The global prevalence of obesity and related comorbidities has increased considerably over the past decades. In addition to an increase in food consumption and a reduction in physical activity, growing evidence implicates the microorganisms in our gastrointestinal tract, referred to as the gut microbiota, in obesity and related metabolic disturbances. The composition of the gut microbiota can fluctuate markedly within an individual and between individuals. Changes in gut microbial composition may be unfavorable and predispose an individual to disease. Studies in mice that are germ free, mice that are cohoused, and mice that are treated with antibiotics have provided some evidence that changes in gut microbiota may causally contribute to metabolic disorders. Several mechanisms have been proposed and explored that may mediate the effects of the gut microbiota on metabolic disorders. In this review, we carefully analyze the literature on the connection between the gut microbiota and metabolic health, with a focus on studies demonstrating a causal relation and clarifying potential underlying mechanisms. Despite a growing appreciation for a role of the gut microbiota in metabolic health, more experimental evidence is needed to substantiate a cause-and-effect relationship. If a clear causal relationship between the gut microbiota and metabolic health can be established, dietary interventions can be targeted toward improving gut microbial composition in the prevention and perhaps even the treatment of metabolic diseases.

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Objective— Macrophage foam cells play a crucial role in several pathologies including multiple sclerosis, glomerulosclerosis, and atherosclerosis. Angiopoietin-like protein 4 (Angptl4) was previously shown to inhibit chyle-induced foam cell formation in mesenteric lymph nodes. Here we characterized the regulation of Angptl4 expression in macrophages and examined the impact of Angptl4 on atherosclerosis development. Approach and Results— Macrophage activation elicited by pathogen-recognition receptor agonists decreased Angptl4 expression, whereas lipid loading by intralipid and oxidized low-density lipoprotein increased Angptl4 expression. Consistent with an antilipotoxic role of Angptl4, recombinant Angptl4 significantly decreased uptake of oxidized low-density lipoprotein by macrophages, via lipolysis-dependent and -independent mechanisms. Angptl4 protein was detectable in human atherosclerotic lesions and localized to macrophages. Transgenic overexpression of Angptl4 in atherosclerosis-prone apolipoprotein E*3-Leiden mice did not significantly alter plasma cholesterol and triglyceride levels. Nevertheless, Angptl4 overexpression reduced lesion area by 34% ( P <0.05). In addition, Angptl4 overexpression decreased macrophage content (−41%; P <0.05) and numbers of monocytes adhering to the endothelium wall (−37%; P <0.01). Finally, plasma Angptl4 was independently and negatively associated with carotid artery sclerosis measured by 3-T MRI in subjects with metabolic syndrome and low-grade systemic inflammation. Conclusions— Angptl4 suppresses foam cell formation to reduce atherosclerosis development. Stimulation of Angptl4 in macrophages by oxidized low-density lipoprotein may protect against lipid overload.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, yet the pathogenesis of NAFLD is only partially understood. Here, we investigated the role of the gut bacteria in NAFLD by stimulating the gut bacteria via feeding mice the fermentable dietary fiber, guar gum (GG), and suppressing the gut bacteria via chronic oral administration of antibiotics. GG feeding profoundly altered the gut microbiota composition, in parallel with reduced diet-induced obesity and improved glucose tolerance. Strikingly, despite reducing adipose tissue mass and inflammation, GG enhanced hepatic inflammation and fibrosis, concurrent with markedly elevated plasma and hepatic bile acid levels. Consistent with a role of elevated bile acids in the liver phenotype, treatment of mice with taurocholic acid stimulated hepatic inflammation and fibrosis. In contrast to GG, chronic oral administration of antibiotics effectively suppressed the gut bacteria, decreased portal secondary bile acid levels, and attenuated hepatic inflammation and fibrosis. Neither GG nor antibiotics influenced plasma lipopolysaccharide levels. In conclusion, our data indicate a causal link between changes in gut microbiota and hepatic inflammation and fibrosis in a mouse model of NAFLD, possibly via alterations in bile acids.