Amelioration of metabolic syndrome by metformin associates with reduced indices of low-grade inflammation independently of the gut microbiota

Metformin beneficially impacts several aspects of metabolic syndrome including dysglycemia, obesity, and liver dysfunction, thus making it a widely used frontline treatment for early-stage type 2 diabetes, which is associated with these disorders. Several mechanisms of action for metformin have been proposed, including that it acts as an anti-inflammatory agent, possibly as a result of its impact on intestinal microbiota. In accord with this possibility, we observed herein that, in mice with diet-induced metabolic syndrome, metformin impacts the gut microbiota by preventing its encroachment upon the host, a feature of metabolic syndrome in mice and humans. However, the ability of metformin to beneficially impact metabolic syndrome in mice was not markedly altered by reduction or elimination of gut microbiota, achieved by the use of antibiotics or germfree mice. Although reducing or eliminating microbiota by itself suppressed diet-induced dysglycemia, other features of metabolic syndrome including obesity, hepatic steatosis, and low-grade inflammation remained suppressed by metformin in the presence or absence of gut microbiota. These results support a role for anti-inflammatory activity of metformin, irrespective of gut microbiota, in driving some of the beneficial impacts of this drug on metabolic syndrome.

Download Full-text

A Genetic Score of Predisposition to Low-Grade Inflammation Associated with Obesity May Contribute to Discern Population at Risk for Metabolic Syndrome

Nutrients ◽

10.3390/nu11020298 ◽

2019 ◽

Vol 11 (2) ◽

pp. 298 ◽

Cited By ~ 6

Author(s):

Sebastià Galmés ◽

Margalida Cifre ◽

Andreu Palou ◽

Paula Oliver ◽

Francisca Serra

Keyword(s):

Metabolic Syndrome ◽

At Risk ◽

Ex Vivo ◽

Low Grade ◽

Omega 3 ◽

Genetic Score ◽

Population At Risk ◽

Inflammatory Status ◽

Anti Inflammatory ◽

Low Grade Inflammation

Omega-3 rich diets have been shown to improve inflammatory status. However, in an ex vivo system of human blood cells, the efficacy of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) modulating lipid metabolism and cytokine response is attenuated in overweight subjects and shows high inter-individual variability. This suggests that obesity may be exerting a synergistic effect with genetic background disturbing the anti-inflammatory potential of omega-3 long-chain polyunsaturated fatty acids (PUFA). In the present work, a genetic score aiming to explore the risk associated to low grade inflammation and obesity (LGI-Ob) has been elaborated and assessed as a tool to contribute to discern population at risk for metabolic syndrome. Pro-inflammatory gene expression and cytokine production as a response to omega-3 were associated with LGI-Ob score; and lower anti-inflammatory effect of PUFA was observed in subjects with a high genetic score. Furthermore, overweight/obese individuals showed positive correlation of both plasma C-Reactive Protein and triglyceride/HDLc-index with LGI-Ob; and high LGI-Ob score was associated with greater hypertension (p = 0.047), Type 2 diabetes (p = 0.026), and metabolic risk (p = 0.021). The study shows that genetic variation can influence inflammation and omega-3 response, and that the LGI-Ob score could be a useful tool to classify subjects at inflammatory risk and more prone to suffer metabolic syndrome and associated metabolic disturbances.

Download Full-text

Mechanisms Mediating Anti-Inflammatory Effects of Delta-Tocotrienol and Tart Cherry Anthocyanins in 3T3-L1 Adipocytes

Nutrients ◽

10.3390/nu12113356 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3356

Author(s):

Lexie Harlan ◽

London T. Mena ◽

Latha Ramalingam ◽

Shasika Jayarathne ◽

Chwan-Li Shen ◽

...

Keyword(s):

Metabolic Diseases ◽

Combined Treatment ◽

Low Grade ◽

Tart Cherry ◽

Metabolic Complications ◽

Inflammatory Protein ◽

Anti Inflammatory ◽

Low Grade Inflammation ◽

Macrophage Inflammatory Protein

Chronic low-grade inflammation is a primary characteristic of obesity and can lead to other metabolic complications including insulin resistance and type 2 diabetes (T2D). Several anti-inflammatory dietary bioactives decrease inflammation that accompanies metabolic diseases. We are specifically interested in delta-tocotrienol, (DT3) an isomer of vitamin E, and tart cherry anthocyanins (TCA), both of which possess individual anti-inflammatory properties. We have previously demonstrated that DT3 and TCA, individually, reduced systemic and adipose tissue inflammation in rodent models of obesity. However, whether these compounds have combinatorial effects has not been determined yet. Hence, we hypothesize that a combined treatment of DT3 and TCA will have great effects in reducing inflammation in adipocytes, and that these effects are mediated via the nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), a major inflammatory transcription factor. We used 3T3-L1 adipocytes and treated them with 1–5 µM doses of DT3 along with tart cherry containing 18–36 µg anthocyanin/mL, to assess effects on inflammation. Neither DT3 nor TCA, nor their combinations had toxic effects on adipocytes. Furthermore, pro-inflammatory markers interleukin-6 (IL-6) and p-65 (subunit of NFkB) were reduced at the protein level in media collected from adipocytes with both individual and combined treatments. Additionally, other downstream targets of NFkB including macrophage inflammatory protein 2 (Mip2), and Cyclooxygenase-2 (Cox2) were also significantly downregulated (p ≤ 0.05) when treated with individual and combined doses of DT3 and TCA with no additional combinatorial effects. In summary, DT3 and TCA individually, are beneficial in reducing inflammation with no additional combinatorial effects.

Download Full-text

Metabolic Syndrome and Its Effect on the Brain: Possible Mechanism

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527317666180724143258 ◽

2018 ◽

Vol 17 (8) ◽

pp. 595-603 ◽

Cited By ~ 10

Author(s):

Nurul ‘Ain Arshad ◽

Teoh Seong Lin ◽

Mohamad Fairuz Yahaya

Keyword(s):

Diabetes Mellitus ◽

Metabolic Syndrome ◽

Neurodegenerative Diseases ◽

Disease Type ◽

Low Grade ◽

Oxygen Species ◽

Metabolic Factors ◽

Low Grade Inflammation ◽

The Brain

Background & Objective: Metabolic syndrome (MetS) is an interconnected group of physiological, biochemical, clinical and metabolic factors that directly increase the risk of cardiovascular disease, type 2 diabetes mellitus (T2DM) and mortality. Rising evidence suggests that MetS plays a significant role in the progression of Alzheimer’s disease and other neurodegenerative diseases. Nonetheless, the factors linking this association has not yet been elucidated. As we are facing an increasing incidence of obesity and T2DM in all stages of life, understanding the association of MetS and neurodegenerative diseases is crucial to lessen the burden of the disease. Conclusion: In this review, we will discuss the possible mechanisms which may relate the association between MetS and cognitive decline which include vascular damages, elevation of reactive oxygen species (ROS), insulin resistance and low-grade inflammation.

Download Full-text

Microbiota and epigenetic regulation of inflammatory mediators in type 2 diabetes and obesity

Beneficial Microbes ◽

10.3920/bm2013.006 ◽

2014 ◽

Vol 5 (1) ◽

pp. 33-43 ◽

Cited By ~ 72

Author(s):

M. Remely ◽

E. Aumueller ◽

D. Jahn ◽

B. Hippe ◽

H. Brath ◽

...

Keyword(s):

Metabolic Syndrome ◽

Lactic Acid ◽

Lactic Acid Bacteria ◽

Gut Microbiota ◽

Epigenetic Regulation ◽

Control Group ◽

Low Grade ◽

Type 2 Diabetics ◽

Significant Difference

Metabolic syndrome is associated with alterations in the structure of the gut microbiota leading to low-grade inflammatory responses. An increased penetration of the impaired gut membrane by bacterial components is believed to induce this inflammation, possibly involving epigenetic alteration of inflammatory molecules such as Toll-like receptors (TLRs). We evaluated changes of the gut microbiota and epigenetic DNA methylation of TLR2 and TLR4 in three groups of subjects: type 2 diabetics under glucagon-like peptide-1 agonist therapy, obese individuals without established insulin resistance, and a lean control group. Clostridium cluster IV, Clostridium cluster XIVa, lactic acid bacteria, Faecalibacterium prausnitzii and Bacteroidetes abundances were analysed by PCR and 454 high-throughput sequencing. The epigenetic methylation in the regulatory region of TLR4 and TLR2 was analysed using bisulfite conversion and pyrosequencing. We observed a significantly higher ratio of Firmicutes/ Bacteroidetes in type 2 diabetics compared to lean controls and obese. Major differences were shown in lactic acid bacteria, with the highest abundance in type 2 diabetics, followed by obese and lean participants. In comparison, F. prausnitzii was least abundant in type 2 diabetics, and most abundant in lean controls. Methylation analysis of four CpGs in the first exon of TLR4 showed significantly lower methylation in obese individuals, but no significant difference between type 2 diabetics and lean controls. Methylation of seven CpGs in the promoter region of TLR2 was significantly lower in type 2 diabetics compared to obese subjects and lean controls. The methylation levels of both TLRs were significantly correlated with body mass index. Our data suggest that changes in gut microbiota and thus cell wall components are involved in the epigenetic regulation of inflammatory reactions. An improved diet targeted to induce gut microbial balance and in the following even epigenetic changes of pro-inflammatory genes may be effective in the prevention of metabolic syndrome.

Download Full-text

Gut Microbiota, Low‐Grade Inflammation, and Metabolic Syndrome

The FASEB Journal ◽

10.1096/fasebj.29.1_supplement.368.2 ◽

2015 ◽

Vol 29 (S1) ◽

Author(s):

Andrew Gewirtz

Keyword(s):

Metabolic Syndrome ◽

Gut Microbiota ◽

Low Grade ◽

Low Grade Inflammation

Download Full-text

Distinct Gut Microbiota Induced by Different Fat-to-Sugar-Ratio High-Energy Diets Share Similar Pro-obesity Genetic and Metabolite Profiles in Prediabetic Mice

mSystems ◽

10.1128/msystems.00219-19 ◽

2019 ◽

Vol 4 (5) ◽

Cited By ~ 3

Author(s):

Kai Shan ◽

Hongyan Qu ◽

Keru Zhou ◽

Liangfang Wang ◽

Congmin Zhu ◽

...

Keyword(s):

Metabolic Syndrome ◽

Gut Microbiota ◽

Early Stage ◽

Amplicon Sequencing ◽

High Energy ◽

Diabetic Patients ◽

Type 2 Diabetic Patients

ABSTRACT Gut microbiota play important roles in host metabolism, especially in diabetes. However, why different diets lead to similar diabetic states despite being associated with different microbiota is not clear. Mice were fed two high-energy diets (HED) with the same energy density but different fat-to-sugar ratios to determine the associations between the microbiota and early-stage metabolic syndrome. The two diets resulted in different microbiota but similar diabetic states. Interestingly, the microbial gene profiles were not significantly different, and many common metabolites were identified, including l-aspartic acid, cholestan-3-ol (5β, 3α), and campesterol, which have been associated with lipogenesis and inflammation. Our study suggests that different metabolic-syndrome-inducing diets may result in different microbiota but similar microbiomes and metabolomes. This suggests that the metagenome and metabolome are crucial for the prognosis and pathogenesis of obesity and metabolic syndrome. IMPORTANCE Various types of diet can lead to type 2 diabetes. The gut microbiota in type 2 diabetic patients are also different. So, two questions arise: whether there are any commonalities between gut microbiota induced by different pro-obese diets and whether these commonalities lead to disease. Here we found that high-energy diets with two different fat-to-sugar ratios can both cause obesity and prediabetes but enrich different gut microbiota. Still, these different gut microbiota have similar genetic and metabolite compositions. The microbial metabolites in common between the diets modulate lipid accumulation and macrophage inflammation in vivo and in vitro. This work suggests that studies that only use 16S rRNA amplicon sequencing to determine how the microbes respond to diet and associate with diabetic state are missing vital information.

Download Full-text

Lifestyle Measures to Reduce Inflammation

American Journal of Lifestyle Medicine ◽

10.1177/1559827611411646 ◽

2011 ◽

Vol 6 (1) ◽

pp. 4-13 ◽

Cited By ~ 6

Author(s):

Glenn A. Gaesser ◽

Siddhartha S. Angadi ◽

Dana M. Ryan ◽

Carol S. Johnston

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Aerobic Exercise ◽

Inflammatory Markers ◽

Dietary Factors ◽

Low Grade ◽

Inflammatory Status ◽

Anti Inflammatory ◽

Low Grade Inflammation

Chronic low-grade inflammation associated with cardiovascular disease and type 2 diabetes (T2D) may be ameliorated with exercise and/or diet. High levels of physical activity and/or cardiorespiratory fitness are associated with reduced risk of low-grade inflammation. Both aerobic and resistance exercise have been found to improve inflammatory status, with the majority of evidence suggesting that aerobic exercise may have broader anti-inflammatory effects. In particular, aerobic exercise appears to improve the balance between pro- and anti-inflammatory markers. Improvement in inflammatory status is most likely to occur in persons with elevated levels of pro-inflammatory markers prior to intervention. A number of dietary factors, including fiber-rich foods, whole grains, fruits (especially berries), omega-3 fatty acids, antioxidant vitamins (eg, C and E), and certain trace minerals (eg, zinc) have been documented to reduce blood concentrations of inflammatory markers. Anti-inflammatory foods may also help mitigate the pro-inflammatory postprandial state that is particularly evident after ingestion of meals high in saturated fat. Intensive lifestyle interventions involving both exercise and diet appear to be most effective. For the most part, anti-inflammatory effects of exercise and diet are independent of weight loss. Thus overweight and obese men and women, who are most likely to have a pro-inflammatory profile, do not necessarily have to normalize body mass index to improve inflammatory status and reduce risk of type 2 diabetes and cardiovascular disease.

Download Full-text

Berries as a Treatment for Obesity-Induced Inflammation: Evidence from Preclinical Models

Nutrients ◽

10.3390/nu13020334 ◽

2021 ◽

Vol 13 (2) ◽

pp. 334

Author(s):

Hannah Land Lail ◽

Rafaela G. Feresin ◽

Dominique Hicks ◽

Blakely Stone ◽

Emily Price ◽

...

Keyword(s):

Chronic Diseases ◽

Low Grade ◽

Bioactive Components ◽

Preclinical Models ◽

Beneficial Effects ◽

Increased Risk ◽

Anti Inflammatory ◽

Treatment Of Obesity ◽

Low Grade Inflammation

Inflammation that accompanies obesity is associated with the infiltration of metabolically active tissues by inflammatory immune cells. This propagates a chronic low-grade inflammation associated with increased signaling of common inflammatory pathways such as NF-κB and Toll-like receptor 4 (TLR4). Obesity-associated inflammation is linked to an increased risk of chronic diseases, including type 2 diabetes, cardiovascular disease, and cancer. Preclinical rodent and cell culture studies provide robust evidence that berries and their bioactive components have beneficial effects not only on inflammation, but also on biomarkers of many of these chronic diseases. Berries contain an abundance of bioactive compounds that have been shown to inhibit inflammation and to reduce reactive oxygen species. Therefore, berries represent an intriguing possibility for the treatment of obesity-induced inflammation and associated comorbidities. This review summarizes the anti-inflammatory properties of blackberries, blueberries, strawberries, and raspberries. This review highlights the anti-inflammatory mechanisms of berries and their bioactive components that have been elucidated through the use of preclinical models. The primary mechanisms mediating the anti-inflammatory effects of berries include a reduction in NF-κB signaling that may be secondary to reduced oxidative stress, a down-regulation of TLR4 signaling, and an increase in Nrf2.

Download Full-text