Diet-driven microbiota dysbiosis is associated with vagal remodeling and obesity
Introduction
Obesity has reached epidemic proportion in Western countries, including the United States [1]. Evidence suggests that consumption of an energy-dense high-fat/high-sugar diet (HF/HSD) promotes excessive weight gain and that there is a direct relationship between the amount of dietary fat and the degree of obesity [2]. Consequently, lowering dietary fat intake has been considered one of the best approaches for weight management. However, a growing body of evidence has been pointing to its inadequacy for weight loss or disease prevention [3], [4]. Interestingly, many commercial low-fat foods are high in sugar and refined carbohydrates [5] and increased intake of sugars, especially fructose has been linked to increased body fat accumulation and obesity [6].
There is evidence that the gut microbiota plays a role in obesity [7]. In humans and animal models, changes in diet composition can rapidly trigger changes in gut microbiota composition [8], [9]. Interestingly, colonization of germ-free (GF) animals with either a “lean” or an “obese” microbiota leads to a recapitulation of the donor phenotype, identifying the gut microbiota as a potential driver of obesity [10]. The gut microbiota impacts the host metabolism and notably affects energy harvest and fat storage [8], [10] as well as inflammatory status [10], [11]. Consumption of HF/HSD has been associated with increased production of bacterial pro-inflammatory factors, such a lipopolysaccharide (LPS, a breakdown product of the outer membrane of Gram-negative bacteria) [7], [11]. Moreover, diet-driven gut inflammation results in impairment in the gut epithelial barrier leading to enhanced LPS uptake into the plasma [7], [12]. An increase in circulating LPS, also called metabolic endotoxemia, can trigger systemic inflammation, impair liver function, alter food intake [12] and promote body fat accumulation [11], [12]. Interestingly, LPS has been shown in culture to activate vagal afferent neurons [13] and chronic treatment with low doses of LPS results in NG inflammation and impairs vagal satiety signaling [12].
Gut-originating peptides signal via the vagus nerve to control meal initiation and termination [14], [15]. Disruption of vagal afferent signaling is sufficient to drive obesity in a diet-induced rat obesity model [13]. Therefore, microbiota-mediated dysregulation of gut-brain vagal communication might contribute to the pathogenesis of obesity and its related diseases.
In the present study, we investigated the influence of diets rich in sugars, with different fat contents, on microbiota composition and gut-brain axis inflammation. Results show that regardless of fat contents, diets rich in sugars promote gut microbiota dysbiosis, induce gut inflammation, increase gut permeability, and alter vagal gut-brain communication when compared to control chow diet.
Section snippets
Animals and diet
Male Sprague-Dawley rats (6 weeks old; Envigo, Indianapolis, IN) were housed in individual plastic cages in a temperature-controlled vivarium with ad libitum access to food and water. Rats were maintained on a 12-h light/dark schedule and habituated to laboratory conditions for one week before their diet was changed. All animal procedures were approved by the University of Georgia Institutional Animal Care and Use Committee and conformed to National Institutes of Health guidelines for the care
Consumption of diets rich in sugars can promote obesity
We determined the animals' body weight, body fat mass, and lean mass at baseline and throughout the four-week feeding study. As expected, there were no significant differences in body weight and body composition between groups at baseline (Fig. 1A). However, body weights of the LF/HSD and HF/HSD fed rats were significantly increased after 4 weeks on their respective diets when compared to the LF/LSD control rats (Fig. 1A). The HF/HSD fed animals weighed significantly more than the LF/LSD after
Conclusion
Summarizing the present data and considering our previous observations, we propose that ingestion of an HSD leads to changes in gut microbiota, which, possibly via an increase in LPS and inflammatory cytokines leads to withdrawal of vagal innervation in the gut and hindbrain. Dysbiosis-driven gastrointestinal inflammation could lead to an increase in gut permeability allowing passage of LPS and other pro-inflammatory signals from the lumen to the lamina propria. These pro-inflammatory products
Conflict of interest statement
All authors declare that there are no conflicts of interest.
The following are the supplementary data related to this article.
Acknowledgments
This research is supported by grant 5R01DC013904 from the National Institute of Health. The authors thank Brent Joseph Gawey, Mariam Ahmed, Jeremy Alan Long, and Rebecca Kirkland for their valuable time and useful contribution to complete this manuscript.
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