Gut Microbiota and Nonalcoholic Fatty Liver Disease: Insights on Mechanism and Application of Metabolomics

Gut microbiota are intricately involved in the development of obesity-related metabolic diseases such as nonalcoholic fatty liver disease (NAFLD), type 2 diabetes, and insulin resistance. In the current review, we discuss the role of gut microbiota in the development of NAFLD by focusing on the mechanisms of gut microbiota-mediated host energy metabolism, insulin resistance, regulation of bile acids and choline metabolism, as well as gut microbiota-targeted therapy. We also discuss the application of a metabolomic approach to characterize gut microbial metabotypes in NAFLD.     

Impact of Nutrition,Microbiota Transplant and Weight Loss Surgery on Dopaminergic Alterations in Parkinson’s Disease and Obesity

Parkinson’s disease (PD), the second most common neurodegenerative disorder worldwide, is characterized by dopaminergic neuron degeneration and α-synuclein aggregation in the substantia nigra pars compacta of the midbrain. Emerging evidence has shown that dietary intake affects the microbial composition in the gut, which in turn contributes to, or protects against, the degeneration of dopaminergic neurons in affected regions of the brain. More specifically, the Mediterranean diet and Western diet, composed of varying amounts of proteins, carbohydrates, and fats, exert contrasting effects on PD pathophysiology via alterations in the gut microbiota and dopamine levels. Interestingly, the negative changes in the gut microbiota of patients with PD parallel changes that are seen in individuals that consume a Western diet, and are opposite to those that adhere to a Mediterranean diet. In this review, we first examine the role of prominent food groups on dopamine bioavailability, how they modulate the composition and function of the gut microbiota and the subsequent effects on PD and obesity pathophysiology. We then highlight evidence on how microbiota transplant and weight loss surgery can be used as therapeutic tools to restore dopaminergic deficits through optimizing gut microbial composition. In the process, we revisit dietary metabolites and their role in therapeutic approaches involving dopaminergic pathways. Overall, understanding the role of nutrition on dopamine bioavailability and gut microbiota in dopamine-related pathologies such as PD will help develop more precise therapeutic targets to rescue dopaminergic deficits in neurologic and metabolic disorders.     

Beneficial Effects of Phenolic Compounds on Gut Microbiota and Metabolic Syndrome

The human intestine contains an intricate community of microorganisms, referred to as the gut microbiota (GM), which plays a pivotal role in host homeostasis. Multiple factors could interfere with this delicate balance, including genetics, age, medicines and environmental factors, particularly diet. Growing evidence supports the involvement of GM dysbiosis in gastrointestinal (GI) and extraintestinal metabolic diseases. The beneficial effects of dietary polyphenols in preventing metabolic diseases have been subjected to intense investigation over the last twenty years. As our understanding of the role of the gut microbiota advances and our knowledge of the antioxidant and anti-inflammatory functions of polyphenols accumulates, there emerges a need to examine the prebiotic role of dietary polyphenols. This review firstly overviews the importance of the GM in health and disease and then reviews the role of dietary polyphenols on the modulation of the gut microbiota, their metabolites and how they impact on host health benefits. Inter-dependence between the gut microbiota and polyphenol metabolites and the vital balance between the two in maintaining the host gut homeostasis are also discussed.     

Mediterranean Diet and Health: Food Effects on Gut Microbiota and Disease Control

The Mediterranean diet (MD) is considered one of the healthiest dietary models. Many of the characteristic components of the MD have functional features with positive effects on health and wellness. The MD adherence, calculated through various computational scores, can lead to a reduction of the incidence of major diseases (e.g., cancers, metabolic and cardiovascular syndromes, neurodegenerative diseases, type 2 diabetes and allergy). Furthermore, eating habits are the main significant determinants of the microbial multiplicity of the gut, and dietary components influence both microbial populations and their metabolic activities from the early stages of life. For this purpose, we present a study proposal relying on the generation of individual gut microbiota maps from MD-aware children/adolescents. The maps, based on meta-omics approaches, may be considered as new tools, acting as a systems biology-based proof of evidence to evaluate MD effects on gut microbiota homeostasis. Data integration of food metabotypes and gut microbiota “enterotypes” may allow one to interpret MD adherence and its effects on health in a new way, employable for the design of targeted diets and nutraceutical interventions in childcare and clinical management of food-related diseases, whose onset has been significantly shifted early in life.     

Crohn’s Disease,Host–Microbiota Interactions,and Immunonutrition: Dietary Strategies Targeting Gut Microbiome as Novel Therapeutic Approaches

Crohn’s disease (CD) is a complex, disabling, idiopathic, progressive, and destructive disorder with an unknown etiology. The pathogenesis of CD is multifactorial and involves the interplay between host genetics, and environmental factors, resulting in an aberrant immune response leading to intestinal inflammation. Due to the high morbidity and long-term management of CD, the development of non-pharmacological approaches to mitigate the severity of CD has recently attracted great attention. The gut microbiota has been recognized as an important player in the development of CD, and general alterations in the gut microbiome have been established in these patients. Thus, the gut microbiome has emerged as a pre-eminent target for potential new treatments in CD. Epidemiological and interventional studies have demonstrated that diet could impact the gut microbiome in terms of composition and functionality. However, how specific dietary strategies could modulate the gut microbiota composition and how this would impact host–microbe interactions in CD are still unclear. In this review, we discuss the most recent knowledge on host–microbe interactions and their involvement in CD pathogenesis and severity, and we highlight the most up-to-date information on gut microbiota modulation through nutritional strategies, focusing on the role of the microbiota in gut inflammation and immunity.     

Ketogenic and Low FODMAP Diet in Therapeutic Management of a Young Autistic Patient with Epilepsy and Dysmetabolism Poorly Responsive to Therapies: Clinical Response and Effects of Intestinal Microbiota

Autism spectrum disorder (ASD) is often associated with several intestinal and/or metabolic disorders as well as neurological manifestations such as epilepsy (ASD-E). Those presenting these neuropathological conditions share common aspects in terms of gut microbiota composition. The use of microbiota intervention strategies may be an approach to consider in the management of these cases. We describe the case of a 17-year-old girl affected by ASD, reduced growth, neurological development delay, mutations in the PGM1 and EEF1A2 genes (in the absence of clinically manifested disease) and, intestinal disorders such as abdominal pain and diarrhea associated with weight loss. As she demonstrated poor responsiveness to the therapies provided, we attempted two specific dietary patterns: a ketogenic diet, followed by a low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet, with the aim of improving her neurological, metabolic, and intestinal symptoms through modulation of the gut microbiota’s composition. The ketogenic diet (KD) provided a reduction in Firmicutes, Bacteroidetes, and Proteobacteria. Although her intestinal symptoms improved, KD was poorly tolerated. On the other hand, the passage to a low FODMAPs diet produced a significant improvement in all neurological, intestinal, and metabolic symptoms and was well-tolerated. The following gut microbiota analysis showed reductions in Actinobacteria, Firmicutes, Lactobacilli, and Bifidobacteria. The alpha biodiversity was consistently increased and the Firmicutes/Bacteroidetes ratio decreased, reducing the extent of fermentative dysbiosis. Gut microbiota could be a therapeutic target to improve ASD-related symptoms. Further studies are needed to better understand the correlation between gut microbiota composition and ASD, and its possible involvement in the physiopathology of ASD.     

Modulation of Gut Microbiota in the Management of Metabolic Disorders: The Prospects and Challenges

The gut microbiota plays a number of important roles including digestion, metabolism, extraction of nutrients, synthesis of vitamins, prevention against pathogen colonization, and modulation of the immune system. Alterations or changes in composition and biodiversity of the gut microbiota have been associated with many gastrointestinal tract (GIT) disorders such as inflammatory bowel disease and colon cancer. Recent evidence suggests that altered composition and diversity of gut microbiota may play a role in the increased prevalence of metabolic diseases. This review article has two main objectives. First, it underscores approaches (such as probiotics, prebiotics, antimicrobial agents, bariatric surgery, and weight loss strategies) and their prospects in modulating the gut microbiota in the management of metabolic diseases. Second, it highlights some of the current challenges and discusses areas of future research as it relates to the gut microbiota and metabolic diseases. The prospect of modulating the gut microbiota seems promising. However, considering that research investigating the role of gut microbiota in metabolic diseases is still in its infancy, more rigorous and well-designed in vitro, animal and clinical studies are needed.     

Role of Short-Chain Fatty Acids Produced by Gut Microbiota in Innate Lung Immunity and Pathogenesis of the Heterogeneous Course of Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a widespread socially significant disease. The development of COPD involves the innate immune system. Interestingly, the regulation of the innate lung immune system is related to the gut microbiota. This connection is due to the production by gut microorganisms of short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate. Nutritional disturbances and changes in the structure of the intestinal microbiota lead to a decrease in SCFAs production and their effect on pulmonary immunity. The presence of a metabolic and immune axis linking the lungs and gut plays an important role in the pathogenesis of COPD. In addition, the nature of nutrition and SCFAs may participate in the development of the clinically heterogeneous course of COPD.     

Gut Microbiota and Short Chain Fatty Acids: Implications in Glucose Homeostasis

Gut microbiota encompasses a wide variety of commensal microorganisms consisting of trillions of bacteria, fungi, and viruses. This microbial population coexists in symbiosis with the host, and related metabolites have profound effects on human health. In this respect, gut microbiota plays a pivotal role in the regulation of metabolic, endocrine, and immune functions. Bacterial metabolites include the short chain fatty acids (SCFAs) acetate (C2), propionate (C3), and butyrate (C4), which are the most abundant SCFAs in the human body and the most abundant anions in the colon. SCFAs are made from fermentation of dietary fiber and resistant starch in the gut. They modulate several metabolic pathways and are involved in obesity, insulin resistance, and type 2 diabetes. Thus, diet might influence gut microbiota composition and activity, SCFAs production, and metabolic effects. In this narrative review, we discuss the relevant research focusing on the relationship between gut microbiota, SCFAs, and glucose metabolism.     

Involvement of Gut Microbial Metabolites Derived from Diet on Host Energy Homeostasis

Due to the excess energy intake, which is a result of a high fat and high carbohydrate diet, dysfunction of energy balance leads to metabolic disorders such as obesity and type II diabetes mellitus (T2DM). Since obesity can be a risk factor for various diseases, including T2DM, hypertension, hyperlipidemia, and metabolic syndrome, novel prevention and treatment are expected. Moreover, host diseases linked to metabolic disorders are associated with changes in gut microbiota profile. Gut microbiota is affected by diet, and nutrients are used as substrates by gut microbiota for produced metabolites, such as short-chain and long-chain fatty acids, that may modulate host energy homeostasis. These free fatty acids are not only essential energy sources but also signaling molecules via G-protein coupled receptors (GPCRs). Some GPCRs are critical for metabolic functions, such as hormone secretion and immune function in various types of cells and tissues and contribute to energy homeostasis. The current studies have shown that GPCRs for gut microbial metabolites improved host energy homeostasis and systemic metabolic disorders. Here, we will review the association between diet, gut microbiota, and host energy homeostasis.     

Therapeutic Advances in Gut Microbiome Modulation in Patients with Inflammatory Bowel Disease from Pediatrics to Adulthood

There is mounting evidence that the gut microbiota plays an important role in the pathogenesis of inflammatory bowel disease (IBD). For the past decade, high throughput sequencing-based gut microbiome research has identified characteristic shifts in the composition of the intestinal microbiota in patients with IBD, suggesting that IBD results from alterations in the interactions between intestinal microbes and the host’s mucosal immune system. These studies have been the impetus for the development of new therapeutic approaches targeting the gut microbiome, such as nutritional therapies, probiotics, fecal microbiota transplant and beneficial metabolic derivatives. Innovative technologies can further our understanding of the role the microbiome plays as well as help to evaluate how the different approaches in microbiome modulation impact clinical responses in adult and pediatric patients. In this review, we highlight important microbiome studies in patients with IBD and their response to different microbiome modulation therapies, and describe the differences in therapeutic response between pediatric and adult patient cohorts.     

Meta-Omic Platforms to Assist in the Understanding of NAFLD Gut Microbiota Alterations: Tools and Applications

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide as a result of the increasing prevalence of obesity, starting from early life stages. It is characterized by a spectrum of liver diseases ranging from simple fatty liver (NAFL) to steatohepatitis (NASH), with a possible progression to fibrosis, thus increasing liver-related morbidity and mortality. NAFLD development is driven by the co-action of several risk factors, including obesity and metabolic syndrome, which may be both genetically induced and diet-related. Recently, particular attention has been paid to the gut-liver axis, which may play a physio-pathological role in the onset and progression of the disease. The gut microbiota is intended to act as a bioreactor that can guarantee autonomous metabolic and immunological functions and that can drive functional strategies within the environment of the body in response to external stimuli. The complexity of the gut microbiota suggests that it behaves as an organ. Therefore, the concept of the gut-liver axis must be complemented with the gut-microbiota-liver network due to the high intricacy of the microbiota components and metabolic activities; these activities form the active diet-driven power plant of the host. Such complexity can only be revealed using systems biology, which can integrate clinical phenomics and gut microbiota data.     

Short Term High Fat Diet Induces Obesity-Enhancing Changes in Mouse Gut Microbiota That are Partially Reversed by Cessation of the High Fat Diet

The gut microbiota is proposed as a “metabolic organ” involved in energy utilization and is associated with obesity. Dietary intervention is one of the approaches for obesity management. Changes in dietary components have significant impacts on host metabolism and gut microbiota. In the present study, we examined the influence of dietary fat intervention on the modification of gut mucosa-associated microbiota profile along with body weight and metabolic parameter changes. Male C57BL/6J mice (6-week old) were fed a low fat diet (10% kcal fat) as a control or a high fat diet (HFD 60% kcal fat) for 7 weeks. In another group, mice were fed HFD for 5 weeks followed by low fat control diet for 2 weeks (HFD + Control). At 7 weeks, body weight gain, blood glucose and hepatic triacylglycerol levels of mice fed a HFD were significantly higher than that of the control group and the HFD + Control group. There were significant differences in the diversity and predicted functional properties of microbiota in the cecum and colon mucosa between the control group and the HFD group. HFD feeding reduced the ratio of Bacteroidetes to Firmicutes, a microbiota pattern often associated with obesity. The HFD + Control diet partially restored the diversity and composition of microbiota in the cecum to the pattern observed in mice fed a control diet. These results suggest that short-term high fat diet withdrawal can restore metabolic changes and prevent excess body weight gain, however, long-term dietary intervention may be required to optimize the restoration of gut microbiota in mouse.     

The Immune System through the Lens of Alcohol Intake and Gut Microbiota

The human gut is the largest organ with immune function in our body, responsible for regulating the homeostasis of the intestinal barrier. A diverse, complex and dynamic population of microorganisms, called microbiota, which exert a significant impact on the host during homeostasis and disease, supports this role. In fact, intestinal bacteria maintain immune and metabolic homeostasis, protecting our organism against pathogens. The development of numerous inflammatory disorders and infections has been linked to altered gut bacterial composition or dysbiosis. Multiple factors contribute to the establishment of the human gut microbiota. For instance, diet is considered as one of the many drivers in shaping the gut microbiota across the lifetime. By contrast, alcohol is one of the many factors that disrupt the proper functioning of the gut, leading to a disruption of the intestinal barrier integrity that increases the permeability of the mucosa, with the final result of a disrupted mucosal immunity. This damage to the permeability of the intestinal membrane allows bacteria and their components to enter the blood tissue, reaching other organs such as the liver or the brain. Although chronic heavy drinking has harmful effects on the immune system cells at the systemic level, this review focuses on the effect produced on gut, brain and liver, because of their significance in the link between alcohol consumption, gut microbiota and the immune system.     

Gut Microbiota and Sex Hormones: Crosstalking Players in Cardiometabolic and Cardiovascular Disease

The available evidence indicates a close connection between gut microbiota (GM) disturbance and increased risk of cardiometabolic (CM) disorders and cardiovascular (CV) disease. One major objective of this narrative review is to discuss the key contribution of dietary regimen in determining the GM biodiversity and the implications of GM dysbiosis for the overall health of the CV system. In particular, emerging molecular pathways are presented, linking microbiota-derived signals to the local activation of the immune system as the driver of a systemic proinflammatory state and permissive condition for the onset and progression of CM and CV disease. We further outline how the cross-talk between sex hormones and GM impacts disease susceptibility, thereby offering a mechanistic insight into sexual dimorphism observed in CVD. A better understanding of these relationships could help unravel novel disease targets and pave the way to the development of innovative, low-risk therapeutic strategies based on diet interventions, GM manipulation, and sex hormone analogues.     

Dietary Influences on the Microbiota–Gut–Brain Axis

Over unimaginable expanses of evolutionary time, our gut microbiota have co-evolved with us, creating a symbiotic relationship in which each is utterly dependent upon the other. Far from confined to the recesses of the alimentary tract, our gut microbiota engage in complex and bi-directional communication with their host, which have far-reaching implications for overall health, wellbeing and normal physiological functioning. Amongst such communication streams, the microbiota–gut–brain axis predominates. Numerous complex mechanisms involve direct effects of the microbiota, or indirect effects through the release and absorption of the metabolic by-products of the gut microbiota. Proposed mechanisms implicate mitochondrial function, the hypothalamus–pituitary–adrenal axis, and autonomic, neuro-humeral, entero-endocrine and immunomodulatory pathways. Furthermore, dietary composition influences the relative abundance of gut microbiota species. Recent human-based data reveal that dietary effects on the gut microbiota can occur rapidly, and that our gut microbiota reflect our diet at any given time, although much inter-individual variation pertains. Although most studies on the effects of dietary macronutrients on the gut microbiota report on associations with relative changes in the abundance of particular species of bacteria, in broad terms, our modern-day animal-based Westernized diets are relatively high in fats and proteins and impoverished in fibres. This creates a perfect storm within the gut in which dysbiosis promotes localized inflammation, enhanced gut wall permeability, increased production of lipopolysaccharides, chronic endotoxemia and a resultant low-grade systemic inflammatory milieu, a harbinger of metabolic dysfunction and many modern-day chronic illnesses. Research should further focus on the colony effects of the gut microbiota on health and wellbeing, and dysbiotic effects on pathogenic pathways. Finally, we should revise our view of the gut microbiota from that of a seething mass of microbes to one of organ-status, on which our health and wellbeing utterly depends. Future guidelines on lifestyle strategies for wellbeing should integrate advice on the optimal establishment and maintenance of a healthy gut microbiota through dietary and other means. Although we are what we eat, perhaps more importantly, we are what our gut microbiota thrive on and they thrive on what we eat.     

The New Therapeutic Approaches in the Treatment of Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease which is characterized by extremely complex pathogenetic mechanisms and multifactorial etiology. Some of the many pathophysiological mechanisms involved in the development of NAFLD include oxidative stress, impaired mitochondrial metabolism, inflammation, gut microbiota, and interaction between the brain-liver-axis and the regulation of hepatic lipid metabolism. The new therapeutic approaches in the treatment of NAFLD are targeting some of these milestones along the pathophysiological pathway and include drugs like agonists of peroxisome proliferator-activated receptors (PPARs), glucagon-like peptide-1 (GLP-1) agonists, sodium/glucose transport protein 2 (SGLT2) inhibitors, farnesoid X receptor (FXR) agonists, probiotics, and symbiotics. Further efforts in biomedical sciences should focus on the investigation of the relationship between the microbiome, liver metabolism, and response to inflammation, systemic consequences of metabolic syndrome.     

Developmental Programming and Reprogramming of Hypertension and Kidney Disease: Impact of Tryptophan Metabolism

The concept that hypertension and chronic kidney disease (CKD) originate in early life has emerged recently. During pregnancy, tryptophan is crucial for maternal protein synthesis and fetal development. On one hand, impaired tryptophan metabolic pathway in pregnancy impacts fetal programming, resulting in the developmental programming of hypertension and kidney disease in adult offspring. On the other hand, tryptophan-related interventions might serve as reprogramming strategies to prevent a disease from occurring. In the present review, we aim to summarize (1) the three major tryptophan metabolic pathways, (2) the impact of tryptophan metabolism in pregnancy, (3) the interplay occurring between tryptophan metabolites and gut microbiota on the production of uremic toxins, (4) the role of tryptophan-derived metabolites-induced hypertension and CKD of developmental origin, (5) the therapeutic options in pregnancy that could aid in reprogramming adverse effects to protect offspring against hypertension and CKD, and (6) possible mechanisms linking tryptophan metabolism to developmental programming of hypertension and kidney disease.     

The Role of Gut Microbiota and Gut–Brain Interplay in Selected Diseases of the Central Nervous System

The gut microbiome has attracted increasing attention from researchers in recent years. The microbiota can have a specific and complex cross-talk with the host, particularly with the central nervous system (CNS), creating the so-called “gut–brain axis”. Communication between the gut, intestinal microbiota, and the brain involves the secretion of various metabolites such as short-chain fatty acids (SCFAs), structural components of bacteria, and signaling molecules. Moreover, an imbalance in the gut microbiota composition modulates the immune system and function of tissue barriers such as the blood–brain barrier (BBB). Therefore, the aim of this literature review is to describe how the gut–brain interplay may contribute to the development of various neurological disorders, combining the fields of gastroenterology and neuroscience. We present recent findings concerning the effect of the altered microbiota on neurodegeneration and neuroinflammation, including Alzheimer’s and Parkinson’s diseases, as well as multiple sclerosis. Moreover, the impact of the pathological shift in the microbiome on selected neuropsychological disorders, i.e., major depressive disorders (MDD) and autism spectrum disorder (ASD), is also discussed. Future research on the effect of balanced gut microbiota composition on the gut–brain axis would help to identify new potential opportunities for therapeutic interventions in the presented diseases.