The human gut is home to a complex array of microorganisms interacting with the host and each other, forming a community known as the microbiome. This community has been linked to human health and ...disease, but understanding the underlying interactions is still challenging for researchers. Standard studies typically use high-throughput sequencing to analyze microbiome distribution in patient samples. Recent advancements in meta-omic data analysis have enabled computational modeling strategies to integrate this information into an in silico model. However, there is a need for improved parameter fitting and data integration features in microbial community modeling. This study proposes a novel alternative strategy utilizing state-of-the-art dynamic flux balance analysis (dFBA) to provide a simple protocol enabling accurate replication of abundance data composition through dynamic parameter estimation and integration of metagenomic data. We used a recurrent optimization algorithm to replicate community distributions from three different sources: mock, in vitro, and clinical microbiome. Our results show an accuracy of 98% and 96% when using in vitro and clinical bacterial abundance distributions, respectively. The proposed modeling scheme allowed us to observe the evolution of metabolites. It could provide a deeper understanding of metabolic interactions while taking advantage of the high contextualization features of GEM schemes to fit the study case. The proposed modeling scheme could improve the approach in cases where external factors determine specific bacterial distributions, such as drug intake.
Obesity is characterized by an excess of white adipose tissue (WAT). Recent evidence has demonstrated that WAT can change its phenotype to a brown-like adipose tissue known as beige/brite adipose ...tissue. This transition is characterized by an increase in thermogenic capacity mediated by uncoupling protein 1 (UCP1). This browning process is a potential new target for treating obesity. The aim of this review is to integrate the different mechanisms by which beige/brite adipocytes are formed and to describe the physiological, pharmacological and nutritional inducers that can promote browning. An additional aim is to show evidence of how some of these inducers can be used as potential therapeutic agents against obesity and its comorbidities. This review shows the importance of brown and beige/brite adipose tissue and the mechanisms of their formation. Particularly, the two theories of beige/brite adipocyte origin are discussed: de novo differentiation and transdifferentiation. The gene markers that identify these types of adipocytes and the involvement of microRNAs in the epigenetic regulation of the browning process is also discussed. Additionally, we describe the transcriptional control of UCP1 expression by some of the inducers of browning. Furthermore, we describe in detail how some bioactive dietary compounds can induce browning and their subsequent beneficial health effects. The evidence suggests that browning is a new potential strategy for the treatment of obesity and obesity-associated metabolic disorders.
Fiber intake is associated with a lower risk for Alzheimer´s disease (AD) in older adults. Intake of plant-based diets rich in soluble fiber promotes the production of short-chain fatty acids (SCFAs: ...butyrate, acetate, propionate) by gut bacteria. Butyrate administration has antiinflammatory actions, but propionate promotes neuroinflammation. In AD patients, gut microbiota dysbiosis is a common feature even in the prodromal stages of the disease. It is unclear whether the neuroprotective effects of fiber intake rely on gut microbiota modifications and specific actions of SCFAs in brain cells. Here, we show that restoration of the gut microbiota dysbiosis through the intake of soluble fiber resulted in lower propionate and higher butyrate production, reduced astrocyte activation and improved cognitive function in 6-month-old male APP/PS1 mice. The neuroprotective effects were lost in antibiotic-treated mice. Moreover, propionate promoted higher glycolysis and mitochondrial respiration in astrocytes, while butyrate induced a more quiescent metabolism. Therefore, fiber intake neuroprotective action depends on the modulation of butyrate/propionate production by gut bacteria. Our data further support and provide a mechanism to explain the beneficial effects of dietary interventions rich in soluble fiber to prevent dementia and AD.
Graphical Abstract
Fiber intake restored the concentration of propionate and butyrate by modulating the composition of gut microbiota in male transgenic (Tg) mice with Alzheimer´s disease. Gut dysbiosis was associated with intestinal damage and high propionate levels in control diet fed-Tg mice. Fiber-rich diet restored intestinal integrity and promoted the abundance of butyrate-producing bacteria. Butyrate concentration was associated with better cognitive performance in fiber-fed Tg mice. A fiber-rich diet may prevent the development of a dysbiotic microbiome and the related cognitive dysfunction in people at risk of developing Alzheimer´s disease.
Due to the public health problem represented by obesity, the study of adipose tissue, particularly of the adipocyte, is central to the understanding of metabolic abnormalities associated with the ...development of obesity. The concept of adipocyte as endocrine and functional cell is not totally understood and can be currently defined as the capacity of the adipocyte to sense, manage, and send signals to maintain energy equilibrium in the body. Adipocyte functionality is lost during obesity and has been related to adipocyte hypertrophy, disequilibrium between lipogenesis and lipolysis, impaired transcriptional regulation of the key factors that control adipogenesis, and lack of sensitivity to external signals, as well as a failure in the signal transduction process. Thus, dysfunctional adipocytes contribute to abnormal utilization of fatty acids causing lipotoxicity in non-adipose tissue such as liver, pancreas and heart, among others. To understand the metabolism of the adipocyte it is necessary to have an overview of the developmental process of new adipocytes, regulation of adipogenesis, lipogenesis and lipolysis, endocrine function of adipocytes and metabolic consequences of its dysfunction. Finally, the key role of adipose tissue is shown by studies in transgenic animals or in animal models of diet-induced obesity that indicate the contribution of adipose tissue during the development of metabolic syndrome. Thus, understanding of the molecular process that occurs in the adipocyte will provide new tools for the treatment of metabolic abnormalities during obesity.
The malignant energetic demands are satisfied through glycolysis, glutaminolysis and de novo synthesis of fatty acids, while the host curses with a state of catabolism and systemic inflammation. The ...concurrent inhibition of both, tumor anabolism and host catabolism, and their effect upon tumor growth and whole animal metabolism, have not been evaluated. We aimed to evaluate in colon cancer cells a combination of six agents directed to block the tumor anabolism (orlistat + lonidamine + DON) and the host catabolism (growth hormone + insulin + indomethacin). Treatment reduced cellular viability, clonogenic capacity and cell cycle progression. These effects were associated with decreased glycolysis and oxidative phosphorylation, leading to a quiescent energetic phenotype, and with an aberrant transcriptomic landscape showing dysregulation in multiple metabolic pathways. The in vivo evaluation revealed a significant tumor volume inhibition, without damage to normal tissues. The six-drug combination preserved lean tissue and decreased fat loss, while the energy expenditure got decreased. Finally, a reduction in gene expression associated with thermogenesis was observed. Our findings demonstrate that the simultaneous use of this six-drug combination has anticancer effects by inducing a quiescent energetic phenotype of cultured cancer cells. Besides, the treatment is well-tolerated in mice and reduces whole animal energetic expenditure and fat loss.
Fat and sweeteners contribute to obesity. However, it is unknown whether specific bacteria are selectively modified by different caloric and noncaloric sweeteners with or without a high-fat diet ...(HFD). Here, we combined extensive host phenotyping and shotgun metagenomics of the gut microbiota to investigate this question. We found that the type of sweetener and its combination with an HFD selectively modified the gut microbiota. Sucralose and steviol glycosides led to the lowest α-diversity of the gut microbiota. Sucralose increased the abundance of B. fragilis in particular, resulting in a decrease in the abundance of occludin and an increase in proinflammatory cytokines, glucose intolerance, fatty acid oxidation and ketone bodies. Sucrose+HFD showed the highest metabolic endotoxemia, weight gain, body fat, total short chain fatty acids (SCFAs), serum TNFα concentration and glucose intolerance. Consumption of sucralose or sucrose resulted in enrichment of the bacterial genes involved in the synthesis of LPS and SCFAs. Notably, brown sugar and honey were associated with the absence of metabolic endotoxemia, increases in bacterial gene diversity and anti-inflammatory markers such as IL-10 and sIgA, the maintenance of glucose tolerance and energy expenditure, similar to the control group, despite the consumption of an HFD. These findings indicate that the type of sweetener and an HFD selectively modify the gut microbiota, bacterial gene enrichment of metabolic pathways involved in LPS and SCFA synthesis, and metabolic endotoxemia associated with different metabolic profiles.
Current efforts are directed to reducing the gut dysbiosis and inflammation produced by obesity. The purpose of this study was to investigate whether consuming nopal, a vegetable rich in dietary ...fibre, vitamin C, and polyphenols can reduce the metabolic consequences of obesity by modifying the gut microbiota and preventing metabolic endotoxemia in rats fed a high fat and sucrose diet. With this aim, rats were fed a high fat diet with 5% sucrose in the drinking water (HFS) for 7 months and then were fed for 1 month with HFS + 5% nopal (HFS + N). The composition of gut microbiota was assessed by sequencing the 16S rRNA gene. Nopal modified gut microbiota and increased intestinal occludin-1 in the HFS + N group. This was associated with a decrease in metabolic endotoxemia, glucose insulinotropic peptide, glucose intolerance, lipogenesis, and metabolic inflexibility. These changes were accompanied by reduced hepatic steatosis and oxidative stress in adipose tissue and brain, and improved cognitive function, associated with an increase in B. fragilis. This study supports the use of nopal as a functional food and prebiotic for its ability to modify gut microbiota and to reduce metabolic endotoxemia and other obesity-related biochemical abnormalities.
Background Metabolic syndrome (MetS) is a serious health problem over the world; thus, the aim of the present work was to develop a lifestyle intervention to decrease the dysbiosis of gut microbiota ...and reduce the biochemical abnormalities of MetS. Methods and Results The prevalence of MetS was evaluated in 1065 subjects of Mexico City, Mexico, and the gut microbiota in a subsample. Subjects with MetS were selected for a pragmatic study based on a lifestyle intervention with a low-saturated-fat diet, reduced-energy intake, with functional foods and physical activity, and a second group was selected for a randomized control-placebo study to assess the gut microbiota after the dietary intervention. Prevalence of MetS was 53%, and the higher the body mass index, the higher the gut microbiota dysbiosis. The higher the Homeostatic Model Assessment for Insulin Resistance, the lower the high-density lipoprotein cholesterol concentration. The pragmatic study revealed that after 15 days on a low-saturated-fat diet, there was a 24% reduction in serum triglycerides; and after a 75-day lifestyle intervention, MetS was reduced by 44.8%, with a reduction in low-density lipoprotein cholesterol, small low-density lipoprotein particles, glucose intolerance, lipopolysaccharide, and branched-chain amino acid. The randomized control-placebo study showed that after the lifestyle intervention, there was a decrease in the dysbiosis of the gut microbiota associated with a reduction in the Prevotella/ Bacteroides ratio and an increase in the abundance of Akkermansia muciniphila and Faecalibacterium prausnitzii. Conclusions A lifestyle intervention significantly decreased MetS components, small low-density lipoprotein particle concentration, gut microbiota dysbiosis, and metabolic endotoxemia, reducing the risk of atherosclerosis. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT03611140.
Well-characterized and standardized extracts of a Mexican genotype of Ganoderma lucidum (Gl), a medicinal mushroom, cultivated on oak sawdust (Gl-1) or oak sawdust plus acetylsalicylic acid (Gl-2, ...ASA), have been shown to exert antioxidant, hypocholesterolemic, anti-inflammatory, prebiotic, and anticancer properties. However, toxicity analyses still need to be carried out. Different doses of these Gl-1 or Gl-2 extracts were administered to Wistar rats for 14 days in a repeated dose oral toxicity study. We assessed the external clinical signs, biochemical parameters, liver and kidney tissues, injury and inflammation biomarkers, gene expression, inflammatory responses, proinflammatory mediators, and gut microbiota. Gl extracts had no significant adverse, toxic or harmful effects on male and female rats compared to the control groups. No injury or dysfunction were recorded in the kidney or liver, as there were no significant abnormal variations in organ weight, tissue histopathology, serum biochemical parameters (C-reactive protein, creatinine, urea, glucose, ALT and AST transaminases, TC, LDL-c, TG, HDL-c), urinary parameters (creatinine, urea nitrogen, albumin, the albumin-to-creatinine ratio, glucose), injury and inflammatory biomarkers (KIM-1/TIM-1, TLR4, and NF-кB protein expression; IL-1β, TNF-α and IL-6 gene expression), or the expression of genes linked to cholesterol metabolism (HMG-CoA, Srebp2, Ldlr). Gl-1 and Gl-2 extracts showed prebiotic effects on the gut microbiota of male and female Wistar rats. Bacterial diversity and relative bacterial abundance (BRA) increased, positively modulating the Firmicutes/Bacteroidetes ratio. The ASA (10 mM) added to the substrate used for mushroom cultivation changed properties and effects of the Gl-2 extract on Wistar rats. The no-observed-adverse-effect-level (NOAEL) was 1000 mg/kg body weight/day of Gl-1 or Gl-2 extracts. Clinical trials are recommended for further exploring the potential therapeutic applications of studied extracts.
Abstract Nopal is a plant used in traditional Mexican medicine to treat diabetes. However, there is insufficient scientific evidence to demonstrate whether nopal can regulate postprandial glucose. ...The purpose for conducting this study was to evaluate the glycemic index, insulinemic index, glucose-dependent insulinotropic peptide (GIP) index, and the glucagon-like peptide 1 (GLP-1) index, and the effect of nopal on patients with type 2 diabetes after consumption of a high-carbohydrate breakfast (HCB) or high-soy-protein breakfast (HSPB) on the postprandial response of glucose, insulin, GIP, GLP-1, and antioxidant activity. In study 1, the glycemic index, insulinemic index, GIP index, and GLP-1 index were calculated for seven healthy participants who consumed 50 g of available carbohydrates from glucose or dehydrated nopal. In study 2, 14 patients with type 2 diabetes consumed nopal in HCB or HSPB with or without 300 g steamed nopal. The glycemic index of nopal was 32.5±4, insulinemic index was 36.1±6, GIP index was 6.5±3.0, and GLP-1 index was 25.9±18. For those patients with type 2 diabetes who consumed the HCB+nopal, there was significantly lower area under the curve for glucose (287±30) than for those who consumed the HCB only (443±49), and lower incremental area under the curve for insulin (5,952±833 vs 7,313±1,090), and those patients with type 2 diabetes who consumed the HSPB avoided postprandial blood glucose peaks. Consumption of the HSPB+nopal significantly reduced the postprandial peaks of GIP concentration at 30 and 45 minutes and increased the antioxidant activity after 2 hours measured by the 2,2-diphenyl-1-picrilhidracyl method. These findings suggest that nopal could reduce postprandial blood glucose, serum insulin, and plasma GIP peaks, as well as increase antioxidant activity in healthy people and patients with type 2 diabetes.
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