Obesity is becoming an increasing problem worldwide and is often, but not invariably, associated with dyslipidemia. The gut microbiota is increasingly linked to cardiovascular disease, nonalcoholic fatty liver disease, and type 2 diabetes mellitus. However, relatively little focus has been attributed to the role of gut-microbiota-derived metabolites in the development of dyslipidemia and alterations in lipid metabolism. In this review, we discuss current data involved in these processes and point out the therapeutic potentials. We cover the ability of gut microbiota metabolites to alter lipoprotein lipase action, VLDL secretion, and plasma triglyceride levels, and its effects on reverse cholesterol transport, adipocyte dysfunction, and adipose tissue inflammation. Finally, the current intervention strategies for treatment of obesity and dyslipidemia is addressed with emphasis on the role of gut microbiota metabolites and its ability to predict treatment efficacies.

The Role of Gut Microbiota and Its Produced Metabolites in Obesity, Dyslipidemia, Adipocyte Dysfunction, and Its Interventions.

Bariatric or weight loss surgery is currently the most effective treatment for obesity and metabolic disease. Unlike dieting and pharmacology, its beneficial effects are sustained over decades in most patients, and mortality is among the lowest for major surgery. Because there are not nearly enough surgeons to implement bariatric surgery on a global scale, intensive research efforts have begun to identify its mechanisms of action on a molecular level in order to replace surgery with targeted behavioral or pharmacological treatments. To date, however, there is no consensus as to the critical mechanisms involved.The purpose of this non-systematic review is to evaluate the existing evidence for specific molecular and inter-organ signaling pathways that play major roles in bariatric surgery-induced weight loss and metabolic benefits, with a focus on Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), in both humans and rodents.Gut-brain communication and its brain targets of food intake control and energy balance regulation are complex and redundant. Although the relatively young science of bariatric surgery has generated a number of hypotheses, no clear and unique mechanism has yet emerged. It seems increasingly likely that the broad physiological and behavioral effects produced by bariatric surgery do not involve a single mechanism, but rather multiple signaling pathways. Besides a need to improve and better validate surgeries in animals, advanced techniques, including inducible, tissue-specific knockout models, and the use of humanized physiological traits will be necessary. State-of-the-art genetically-guided neural identification techniques should be used to more selectively manipulate function-specific pathways. 

https://doi.org/10.1016/j.molmet.2022.101517

Regulation of body weight: Lessons learned from bariatric surgery

Chronic kidney disease (CKD) is a worldwide public health issue and has ultimately progressed to an end-stage renal disease that requires life-long dialysis or renal transplantation. However, the underlying molecular mechanism of these pathological development and progression remains to be fully understood. The human gut microbiota is made up of approximately 100 trillion microbial cells including anaerobic and aerobic species. In recent years, more and more evidence has indicated a clear association between dysbiosis of gut microbiota and CKD including immunoglobulin A (IgA) nephropathy, diabetic kidney disease, membranous nephropathy, chronic renal failure and end-stage renal disease. The current review describes gut microbial dysbiosis and metabolites in patients with CKD thus helping to understand human disease. Treatment with prebiotics, probiotics and natural products can attenuate CKD through improving dysbiosis of gut microbiota, indicating a novel intervention strategy in patients with CKD. This review also discusses therapeutic options, such as prebiotics, probiotics and natural products, for targeting dysbiosis of gut microbiota in patients to provide more specific concept-driven therapy strategy for CKD treatment.

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Recent advances of gut microbiota in chronic kidney disease patients

Non-alcoholic fatty liver disease (NAFLD) is currently related to a heavy socioeconomic burden and increased incidence. Since obesity is the most prevalent risk factor for NAFLD, weight loss is an effective therapeutic solution. Bariatric surgery (BS), which can achieve long-term weight loss, improves the overall health of patients with NAFLD. The two most common surgeries are the Roux-en-Y gastric bypass and sleeve gastrectomy. The gut-liver axis is the complex network of cross-talking between the gut, its microbiome, and the liver. The gut microbiome, involved in the homeostasis of the gut-liver axis, is believed to play a significant role in the pathogenesis of NAFLD and the metabolic improvement after BS. Alterations in the gut microbiome in NAFLD have been confirmed compared to that in healthy individuals. The mechanisms linking the gut microbiome to NAFLD have been proposed, including increased intestinal permeability, higher energy intake, and other pathophysiological alterations. Interestingly, several correlation studies suggested that the gut microbial signatures after BS become more similar to those of lean, healthy controls than that of patients with NAFLD. The resolution of NAFLD after BS is related to changes in the gut microbiome and its metabolites. However, confirming a causal link remains challenging. This review summarizes characteristics of the gut microbiome in patients with NAFLD before and after BS and accumulates existing evidence about the underlying mechanisms of the gut microbiome.

/pdf/gut-microbiome-and-microbial-metabolites-in-nafld-and-after-1xd1t9kc.pdf

Gut microbiome and microbial metabolites in NAFLD and after bariatric surgery: Correlation and causality

Determining biomarkers and better characterizing the biochemical progression of nonalcoholic fatty liver disease (NAFLD) remains a clinical challenge. A targeted 1H-NMR study of serum, combined with clinical variables, detected and localized biomarkers to stages of NAFLD in morbidly obese females. Pre-surgery serum samples from 100 middle-aged, morbidly obese female subjects, grouped on gold-standard liver wedge biopsies (non-NAFLD; steatosis; and fibrosis) were collected, extracted, and analyzed in aqueous (D2O) buffer (1H, 600 MHz). Profiled concentrations were subjected to exploratory statistical analysis. Metabolites varying significantly between the non-NAFLD and steatosis groups included the ketone bodies 3-hydroxybutyrate (↓; p = 0.035) and acetone (↓; p = 0.012), and also alanine (↑; p = 0.004) and a putative pyruvate signal (↑; p = 0.003). In contrast, the steatosis and fibrosis groups were characterized by 2-hydroxyisovalerate (↑; p = 0.023), betaine (↓; p = 0.008), hypoxanthine (↓; p = 0.003), taurine (↓; p = 0.001), 2-hydroxybutyrate (↑; p = 0.045), 3-hydroxyisobutyrate (↑; p = 0.046), and increasing medium chain fatty acids. Exploratory classification models with and without clinical variables exhibited overall success rates ca. 75-85%. In the study conditions, inhibition of fatty acid oxidation and disruption of the hepatic urea cycle are supported as early features of NAFLD that continue in fibrosis. In fibrosis, markers support inflammation, hepatocyte damage, and decreased liver function. Complementarity of NMR concentrations and clinical information in classification models is shown. A broader hypothesis that standard-of-care sera can yield metabolomic information is supported.

Aqueous Metabolite Trends for the Progression of Nonalcoholic Fatty Liver Disease in Female Bariatric Surgery Patients by Targeted 1H-NMR Metabolomics.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing, as are other manifestations of metabolic syndrome such as obesity and type 2 diabetes. NAFLD is currently the number one cause of chronic liver disease worldwide. The pathophysiology of NAFLD and disease progression is poorly understood. A potential contributing role for gut microbiome and metabolites in NAFLD is proposed. Currently, bariatric surgery is an effective therapy to prevent the progression of NAFLD and other manifestations of metabolic syndrome such as obesity and type 2 diabetes. This review provides an overview of gut microbiome composition and related metabolites in individuals with NAFLD and after bariatric surgery. Causality remains to be proven. Furthermore, the clinical effects of bariatric surgery on NAFLD are illustrated. Whether the gut microbiome and metabolites contribute to the metabolic improvement and improvement of NAFLD seen after bariatric surgery has not yet been proven. Future microbiome and metabolome research is necessary for elucidating the pathophysiology and underlying metabolic pathways and phenotypes and providing better methods for diagnostics, prognostics and surveillance to optimize clinical care.

Jacqueline Hoozemans

Papers

Gut Microbiome and Metabolites in Patients with NAFLD and after Bariatric Surgery: A Comprehensive Review.