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The Microbial Hypothesis: Contributions of Adenovirus Infection and Metabolic Endotoxaemia to the Pathogenesis of Obesity.

ABSTRACT: The global obesity epidemic, dubbed "globesity" by the World Health Organisation, is a pressing public health issue. The aetiology of obesity is multifactorial incorporating both genetic and environmental factors. Recently, epidemiological studies have observed an association between microbes and obesity. Obesity-promoting microbiome and resultant gut barrier disintegration have been implicated as key factors facilitating metabolic endotoxaemia. This is an influx of bacterial endotoxins into the systemic circulation, believed to underpin obesity pathogenesis. Adipocyte dysfunction and subsequent adipokine secretion characterised by low grade inflammation, were conventionally attributed to persistent hyperlipidaemia. They were thought of as pivotal in perpetuating obesity. It is now debated whether infection and endotoxaemia are also implicated in initiating and perpetuating low grade inflammation. The fact that obesity has a prevalence of over 600 million and serves as a risk factor for chronic diseases including cardiovascular disease and type 2 diabetes mellitus is testament to the importance of exploring the role of microbes in obesity pathobiology. It is on this basis that Massachusetts General Hospital is sponsoring the Faecal Microbiota Transplant for Obesity and Metabolism clinical trial, to study the impact of microbiome composition on weight. The association of microbes with obesity, namely, adenovirus infection and metabolic endotoxaemia, is reviewed.

SUBMITTER: Tambo A

PROVIDER: S-EPMC5143720 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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The Microbial Hypothesis: Contributions of Adenovirus Infection and Metabolic Endotoxaemia to the Pathogenesis of Obesity.

Tambo Amos A Roshan Mohsin H K MH Pace Nikolai P NP

International journal of chronic diseases 20161124

The global obesity epidemic, dubbed "globesity" by the World Health Organisation, is a pressing public health issue. The aetiology of obesity is multifactorial incorporating both genetic and environmental factors. Recently, epidemiological studies have observed an association between microbes and obesity. Obesity-promoting microbiome and resultant gut barrier disintegration have been implicated as key factors facilitating metabolic endotoxaemia. This is an influx of bacterial endotoxins into the ...[more]

PMID: 28004036

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Project description:Childhood obesity is associated with chronic low-grade inflammation considered as a precursor to metabolic disease; however, the underlying mechanisms for this remain unclear. Studies in adults have implicated gut derived gram-negative bacterial fragments known as lipopolysaccharide or endotoxin, activating the inflammatory response, whilst the importance in childhood obesity is unclear. The aim of this research is to understand the relationship between circulating endotoxin in childhood obesity, and its' association with inflammatory and cardiovascular (CV) injury biomarkers.Fasted blood was obtained from children with varying degrees of obesity (age: 13.9 ± 2.3Yr; BMI: 35.1 ± 5.2 Kg/m(2); n = 60). Multiplex CVD biomarker immunoassays were used to determine systemic levels of inflammatory and vascular injury biomarkers, such as tumour necrosis factor-α (TNF-α), interleukin (IL-) 1β, 6, 8 and 10, plasminogen activator inhibitor-1 (PAI-1), soluble intercellular adhesion molecule type-1 (sICAM-1), matrix metalloproteinase-9 (MMP-9), myeloperoxidase (MPO) and vascular endothelial growth factor (VEGF) as well as endotoxin levels.Endotoxin levels demonstrated a significant and positive correlation with the markers for inflammation, vascular injury and atherogenesis (TNF-α: r(2) = 0.077, p < 0.05; PAI-1: r(2) = 0.215, p < 0.01; sICAM-1: r(2) = 0.159, p < 0.01; MMP-9: r(2) = 0.159, p < 0.01; MPO: r(2) = 0.07, p < 0.05; VEGF: r(2) = 0.161, p < 0.01). Males demonstrated significantly higher circulating endotoxin than females (Males: 9.63 ± 5.34 EU/ml; p = 0.004; Females: 5.56 ± 4.06 EU/ml; n = 60) in these BMI and age-matched cohorts.The present study demonstrates for the first time a significant association between circulating endotoxin and biomarkers of metabolic risk in children as young as 11 years. Thus, endotoxin-mediated sub-clinical inflammation during childhood obesity may be a key contributor to T2DM and CVD development later in life.

Project description:BackgroundSeveral studies have shown that Adenovirus 36 (Ad36) influences the risk of obesity in humans. Clarifying the relationship between Ad36 infection and obesity could lead to more effective approaches for the management of obesity. The objective of this study was to conduct a meta-analysis to confirm the influence of Ad36 infection on obesity and metabolic markers.Methodology/principal findingsWe searched MEDLINE and the Cochrane Library for pertinent articles (including their references) published between 1951 and April 22, 2012. Only English language reports of original observational studies were included in this meta-analysis. Data extraction was performed independently by two reviewers. Weighted mean differences (WMDs) and pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated using the random effects model. Of 237 potentially relevant studies, 10 cross-sectional studies (n?=?2,870) conformed to the selection criteria. Pooled analysis showed that the WMD for BMI of Ad36 infection compared with non-infection was 3.19 (95% CI 1.44-4.93; P<0.001). Sensitivity analysis restricted to studies of adults yielded a similar result of 3.18 (95% CI 0.78-5.57; P?=?0.009). The increased risk of obesity associated with Ad36 infection was also significant (OR: 1.9; 95% CI: 1.01-3.56; P?=?0.047). No significant differences were found in relation to total cholesterol (P?=?0.83), triglycerides (P?=?0.64), HDL (P?=?0.69), blood glucose (P?=?0.08), waist circumstance (P?=?0.09), and systolic blood pressure (P?=?0.25).Conclusion/significanceAd36 infection was associated with the risk of obesity and weight gain, but was not associated with abnormal metabolic markers including waist circumstance. It suggests that Ad36 infection is more associated with accumulation of subcutaneous fat than that of visceral fat. The relationship between Ad36 and obesity should be assessed by further studies, including well-designed prospective studies, to gain a better understanding of whether Ad36 plays a role in the etiology of human obesity.

Project description:Dysfunctional adipose tissue (AT) is known to contribute to the pathophysiology of metabolic disease, including type 2 diabetes mellitus (T2DM). This dysfunction may occur, in part, as a consequence of gut-derived endotoxaemia inducing changes in adipocyte mitochondrial function and reducing the proportion of BRITE (brown-in-white) adipocytes. Therefore, the present study investigated whether endotoxin (lipopolysaccharide; LPS) directly contributes to impaired human adipocyte mitochondrial function and browning in human adipocytes, and the relevant impact of obesity status pre and post bariatric surgery. Human differentiated abdominal subcutaneous (AbdSc) adipocytes from participants with obesity and normal-weight participants were treated with endotoxin to assess in vitro changes in mitochondrial function and BRITE phenotype. Ex vivo human AbdSc AT from different groups of participants (normal-weight, obesity, pre- and 6 months post-bariatric surgery) were assessed for similar analyses including circulating endotoxin levels. Ex vivo AT analysis (lean & obese, weight loss post-bariatric surgery) identified that systemic endotoxin negatively correlated with BAT gene expression (p < 0.05). In vitro endotoxin treatment of AbdSc adipocytes (lean & obese) reduced mitochondrial dynamics (74.6% reduction; p < 0.0001), biogenesis (81.2% reduction; p < 0.0001) and the BRITE phenotype (93.8% reduction; p < 0.0001). Lean AbdSc adipocytes were more responsive to adrenergic signalling than obese AbdSc adipocytes; although endotoxin mitigated this response (92.6% reduction; p < 0.0001). Taken together, these data suggest that systemic gut-derived endotoxaemia contributes to both individual adipocyte dysfunction and reduced browning capacity of the adipocyte cell population, exacerbating metabolic consequences. As bariatric surgery reduces endotoxin levels and is associated with improving adipocyte functionality, this may provide further evidence regarding the metabolic benefits of such surgical interventions.

Project description:Human adenovirus 36 (HAdV-36), as the key pathogen, was supposed and discussed to be associated with obesity. We searched the references on the association between HAdV-36 infection and obesity with the different epidemiological methods, to explore the relationship with a larger sample size by meta-analysis and compare the differences of epidemiological methods and population subsets by the subgroup analyses.We conducted literature search on the association between HAdV-36 infections and obesity in English or Chinese published up to July 1, 2015. The primary outcome was the HAdV-36 infection rate in the obese and lean groups; the secondary outcomes were the BMI level and BMI z-score in the HAdV-36 positive and negative groups. The pooled odds ratio (OR) was calculated for the primary outcome; the standardized mean differences (SMDs) were calculated for the secondary and third outcomes. Prediction interval (PI) was graphically presented in the forest plot of the random effect meta-analyses. Metaregression analysis and subgroup analysis were performed.Finally 24 references with 10,191 study subjects were included in the meta-analysis. The obesity subjects were more likely to be infected with HAdV-36 compared to the lean controls (OR = 2.00; 95%CI: 1.46, 2.74; PI: 0.59, 6.76; P < 0.001) with a high heterogeneity (I = 80.1%; P < 0.001) estimated by the random effect model. Subgroup analysis demonstrated that the pooled OR of HAdV-36 infection for obesity were 1.77 (95%CI: 1.19, 2.63; PI: 0.44, 7.03; P = 0.005) and 2.26 (95%CI: 1.67, 3.07; PI: 1.45, 3.54; P < 0.001) in the adults and children, respectively. Compared to the HAdV-36 negative subjects, the SMD of BMI was 0.28 (95% CI: 0.08, 0.47; PI: -0.53, 1.08; P = 0.006) in the HAdV-36 positive subjects with a high heterogeneity (I = 86.5%; P < 0.001). The BMI z-score in the children with HAdV-36 infection was higher than those without HAdV-36 infection (SMD = 0.19; 95%CI: -0.31, 0.70; PI: -2.10, 2.49), which had no significantly statistical difference (P = 0.453).HAdV-36 infection increased the risk of obesity. HAdV-36 also increased the risk of weight gain in adults, which was not observed in children.

Dataset Information

The Microbial Hypothesis: Contributions of Adenovirus Infection and Metabolic Endotoxaemia to the Pathogenesis of Obesity.

Publications

The Microbial Hypothesis: Contributions of Adenovirus Infection and Metabolic Endotoxaemia to the Pathogenesis of Obesity.

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