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Abstract
Due to its immunomodulatory potential, the intestinal microbiota has been implicated as a contributing factor in the development of the meta-inflammatory state that drives obesity-associated insulin resistance and type 2 diabetes. A better understanding of this link would facilitate the development of targeted treatments and therapies to treat the metabolic complications of obesity. To this end, we validated and utilized a novel swine model of obesity, the Mangalica pig, to characterize changes in the gut microbiota during the development of an obese phenotype, and in response to dietary differences. In the first study, we characterized the metabolic phenotype and gut microbiota in lean and obese adult Mangalica pigs. Obese or lean groups were created by allowing either ad libitum (obese) or restricted (lean) access to a standard diet for 54 weeks. Mature obese pigs were significantly heavier and exhibited 170% greater subcutaneous adipose tissue mass, with no differences in muscle mass compared to their lean counterparts. Obese pigs displayed impaired glucose tolerance and hyperinsulinemia following oral glucose challenge, indicating that a metabolic phenotype also manifested with changes in body composition. Consistent with observations in human obesity, the gut microbiota of obese pigs displayed altered bacterial composition. In the second study, we characterized the longitudinal changes in the gut microbiota in response to diet and aging in growing Mangalica pigs that were either limit fed a standard diet, allowed ad libitum access to a standard diet, or allowed ad libitum access to a high fat-supplemented diet over an 18-week period. As expected, weight gain was highest in pigs fed the high fat diet compared to ad libitum and limit fed groups. Furthermore, the ad libitum and high fat groups displayed significantly greater adiposity consistent with the development of obesity relative to the limit fed pigs. The intestinal microbiota was generally resilient to differences in dietary intake (limit fed vs ad libitum), though changes in the microbiota of pigs fed the high fat diet mirrored changes observed in mature obese pigs during the first study. This is consistent with the link observed between the microbiota and adiposity. In contrast to intestinal bacterial populations, bacteriophage populations within the gut microbiota responded rapidly to differences in diet, with significant compositional changes in bacteriophage genera observed between the dietary treatment groups as pigs aged. These studies are the first to describe the development of the intestinal microbiota in the Mangalica pig, and are the first to provide evidence that changes in body composition and dietary conditions are associated with changes in the microbiome of this novel porcine model of obesity.
Highlights
The prevalence of obesity in adult populations is approaching pandemic levels
Insulin resistant metabolic phenotype that develops concomitant with its extreme, early onset, morbidly obese body type, the Mangalica pig displays great potential to serve as a relevant animal model of obesity
The aim of this study was to extend such observations by characterizing the intestinal microbiota in mature lean and obese Mangalica pigs and by determining the longitudinal effects of age and diet on the developing gut microbiota in juvenile Mangalica. These studies are the first to describe the overall development of the intestinal microbiome in the Mangalica pig and represent a key first step toward the development of this breed as a useful model to study mechanisms linking the intestinal microbiota and obesity
Summary
The prevalence of obesity in adult populations is approaching pandemic levels. For instance, currently more than 650 million adults worldwide and greater than 40% of adults in the United States are considered obese (CDC, 2020) This poses a serious public health crisis as obesity is associated with multiple comorbidities including metabolic disease, cardiovascular disease, and gastrointestinal diseases (Obesity and overweight). While the etiology of obesity is not fully understood, it is clear that a chronic dysregulation of energy balance drives expansion of adipose tissue, and this associates with the development of metainflammation that in turn promotes impaired insulin sensitivity and the myriad of downstream comorbidities (Li et al, 2018). Obesityassociated changes in the intestinal microbiota have been linked to the promotion of the overnutrition underlying the expansion of adipose tissue (Turnbaugh et al, 2009; Ley, 2010; Ridaura et al, 2013; Duvallet et al, 2017; González-Muniesa et al, 2017; Gomes et al, 2018; Yang et al, 2021). A better understanding of these links could allow the development of targeted therapies to either prevent the onset of obesity or to uncouple obesity from downstream disease states
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