Metabolite-Sensing G Protein-Coupled Receptors-Facilitators of Diet-Related Immune Regulation.

Nutrition and the gut microbiome regulate many systems, including the immune, metabolic, and nervous systems. We propose that the host responds to deficiency (or sufficiency) of dietary and bacterial metabolites in a dynamic way, to optimize responses and survival. A family of G protein-coupled receptors (GPCRs) termed the metabolite-sensing GPCRs bind to various metabolites and transmit signals that are important for proper immune and metabolic functions. Members of this family include GPR43, GPR41, GPR109A, GPR120, GPR40, GPR84, GPR35, and GPR91. In addition, bile acid receptors such as GPR131 (TGR5) and proton-sensing receptors such as GPR65 show similar features. A consistent feature of this family of GPCRs is that they provide anti-inflammatory signals; many also regulate metabolism and gut homeostasis. These receptors represent one of the main mechanisms whereby the gut microbiome affects vertebrate physiology, and they also provide a link between the immune and metabolic systems. Insufficient signaling through one or more of these metabolite-sensing GPCRs likely contributes to human diseases such as asthma, food allergies, type 1 and type 2 diabetes, hepatic steatosis, cardiovascular disease, and inflammatory bowel diseases.

Food processing, gut microbiota and the globesity problem.

In the context of diseases of affluence, western diets have in the past years mainly been studied on their fat and sugar content and lack of dietary fiber. Yet, the more general aspect of food processing has recently sparked scientific interest as well. In addition, the gut microbiota have been put forward as an important link between diet, obesity and non-communicable diseases (NCD). Western dietary patterns, containing large amounts of processed foods might create an imbalance in the gut system by affecting gut bacteria and their metabolism. Here we discuss what has been already published regarding the relationship between several recently researched features of processed foods and the etiology of obesity and NCD. The addressed features concern micronutrient and energy density, several types of food additives and the generation of advanced glycation end products by thermal treatment during food processing. Overall, literature indicates that all discussed aspects can be linked to western ailments and that they can have a potential negative impact on human microbiota. Therefore, we propose that the thesis that a distressed gut microbiota is a mechanism that might explain how food processing features could harm human health is gaining empirical evidence. Future research will need to address the question whether the alteration of the gut microbiota is a direct or an indirect (via the host) effect. These conclusions are important assets in the fight against the continuing worldwide upsurge of obesity and NCD.

Dietary Transitions and Health Outcomes in Four Populations - Systematic Review.

IMPORTANCE: Non-communicable chronic diseases (NCDs) such as obesity, type 2 diabetes, heart disease, and cancer were rare among non-western populations with traditional diets and lifestyles. As populations transitioned toward industrialized diets and lifestyles, NCDs developed. OBJECTIVE: We performed a systematic literature review to examine the effects of diet and lifestyle transitions on NCDs. EVIDENCE REVIEW: We identified 22 populations that underwent a nutrition transition, eleven of which had sufficient data. Of these, we chose four populations with diverse geographies, diets and lifestyles who underwent a dietary and lifestyle transition and explored the relationship between dietary changes and health outcomes. We excluded populations with features overlapping with selected populations or with complicating factors such as inadequate data, subgroups, and different study methodologies over different periods. The selected populations were Yemenite Jews, Tokelauans, Tanushimaru Japanese, and Maasai. We also review transition data from seven excluded populations (Pima, Navajo, Aboriginal Australians, South African Natal Indians and Zulu speakers, Inuit, and Hadza) to assess for bias. FINDINGS: The three groups that replaced saturated fats (SFA) from animal (Yemenite Jews, Maasai) or plants (Tokelau) with refined carbohydrates had negative health outcomes (e.g., increased obesity, diabetes, heart disease). Yemenites reduced SFA consumption by >40% post-transition but men's BMI increased 19% and diabetes increased ~40-fold. Tokelauans reduced fat, dramatically reduced SFA, and increased sugar intake: obesity and diabetes rose. The Tanushimaruans transitioned to more fats and less carbohydrates and used more anti-hypertensive medications; stroke and breast cancer declined while heart disease was stable. The Maasai transitioned to lower fat, SFA and higher carbohydrates and had increased BMI and diabetes. Similar patterns were observed in the seven other populations. CONCLUSION: The nutrient category most strongly associated with negative health outcomes - especially obesity and diabetes - was sugar (increased 600-650% in Yemenite Jews and Tokelauans) and refined carbohydrates (among Maasai, total carbohydrates increased 39% in men and 362% in women), while increased calories was less strongly associated with these disorders. Across 11 populations, NCDs were associated with increased refined carbohydrates more than increased calories, reduced activity or other factors, but cannot be attributed to SFA or total fat consumption.

Pasteurized non-fermented cow's milk but not fermented milk is a promoter of mTORC1-driven aging and increased mortality.

Recent epidemiological studies in Sweden, a country with traditionally high milk consumption, revealed that the intake of non-fermented pasteurized milk increased all-cause mortality in a dose-dependent manner. In contrast, the majority of epidemiological and clinical studies report beneficial health effects of fermented milk products, especially of yogurt. It is the intention of this review to delineate potential molecular aging mechanisms related to the intake of non-fermented milk versus yogurt on the basis of mechanistic target of rapamycin complex 1 (mTORC1) signaling. Non-fermented pasteurized milk via its high bioavailability of insulinotropic branched-chain amino acids (BCAAs), abundance of lactose (glucosyl-galactose) and bioactive exosomal microRNAs (miRs) enhances mTORC1 signaling, which shortens lifespan and increases all-cause mortality. In contrast, fermentation-associated lactic acid bacteria metabolize BCAAs and degrade galactose and milk exosomes including their mTORC1-activating microRNAs. The Industrial Revolution, with the introduction of pasteurization and refrigeration of milk, restricted the action of beneficial milk-fermenting bacteria, which degrade milk's BCAAs, galactose and bioactive miRs that synergistically activate mTORC1. This unrecognized behavior change in humans after the Neolithic revolution increased aging-related over-activation of mTORC1 signaling in humans, who persistently consume large quantities of non-fermented pasteurized cow's milk, a potential risk factor for aging and all-cause mortality.

The sedentary (r)evolution: Have we lost our metabolic flexibility?

During the course of evolution, up until the agricultural revolution, environmental fluctuations forced the human species to develop a flexible metabolism in order to adapt its energy needs to various climate, seasonal and vegetation conditions. Metabolic flexibility safeguarded human survival independent of food availability. In modern times, humans switched their primal lifestyle towards a constant availability of energy-dense, yet often nutrient-deficient, foods, persistent psycho-emotional stressors and a lack of exercise. As a result, humans progressively gain metabolic disorders, such as the metabolic syndrome, type 2 diabetes, non-alcoholic fatty liver disease, certain types of cancer, cardiovascular disease and Alzheimer´s disease, wherever the sedentary lifestyle spreads in the world. For more than 2.5 million years, our capability to store fat for times of food shortage was an outstanding survival advantage. Nowadays, the same survival strategy in a completely altered surrounding is responsible for a constant accumulation of body fat. In this article, we argue that the metabolic disease epidemic is largely based on a deficit in metabolic flexibility. We hypothesize that the modern energetic inflexibility, typically displayed by symptoms of neuroglycopenia, can be reversed by re-cultivating suppressed metabolic programs, which became obsolete in an affluent environment, particularly the ability to easily switch to ketone body and fat oxidation. In a simplified model, the basic metabolic programs of humans' primal hunter-gatherer lifestyle are opposed to the current sedentary lifestyle. Those metabolic programs, which are chronically neglected in modern surroundings, are identified and conclusions for the prevention of chronic metabolic diseases are drawn.

Inflammatory diseases modelling in zebrafish.

The ingest of diets with high content of fats and carbohydrates, low or no physical exercise and a stressful routine are part of the everyday lifestyle of most people in the western world. These conditions are triggers for different diseases with complex interactions between the host genetics, the metabolism, the immune system and the microbiota, including inflammatory bowel diseases (IBD), obesity and diabetes. The incidence of these disorders is growing worldwide; therefore, new strategies for its study are needed. Nowadays, the majority of researches are in use of murine models for understand the genetics, physiopathology and interaction between cells and signaling pathways to find therapeutic solutions to these diseases. The zebrafish, a little tropical water fish, shares 70% of our genes and conserves anatomic and physiological characteristics, as well as metabolical pathways, with mammals, and is rising as a new complementary model for the study of metabolic and inflammatory diseases. Its high fecundity, fast development, transparency, versatility and low cost of maintenance makes the zebrafish an interesting option for new researches. In this review, we offer a discussion of the existing genetic and induced zebrafish models of two important Western diseases that have a strong inflammatory component, the IBD and the obesity.