The links between gut microbiota and obesity and obesity related diseases

Can We Prevent Obesity-Related Metabolic Diseases by Dietary Modulation of the Gut Microbiota?

The spread of the Western lifestyle across the globe has led to a pandemic in obesity-related metabolic disease. The Mediterranean diet (MedDiet), Okinawa diet (OkD) and Nordic diet, derived from very different regions of the world and culinary traditions, have a large whole plant food component and are associated with reduced disease risk. This review focuses on polyphenol : microbiome interactions as one possible common mechanistic driver linking the protective effects whole plant foods against metabolic disease across healthy dietary patterns irrespective of geography. Although mechanistic evidence in humans is still scarce, animal studies suggest that polyphenol or polyphenol rich foods induce changes within the gut microbiota and its metabolic output of trimethylamine N-oxide, short-chain fatty acids, bile acids and small phenolic acids. These cross-kingdom signaling molecules regulate mammalian lipid and glucose homeostasis, inflammation and energy storage or thermogenesis, physiological processes determining obesity-related metabolic and cardiovascular disease risk. However, it appears that where in the intestine metabolites are produced, the microbiota communities involved, and interactions between the metabolites themselves, can all influence physiological responses, highlighting the need for a greater understanding of the kinetics and site of production of microbial metabolites within the gut. Interactions between polyphenols and metabolites produced by the gut microbiota are emerging as a possible unifying protective mechanism underpinning diverse healthy dietary patterns signaling across culinary traditions, across geography and across domains of life.

Obesity is a multifactorial disease that results in the excessive accumulation of adipose tissue in humans. It poses a major global public health crisis, as it increases the risk of several pathologies. The gut microbiome is considered a potential modulator in the development of obesity, alongside environmental factors, lifestyle, and genetic makeup. The qualitative and quantitative composition of the gut microbiome is greatly influenced by the type, quality, and quantity of diet. We have found that a vegetarian diet facilitates the growth and development of beneficial bacteria in the gut. This review discusses the relationship between the human gut microbiome, energy balance, and various obesity-related diseases. The metabolic products of the gut microbiome (such as short-chain fatty acids and secondary bile acids) and their effects on the gut microbiome, intestinal barrier function, and immune homeostasis are explored in the context of obesity. However, the specific roles of individual gut microbiota species and their interactions with the gut environment, host genetics, and medications (including antibiotics) require further investigation. We also discuss the potential of the gut microbiome in managing obesity-related diseases through dietary modifications, with reference to dietary fiber, resistant starch, gluten, high-fat diets, and proteins and carbohydrates from both vegetarian and animal sources.

Adipose tissue develops lipids, aberrant adipokines, chemokines, and pro-inflammatory cytokines as a consequence of the low-grade systemic inflammation that characterizes obesity. This low-grade systemic inflammation can lead to insulin resistance (IR) and metabolic complications, such as type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD). Although the CXC chemokines consists of numerous regulators of inflammation, cellular function, and cellular migration, it is still unknown that how CXC chemokines and chemokine receptors contribute to the development of metabolic diseases (such as T2D and NAFLD) during obesity. In light of recent research, the objective of this review is to provide an update on the linkage between the CXC chemokine, obesity, and obesity-related metabolic diseases (T2D and NAFLD). We explore the differential migratory and immunomodulatory potential of CXC chemokines and their mechanisms of action to better understand their role in clinical and laboratory contexts. Besides that, because CXC chemokine profiling is strongly linked to leukocyte recruitment, macrophage recruitment, and immunomodulatory potential, we hypothesize that it could be used to predict the therapeutic potential for obesity and obesity-related diseases (T2D and NAFLD).

Nanomaterials for the theranostics of obesity

The advanced glycosylation end product receptor (RAGE) acts as a recognition receptor and interacts with different types of ligands that form and accumulate in the tissues and circulation, such as diabetes, inflammation, insulin resistance, and obesity. In these environments, RAGE is expressed on the surface of various cells associated with tissue disturbance. This review mainly summarizes the characteristics of RAGE-related signalling, with a particular emphasis on the role of RAGE in the development of obesity. We also briefly describe the phenotypes and characteristics of macrophages and focus on the role of adipose tissue macrophages (ATMs) and the regulatory mechanisms in obesity, diabetes, and other related metabolic diseases. Besides, we will also elaborate on the prospect of new strategies for treating diabetes and obesity-related metabolic diseases by inhibiting RAGE signalling and regulating ATMs recruitment and polarization.

The present review aims to summarize and collect data in support of the obesogenic theory to broaden knowledge regarding the intriguing relationship between exposure to environmental chemical disruptors (EDCs), obesity and obesity related diseases. A comprehensive search of the literature from 1990 to 2024 was performed in Pubmed using the word endocrine disruptor chemicals or obesogens and: adipose tissue, metabolic diseases, weight gain, gut microbiota. In the past, genetic factors, an unbalanced diet and a sedentary lifestyle were considered the only risk factors for obesity development. On the other hand, recent studies described the obesogenic theory, suggesting that an interaction between exposure to EDCs with obesogenic activity, especially during early life development, and the endocrine system can play a key role in the greater susceptibility to the onset of obesity, not even excluding the involvement of the gut microbiota and its alterations. Data collected show that there is a close link between environmental exposure to EDCs during early life of development and the onset of obesity and related dysmetabolic diseases that may occur later in life.

Obesity is considered to be a chronic complex disease that increases the risk of diabetes, heart diseases and certain cancers. According to the literature, in obese people the gastrointestinal microbiota is disturbed, which could be the cause of the onset of obesity and related diseases. Moreover, there are small non-coding RNAs (microRNAs) that are disturbed in obesity, which are also considered to be a possible mechanism of probiotics' action. Certain microRNAs are involved in the development and metabolism of adipose tissue cells, as well as the secretion and action of insulin, showing that changed expression of certain miRNAs could have a significant impact on the onset and development of obesity and obesity-related diseases. Thus, miRNAs are considered to be possible markers for the diagnosis and prognosis of various metabolic diseases, and possible therapeutic targets for the treatment of obesity and related diseases. Considering the growing need of the healthcare system for nutraceuticals and dietary supplements that present effective and safe medical nutritive therapy in obese individuals, this work aimed to assess the beneficial effects of probiotics on obesity-related microRNAs. In this review, we described the role of microRNAs and probiotics in obesity and the association between probiotics and obesityrelated microRNAs. Circulating miRNAs' profile in obese individuals significantly differs from that of normal-weight individuals. miRNAs such as miR-155, miR-221, miR-24-3p, and miR181a are over-expressed, while miR-26b and 125a are under-expressed in obese patients compared to non-obese individuals. It has been found that supplementation with Bifidobacterium bifidum and Lactobacillus acidophilus could downregulate the expression of miR-155 and miR221, and upregulate the expression of miR-26b. Supplementation with a probiotic formulation containing S. boulardii, L. plantarum 299v, and octacosanol led to the downregulation of miR155 and miR-24-3p expression. miR-125a and miR-181a were upregulated and downregulated, respectively, after the intervention with L. delbrueckii and L. rhamnosus. After reviewing the available literature, we can conclude that probiotics have beneficial effects on microRNAs altered in obesity, which could provide an effective strategy for the management of obesity.

ABSTRACTThe substantially increased prevalence of obesity and obesity-related diseases has generated considerable concern. Currently, synthetic biological strategies have played an essential role in preventing and treating chronic diseases such as obesity. A growing number of symbiotic bacteria used as vectors for genetic engineering have been applied to create living therapeutics. In this study, using Bacillus subtilis as a cellular chassis, we constructed the engineered butyrate-producing strain BsS-RS06551 with a butyrate yield of 1.5 g/liter. A mouse model of obesity induced by a high-fat diet (HFD) was established to study the long-term intervention effects of this butyrate-producing bacteria on obesity. Combined with phenotypic assay results, we found that BsS-RS06551 could effectively retard body weight gain induced by a high-fat diet and visceral fat accumulation of mice, whereas it could improve glucose tolerance and insulin tolerance, reducing liver damage. We explored the BsS-RS06551 mechanism of action on host function and changes in intestinal flora by integrating multiple omics profiling, including untargeted metabolomics and metagenomics. The results showed that 24 major differential metabolites were involved in the metabolic regulation of BsS-RS06551 to prevent obesity in mice, including bile acid metabolism, branch chain amino acids, aromatic amino acids, and other metabolic pathways. Continuous ingestion of BsS-RS06551 could regulate gut microbiota composition and structure and enhance intestinal flora metabolic function abundance, which was closely related to host interactions. Our results demonstrated that engineered butyrate-producing bacteria had potential as an effective strategy to prevent obesity.IMPORTANCE Obesity is a chronic metabolic disease with an imbalance between energy intake and energy expenditure, and obesity-related metabolic diseases have become increasingly common. There is an urgent need to develop effective interventions for the prevention and treatment of obesity. This study showed that long-term consumption of BsS-RS06551 had a significant inhibitory effect on obesity induced by a high-fat diet and was more potent in inhibiting obesity than prebiotic inulin. In addition, this study showed a beneficial effect on host glucose, lipid metabolism, and gut microbe composition. Considering its colonization potential, this engineered bacteria provided a new strategy for the effective and convenient treatment of obesity in the long term.

Bile acids (BAs), traditionally recognized for their role in dietary fat digestion and cholesterol metabolism, are increasingly implicated as key regulators in obesity-related diseases. 1 Beyond their classical function in the gastrointestinal tract, BAs act as signaling molecules that influence a range of metabolic pathways, including glucose homeostasis, lipid metabolism, and energy expenditure. 2,3 Obesity significantly alters BAs composition and circulation, leading to metabolic dysregulation that contributes to the pathogenesis of various conditions, including type 2 diabetes mellitus (T2DM), metabolicassociated steatotic liver disease (MASLD), and cardiovascular diseases. [4][5][6] These changes can modulate gut microbiota composition and influence inflammatory pathways, establishing a complex network where BAs act as critical mediators of metabolic health. In this Research Topic entitled "Bile Acids in Obesity-Related Diseases" in Frontiers in Endocrinology, we brought 5 original articles on this increasingly important topic.The first study by Dong, et al. investigated the effects of corn silk polysaccharides (CSPs) on diabetic nephropathy (DN) by using a rat model. It evaluated CSPs' therapeutic potential through various indicators, including behavioral, histopathological, and biochemical assessments. The research focused on the interactions between CSPs, gut microbiota, and the host, utilizing a gut microbiota metabolomics approach to elucidate mechanisms that might mitigate DN. Findings revealed that CSPs significantly influence metabolic pathways related to glycerophosphate, fatty acid, BA, tyrosine, tryptophan, and phenylalanine, alongside changes in specific gut microbiota groups. These alterations suggested that CSPs may improve DN by modifying metabolite profiles and gut microbiota characteristics, thus addressing kidney inflammation and damage. The study highlighted CSPs' potential as a safe and natural intervention for DN prevention and treatment.Dai, et al. explored the relationship among gut microbiota, metabolites and neuroendocrine during the menopausal transition. The researchers identified significant differences between pre-and postmenopausal rats in gut microbiota and metabolites related to steroid hormone biosynthesis, primary bile acid synthesis and ovarian steroidogenesis. They hypothesized that specific gut microbial composition changes could regulate BAs, which acted as signaling molecules in the hypothalamus, ultimately triggering neuroendocrine changes of menopausal transition. These findings provided a new perspective for our understanding of the physiological mechanisms underlying menopausal transition, suggesting that gut microbiota and BAs might offer new targets for future interventions and treatments.Yin and colleagues investigated the metabolic changes associated with intrahepatic cholestasis of pregnancy (ICP) by comparing maternal plasma and hair metabolomes between ICP cases and healthy pregnancies. Significant differences were found in three plasma metabolites and 21 hair metabolites between the two groups. Metabolic pathway analysis of hair samples revealed 32 significantly affected pathways, including those related to glutathione metabolism and ATP-binding cassette transporters, while no significant pathway changes were observed in plasma. This study suggested that metabolomic profiling could act as a diagnostic tool for ICP. Compared to plasma, hair exhibited more distinctive metabolic profiles, and had a greater capacity to distinguish ICP from normal pregnancy. Analysis of hair metabolomes offered a fresh perspective on the pathophysiological changes associated with ICP.Liu and colleagues developed risk prediction models for peripheral vascular disease (PVD) in patients with T2DM. This study revealed that total bile acids (TBA) were one of the top four predictors of PVD in T2DM, and patients with higher TBA levels were more prone to developing PVD. This article inspires the monitoring of TBA as it is beneficial for the early identification and intervention of PVD. Further research exploring the specific mechanisms by which TBA affect blood vessels will help broaden our understanding of the pathological mechanisms underlying diabetic vascular complications, facilitating better prevention and treatment of these complications.The study by Cheng, et al. provided supplementary information on the role of BAs in carotid atherosclerosis (CAS). They revealed that various BAs demonstratesd distinct impacts on CAS, where some offered protective benefits, while others were independent risk factors. Additionally, the article offered predictions regarding the potential targets and pathways through which these BAs might exert their effects. These findings provided insights into potential therapeutic strategies targeting BAs for atherosclerosis treatment. The application of machine learning models shed light on developing personalized medical approaches.In conclusion, this Research Topic of studies highlighted the multifaceted role of BAs in pathophysiology and potential treatment of various obesity-related diseases. Bile acids, beyond their traditional role in fat digestion, function as critical regulators influencing metabolic pathways that impact conditions such as DN, menopausal neuroendocrine changes, ICP, PVD and atherosclerosis..Collectively, these findings emphasized the therapeutic and diagnostic significance of BAs and related metabolic pathways, opening avenues for future research and clinical applications targeting obesity-related diseases.

Obesity is now commonly seen worldwide and across all age groups. Obesity is the result of excessive nutrient intake often from sources which are highly processed which have a high energy-to-nutrient ratio. These dietary excuses are then compounded by decreased physical activity levels. Whilst these aetiological influences are thought to be easily modifiable, the reality is that individuals are becoming increasingly over-weight and obesity related diseases are posing more problems than ever before. Obesity has many metabolic consequences including, insulin resistance and predisposition for the development of chronic diseases such as cancers, autoimmune diseases, and type 2 diabetes (T2D). Diabetes then incurs further vascular complications in organs that have intricate microvascular networks such as those within, neurons, eyes and kidneys, leading to gangrenous limbs and amputations, cataracts and blindness, renal failure. Of course the ultimate complication of diabetes is early death, normally as a result of cardiac disease and heart failure. Receptor for advanced glycation end products (RAGE) and its modulation of downstream pathways are recognised pathological contributors to the vascular complications of diabetes including renal disease. There is increasing evidence that obesity is an independent risk factor for kidney disease, in particular in the context of type 2 diabetes. However, the mechanisms by which obesity contributes to kidney disease remain to be determined. Estradiol (17-β-estradiol) has been shown to confer protection against renal and cardiovascular disease when it is the major biologically active estrogen. In obesity, white adipose tissue deposits secrete another estrogen isoform called estrone, which alters the balance of estrogens. Imbalances in estradiol to estrone are the development of obesity related diseases. At the time of beginning this thesis, there were no drugs available for the specific treatment of obesity related renal diseases. Some treatments are borrowed from type 2 diabetes and chronic kidney disease and have modest effects on excretion of albumin or target blood pressure lowering pathways. Others directly target obesity, leading to weight loss although these are often temporary. Therefore this thesis examines the development of obesity related renal disease. I have examined the role of excessive adipose tissue deposition and the ability of estrogens to modulate the receptor for advanced glycation end products (RAGE), to discover potential therapeutic targets to control the growing problem of obesity related kidney disease.

Dysbiosis has been implemented in the etiologies of obesity-related chronic diseases such as type 2 diabetes, NAFLD and cardiovascular diseases. Bile acids, a class of amphipathic steroids produced in the liver and extensively modified by the microbiome, are increasingly recognized as actors in onset and progression of these diseases. Indeed, human obesity is associated with altered bile acid metabolism. Bile acids facilitate intestinal fat absorption but also exert hormone-like functions through activation of nuclear and membrane-bound receptors and thereby modulate glucose, lipid and energy metabolism, intestinal integrity and immunity. Bile acid-signaling pathways have thus been identified as potential pharmacological targets for obesity-related diseases. Interfering with microbiome composition may also be considered, as liver- and microbiome-derived bile acid species have different signaling functions. This review summarizes recent developments in this rapidly expanding field of research and addresses potential clinical prospects of interference with bile acid signaling pathways in human diseases.

Obesity represents one of the major public health issues threatening the global health and promoting chronic metabolic disorders, including type 2 diabetes, insulin resistance (IR), hyperlipidemia, hypertension, polycystic ovary syndrome, metabolic-associated fatty liver disease (MAFLD), and others. Ferroptosis, a novel form of cell death, is a programmed cell death induced by iron-dependent lipid peroxidation. It is characterized by excessive iron accumulation and unregulated lipid peroxidation. The activity of ferroptosis is modulated by multiple factors such as iron, reactive oxygen species, and over 98 unsaturated fatty acids. Mounting evidence indicates that ferroptosis plays a crucial role in obesity-related chronic metabolic diseases like type 2 diabetes, IR, hyperlipidemia, hypertension, polycystic ovary syndrome, and MAFLD. Clarifying the molecular mechanism of ferroptosis may discover potential therapeutic targets for the treatment of these diseases. This article comprehensively reviews the role, pathogenesis, prevention, treatment strategies, current research gaps and future development directions of ferroptosis in obesity-related chronic metabolic diseases have been thoroughly discussed, and novel perspectives for the future treatment and research of ferroptosis in these diseases carefully provided. It points out directions for basic research on ferroptosis, raises urgent needs for developing precise intervention strategies, and provides new insights into the treatment and study of obesity-related chronic metabolic diseases in the future.

The prevalence of obesity around the world has increased sharply. Strong evidence has emerged over the last decades that human exposure to numerous endocrine disrupting chemicals (EDCs) is the cause of obesity and obesity-related metabolic diseases. Many EDCs are manmade chemicals that are released into the environment. EDCs are exogenous compounds that interfere with hormonal regulation and normal endocrine systems, thereby affecting the health of animals and humans. The number of chemicals belonging to EDCs is increasing and some of them are very stable; they persist in the environment (persistent organic pollutants). Although they are banned, their concentrations have been continuously increasing over time. This review gives a brief introduction to common EDCs, and evidence of harmful effects of EDCs on obesity-related diseases; we focus in particular on EDCs’ role in causing mitochondrial dysfunction.

With the improvement of living conditions and the popularity of unhealthy eating and living habits, obesity is becoming a global epidemic. Obesity is now recognized as a disease that not only increases the risk of metabolic diseases such as type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), cardiovascular disease (CVD), and cancer but also negatively affects longevity and the quality of life. The traditional Chinese medicines (TCMs) are highly enriched in bioactive compounds and have been used for the treatment of obesity and obesity-related metabolic diseases over a long period of time. In this review, we selected the most commonly used anti-obesity or anti-hyperlipidemia TCMs and, where known, their major bioactive compounds. We then summarized their multi-target molecular mechanisms, specifically focusing on lipid metabolism, including the modulation of lipid absorption, reduction of lipid synthesis, and increase of lipid decomposition and lipid transportation, as well as the regulation of appetite. This review produces a current and comprehensive understanding of integrative and systematic mechanisms for the use of TCMs for anti-obesity. We also advocate taking advantage of TCMs as another therapy for interventions on obesity-related diseases, as well as stressing the fact that more is needed to be done, scientifically, to determine the active compounds and modes of action of the TCMs.