factor between the environmental pressures (e.g., diet, lifestyle) and host physiology, and its alteration could partly explain the cross-link between those pathologies. Westernized dietary patterns are known to be a major cause of the obesity epidemic, which also promotes a dysbiotic drift in the gut microbiota; this, in turn, seems to contribute to obesity-related complications. Experimental studies in animal models and, to a lesser extent, in humans suggest that the obesity-associated microbiota may contribute to the endocrine, neurochemical and inflammatory alterations underlying obesity and its comorbidities. These include dysregulation of the HPA-axis with overproduction of glucocorticoids, alterations in levels of neuroactive metabolites (e.g., neurotransmitters, short-chain fatty acids) and activation of a pro-inflammatory milieu that can cause neuro-inflammation. This review updates current knowledge about the role and mode of action of the gut microbiota in the cross-link between energy metabolism, mood and cognitive function.
RESUMEN
RhoE is a small GTPase involved in the regulation of actin cytoskeleton dynamics, cell cycle and apoptosis. The role of RhoE in cancer is currently controversial, with reports of both oncogenic and tumor-suppressive functions for RhoE. Using RhoE-deficient mice, we show here that the absence of RhoE blunts contact-inhibition of growth by inhibiting p27Kip1 nuclear translocation and cooperates in oncogenic transformation of mouse primary fibroblasts. Heterozygous RhoE+/gt mice are more susceptible to chemically induced skin tumors and RhoE knock-down results in increased metastatic potential of cancer cells. These results indicate that RhoE plays a role in suppressing tumor initiation and progression.