RESUMO
The aging of populations is a global phenomenon that follows a possible increase in the incidence of neurodegenerative diseases. Alzheimer's, Parkinson's, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, and Huntington's diseases are some neurodegenerative disorders that aging could initiate or aggravate. Recent research has indicated that intestinal microbiota dysbiosis can trigger metabolism and brain functioning, contributing to the etiopathogenesis of those neurodegenerative diseases. The intestinal microbiota and its metabolites show significant functions in various aspects, such as the immune system modulation (development and maturation), the maintenance of the intestinal barrier integrity, the modulation of neuromuscular functions in the intestine, and the facilitation of essential metabolic processes for both the microbiota and humans. The primary evidence supporting the connection between intestinal microbiota and its metabolites with neurodegenerative diseases are epidemiological observations and animal models experimentation. This paper reviews up-to-date evidence on the correlation between the microbiota-gut-brain axis and neurodegenerative diseases, with a specially focus on gut metabolites. Dysbiosis can increase inflammatory cytokines and bacterial metabolites, altering intestinal and blood-brain barrier permeability and causing neuroinflammation, thus facilitating the pathogenesis of neurodegenerative diseases. Clinical data supporting this evidence still needs to be improved. Most of the works found are descriptive and associated with the presence of phyla or species of bacteria with neurodegenerative diseases. Despite the limitations of recent research, the potential for elucidating clinical questions that have thus far eluded clarification within prevailing pathophysiological frameworks of health and disease is promising through investigation of the interplay between the host and microbiota.
Assuntos
Eixo Encéfalo-Intestino , Disbiose , Microbioma Gastrointestinal , Doenças Neurodegenerativas , Humanos , Microbioma Gastrointestinal/fisiologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/microbiologia , Disbiose/metabolismo , Eixo Encéfalo-Intestino/fisiologia , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismoRESUMO
The human gut microbiota is a complex ecosystem made of trillions of microorganisms. The composition can be affected by diet, metabolism, age, geography, stress, seasons, temperature, sleep, and medications. The increasing evidence about the existence of a close and bi-directional correlation between the gut microbiota and the brain indicates that intestinal imbalance may play a vital role in the development, function, and disorders of the central nervous system. The mechanisms of interaction between the gut-microbiota on neuronal activity are widely discussed. Several potential pathways are involved with the brain-gut-microbiota axis, including the vagus nerve, endocrine, immune, and biochemical pathways. Gut dysbiosis has been linked to neurological disorders in different ways that involve activation of the hypothalamic-pituitary-adrenal axis, imbalance in neurotransmitter release, systemic inflammation, and increase in the permeability of the intestinal and the blood-brain barrier. Mental and neurological diseases have become more prevalent during the coronavirus disease 2019pandemic and are an essential issue in public health globally. Understanding the importance of diagnosing, preventing, and treating dysbiosis is critical because gut microbial imbalance is a significant risk factor for these disorders. This review summarizes evidence demonstrating the influence of gut dysbiosis on mental and neurological disorders.
A microbiota intestinal humana é um ecossistema complexo feito de trilhões de microrganismos, cuja composição pode ser afetada pela dieta, pelo metabolismo, pela idade, geografia, pelo estresse, pelas estações do ano, pela temperatura, pelo sono e por medicamentos. A crescente evidência sobre a existência de uma correlação estreita e bidirecional entre a microbiota intestinal e o cérebro indica que o desequilíbrio intestinal pode desempenhar um papel vital no desenvolvimento, na função e nos distúrbios do sistema nervoso central. Os mecanismos de interação entre a microbiota intestinal e a atividade neuronal são amplamente discutidos. Várias vias potenciais estão envolvidas com o eixo microbiota-intestino-cérebro, incluindo o nervo vago e as vias endócrinas, imunes e bioquímicas. A disbiose intestinal tem sido associada a distúrbios neurológicos de diferentes maneiras que envolvem a ativação do eixo hipotálamo-hipófise-adrenal, o desequilíbrio na liberação de neurotransmissores, a inflamação sistêmica e o aumento da permeabilidade das barreiras intestinal e hematoencefálica. As doenças mentais e neurológicas tornaram-se mais prevalentes durante a pandemia de coronavirus disease 2019 e são uma questão global essencial na saúde pública. Compreender a importância de diagnosticar, prevenir e tratar a disbiose é fundamental porque o desequilíbrio microbiano intestinal é um fator de risco significativo para esses distúrbios. Esta revisão resume as evidências que demonstram a influência da disbiose intestinal em distúrbios mentais e neurológicos.
Assuntos
Microbioma Gastrointestinal , Transtornos Mentais , Doenças do Sistema Nervoso , Humanos , Disbiose/metabolismo , Sistema Hipotálamo-Hipofisário , Ecossistema , Sistema Hipófise-Suprarrenal , Encéfalo/metabolismo , Microbioma Gastrointestinal/fisiologiaRESUMO
Pecans (Carya illinoinensis) are considered a functional food due to the high content of polyunsaturated fatty acids, dietary fiber and polyphenols. To determine the effect of whole pecans (WP) or a pecan polyphenol (PP) extract on the development of metabolic abnormalities in mice fed a high-fat (HF) diet, we fed C57BL/6 mice with a Control diet (7% fat), HF diet (23% fat), HF containing 30% WP or an HF diet supplemented with 3.6 or 6 mg/g of PP for 18 weeks. Supplementation of an HF diet with WP or PP reduced fat mass, serum cholesterol, insulin and HOMA-IR by 44, 40, 74 and 91%, respectively, compared to the HF diet. They also enhanced glucose tolerance by 37%, prevented pancreatic islet hypertrophy, and increased oxygen consumption by 27% compared to the HF diet. These beneficial effects were associated with increased thermogenic activity in brown adipose tissue, mitochondrial activity and AMPK activation in skeletal muscle, reduced hypertrophy and macrophage infiltration of subcutaneous and visceral adipocytes, reduced hepatic lipid content and enhanced metabolic signaling. Moreover, the microbial diversity of mice fed WP or PP was higher than those fed HF, and associated with lower circulating lipopolysaccharides (~83-95%). Additionally, a 4-week intervention study with the HF 6PP diet reduced the metabolic abnormalities of obese mice. The present study demonstrates that WP or a PP extract prevented obesity, liver steatosis and diabetes by reducing dysbiosis, inflammation, and increasing mitochondrial content and energy expenditure. Pecan polyphenols were mainly condensed tannin and ellagic acid derivatives including ellagitannins as determined by LC-MS. Herein we also propose a model for the progression of the HF diet-mediated metabolic disorder based on early and late events, and the possible molecular targets of WP and PP extract in preventive and intervention strategies. The body surface area normalization equation gave a conversion equivalent to a daily human intake dose of 2101-3502 mg phenolics that can be obtained from 110-183 g pecan kernels/day (22-38 whole pecans) or 21.6-36 g defatted pecan flour/day for an average person of 60 kg. This work lays the groundwork for future clinical studies.
Assuntos
Carya , Diabetes Mellitus , Fígado Gorduroso , Camundongos , Humanos , Animais , Dieta Hiperlipídica/efeitos adversos , Polifenóis/farmacologia , Polifenóis/metabolismo , Disbiose/prevenção & controle , Disbiose/metabolismo , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/prevenção & controle , Fígado Gorduroso/prevenção & controle , Fígado/metabolismo , Inflamação/prevenção & controle , Inflamação/metabolismo , Diabetes Mellitus/metabolismo , Hipertrofia , Metabolismo EnergéticoRESUMO
BACKGROUND: Obesity and comorbidities onset encompass gut dysbiosis, altered intestinal permeability, and endotoxemia. Treatments that target gut dysbiosis can cope with obesity and nonalcoholic fatty liver disease (NAFLD) management. Peroxisome proliferator-activated receptor (PPAR)-alpha activation and dipeptidyl-peptidase-4 (DPP-4) inhibition alleviate NAFLD, but the mechanism may involve gut microbiota modulation and merits further investigation. AIM: To address the effects of PPAR-alpha activation and DPP-4 inhibition (isolated or combined) upon the gut-liver axis, emphasizing inflammatory pathways in NAFLD management in high-fat-fed C57BL/6J mice. METHODS: Male C57BL/6J mice were fed a control diet (C, 10% of energy as lipids) or a high-fat diet (HFD, 50% of energy as lipids) for 12 wk, when treatments started, forming the groups: C, HF, HFA (HFD + PPAR-alpha agonist WY14643, 2.5 mg/kg body mass), HFL (HFD + DPP-4 inhibitor linagliptin, 15 mg/kg body mass), and HFC (HFD + the combination of WY14643 and linagliptin). RESULTS: The HFD was obesogenic compared to the C diet. All treatments elicited significant body mass loss, and the HFC group showed similar body mass to the C group. All treatments tackled oral glucose intolerance and raised plasma glucagon-like peptide-1 concentrations. These metabolic benefits restored Bacteroidetes/Firmicutes ratio, resulting in increased goblet cells per area of the large intestine and reduced lipopolysaccharides concentrations in treated groups. At the gene level, treated groups showed higher intestinal Mucin 2, Occludin, and Zo-1 expression than the HFD group. The reduced endotoxemia suppressed inflammasome and macrophage gene expression in the liver of treated animals. These observations complied with the mitigation of liver steatosis and reduced hepatic triacylglycerol, reassuring the role of the proposed treatments on NAFLD mitigation. CONCLUSION: PPAR alpha activation and DPP-4 inhibition (isolated or combined) tackled NAFLD in diet-induced obese mice by restoration of gut-liver axis. The reestablishment of the intestinal barrier and the rescued phylogenetic gut bacteria distribution mitigated liver steatosis through anti-inflammatory signals. These results can cope with NAFLD management by providing pre-clinical evidence that drugs used to treat obesity comorbidities can help to alleviate this silent and harmful liver disease.
Assuntos
Inibidores da Dipeptidil Peptidase IV , Endotoxemia , Hepatopatia Gordurosa não Alcoólica , Obesidade , PPAR alfa , Animais , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Disbiose/tratamento farmacológico , Disbiose/metabolismo , Endotoxemia/complicações , Endotoxemia/tratamento farmacológico , Linagliptina/farmacologia , Linagliptina/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/complicações , Obesidade/tratamento farmacológico , Obesidade/metabolismo , PPAR alfa/agonistas , PPAR alfa/metabolismo , FilogeniaRESUMO
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopment disorder resulting from different etiological factors, both genetic and/or environmental. These factors can lead to abnormal neuronal development on dendrite and synaptic function at the central nervous system. Recent studies have shown that a subset of ASD patients display increased circulation levels of the tyrosine metabolite, p-cresol, related to chronic intestinal disorders because of dysbiosis of the intestinal microbiota. In particular, abnormal presence of intestinal Clostridium sp. has been linked to high levels of p-cresol in ASD children younger than 8 years. However, the role of p-cresol during development of the central nervous system is unknown. Here, we evaluated in vitro the effect of p-cresol on neurite outgrowth in N2a and PC12 cell lines and dendritic morphology, synaptic density, neuronal activity, and calcium responses in primary rat hippocampal neurons. p-cresol inhibits neural differentiation and neurites outgrowth in N2a and PC12 neuronal cell lines. In hippocampal neuronal cultures, Sholl's analysis shows a decrease in the dendritic arborization of neurons treated with p-cresol. Synaptic density analyzed with the synaptic markers Piccolo and Shank2 is diminished in hippocampal neurons treated with p-cresol. Electrically evoked intracellular calcium rise was drastically, but reversely, blocked by p-cresol, whereas that spontaneous neuronal activity was severely affected by early addition of the metabolite. These findings show that p-cresol alters dendrite development, synaptogenesis, and synapse function of neurons in culture, therefore, neuronal alterations occurring in ASD children may be related to this metabolite and dysbiosis of the intestinal microbiota.
Assuntos
Transtorno do Espectro Autista , Animais , Transtorno do Espectro Autista/metabolismo , Cálcio/metabolismo , Células Cultivadas , Cresóis , Disbiose/metabolismo , Hipocampo/metabolismo , Humanos , Neurônios/metabolismo , Ratos , Sinapses/metabolismoRESUMO
Metabolic syndrome is a multifactorial disorder originating from central obesity through a high caloric intake and a sedentary lifestyle. Metabolic syndrome increases the risk of type 2 diabetes (T2D) disease, converting it to one of the costliest chronic diseases, which reduces life quality. A strategy proposed by the food industry to reduce this problem is the generation of low-caloric products using sweeteners, which are compounds that can substitute sucrose, given their sweet taste. For many years, it was assumed that sweeteners did not have a relevant interaction in metabolism. However, recent studies have demonstrated that sweeteners interact either with metabolism or with gut microbiota, in which sweet-taste receptors play an essential role. This review presents an overview of the industrial application of most commonly consumed sweeteners. In addition, the interaction of sweeteners within the body, including their absorption, distribution, metabolism, gut microbiota metabolism, and excretion is also reviewed. Furthermore, the complex relationship between metabolic syndrome and sweeteners is also discussed, presenting results from in vivo and clinical trials. Findings from this review indicate that, in order to formulate sugar-free or noncaloric food products for the metabolic syndrome market, several factors need to be considered, including the dose, proportions, human metabolism, and interaction of sweeteners with gut microbiota and sweet-taste receptors. More clinical studies, including the metabolic syndrome, are needed to better understand the interaction of sweeteners with the human body, as well as their possible effect on the generation of dysbiosis.
Assuntos
Microbioma Gastrointestinal , Síndrome Metabólica/prevenção & controle , Receptores Acoplados a Proteínas G/metabolismo , Edulcorantes/química , Edulcorantes/classificação , Edulcorantes/metabolismo , Diabetes Mellitus Tipo 2/prevenção & controle , Disbiose/metabolismo , Humanos , Síndrome Metabólica/dietoterapia , Obesidade/prevenção & controle , Edulcorantes/uso terapêuticoRESUMO
Although dysbiosis in the gut microbiota is known to be involved in several inflammatory diseases, whether any specific bacterial taxa control host response to inflammatory stimuli is still elusive. Here, we hypothesized that dysbiotic indigenous taxa could be involved in modulating host response to inflammatory triggers. To test this hypothesis, we conducted experiments in germ-free (GF) mice and in mice colonized with dysbiotic taxa identified in conventional (CV) mice subjected to chemotherapy-induced mucositis. First, we report that the absence of microbiota decreased inflammation and damage in the small intestine after administration of the chemotherapeutic agent 5-fluorouracil (5-FU). Also, 5-FU induced a shift in CV microbiota resulting in higher amounts of Enterobacteriaceae, including E. coli, in feces and small intestine and tissue damage. Prevention of Enterobacteriaceae outgrowth by treating mice with ciprofloxacin resulted in diminished 5-FU-induced tissue damage, indicating that this bacterial group is necessary for 5-FU-induced inflammatory response. In addition, monocolonization of germ-free (GF) mice with E. coli led to reversal of the protective phenotype during 5-FU chemotherapy. E. coli monocolonization decreased the basal plasma corticosterone levels and blockade of glucocorticoid receptor in GF mice restored inflammation upon 5-FU treatment. In contrast, treatment of CV mice with ciprofloxacin, that presented reduction of Enterobacteriaceae and E. coli content, induced an increase in corticosterone levels. Altogether, these findings demonstrate that Enterobacteriaceae outgrowth during dysbiosis impacts inflammation and tissue injury in the small intestine. Importantly, indigenous Enterobacteriaceae modulates host production of the anti-inflammatory steroid corticosterone and, consequently, controls inflammatory responsiveness in mice.
Assuntos
Corticosterona/metabolismo , Disbiose/microbiologia , Enterobacteriaceae/crescimento & desenvolvimento , Animais , Antineoplásicos/efeitos adversos , Bactérias/classificação , Bactérias/genética , Bactérias/crescimento & desenvolvimento , Bactérias/isolamento & purificação , Corticosterona/imunologia , Disbiose/etiologia , Disbiose/imunologia , Disbiose/metabolismo , Enterobacteriaceae/genética , Fluoruracila/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Intestino Delgado/imunologia , Intestino Delgado/metabolismo , Intestino Delgado/microbiologia , Masculino , CamundongosRESUMO
Renin-Angiotensin System (RAS) is an important peptide cascade involved in physiological processes. RAS homeostasis disruption produces several cardiovascular and metabolic disorders, such as arterial hypertension, atherosclerosis, acute myocardial infarct, obesity, diabetes, metabolic syndrome and increases gastrointestinal tract (GIT) cell proliferation. Angiotensin (Ang)-(1-7) peptide is the main RAS counter-regulatory axis effector. It is formed from ACE2 enzyme and acts mainly through Mas receptor (MasR). In this context, the aim of the present study was to evaluate alterations in small intestine morphology and intestinal microbiota composition in MasR knockout C57BL/6 mice. We analyzed glucose tolerance; insulin sensitivity and blood collected for biochemical parameters as well as small intestine tissues samples for immunohistochemistry. mRNA and bacteria gDNA expression evaluation. mRNA expression was evaluated by qRT-PCR for TLR4, PI3K and AKT. The main results showed that Mas-R-knockout mice presented lower body weight. MasR-knockout mice also presented increased fasted blood glucose and total cholesterol with reduced HDL, lower glucose tolerance and impaired insulin sensitivity. Increased intestinal mucosa length, increased intestinal villi, reduced Lieberkühn crypt depth. The increased expression of cell proliferation markers Ki-67 and Cyclin D1 and increased TLR4, PI3K and AKT expressions were observed with augmented Bacteroidetes and decreased amount of Firmicutes. That results suggests that MasR deletion generated changes in intestinal microbiota, possibly due to a lower neutral amino acids absorption followed by a compensatory increase in intestinal villi length associated with disbiosis and LPS overproduction that ultimately lead to proliferation and cell inflammation.
Assuntos
Disbiose/metabolismo , Intestino Delgado/metabolismo , Intestino Delgado/microbiologia , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Animais , Mucosa Intestinal/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfatidilinositol 3-Quinases/metabolismo , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptor 4 Toll-Like/metabolismoRESUMO
The gut microbiota has been recognized as an important factor in the development of metabolic diseases such as obesity and is considered an endocrine organ involved in the maintenance of energy homeostasis and host immunity. Dysbiosis can change the functioning of the intestinal barrier and the gut-associated lymphoid tissues (GALT) by allowing the passage of structural components of bacteria, such as lipopolysaccharides (LPS), which activate inflammatory pathways that may contribute to the development of insulin resistance. Furthermore, intestinal dysbiosis can alter the production of gastrointestinal peptides related to satiety, resulting in an increased food intake. In obese people, this dysbiosis seems be related to increases of the phylum Firmicutes, the genus Clostridium, and the species Eubacterium rectale, Clostridium coccoides, Lactobacillus reuteri, Akkermansia muciniphila, Clostridium histolyticum, and Staphylococcus aureus.
Assuntos
Microbioma Gastrointestinal , Obesidade/microbiologia , Disbiose/metabolismo , Disbiose/microbiologia , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologia , Humanos , Obesidade/metabolismoRESUMO
The gut microbiome outnumbers the human genome by 150-fold and plays important roles in metabolism, immune system education, tolerance development, and prevention of pathogen colonization. Dysbiosis has been associated with nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and alcoholic liver disease (ALD) as well as cirrhosis and complications. This article provides an overview of this relationship. Liver Transplantation 24 539-550 2018 AASLD.