Sex hormones, intestinal inflammation, and the gut microbiome: Major influencers of the sexual dimorphisms in obesity

Abstract

Obesity is defined as the excessive accumulation of body fat and is associated with an increased risk of developing major health problems such as cardiovascular disease, diabetes and stroke. There are clear sexual dimorphisms in the epidemiology, pathophysiology and sequelae of obesity and its accompanying metabolic disorders, with females often better protected compared to males. This protection has predominantly been attributed to the female sex hormone estrogen and differences in fat distribution. More recently, the sexual dimorphisms of obesity have also been attributed to the differences in the composition and function of the gut microbiota, and the intestinal immune system. This review will comprehensively summarize the pre-clinical and clinical evidence for these sexual dimorphisms and discuss the interplay between sex hormones, intestinal inflammation and the gut microbiome in obesity. Major gaps and limitations of this rapidly growing area of research will also be highlighted in this review.

Keywords: estrogen (17β-estradiol); gut microbiota; leukocytes; obesity; testosterone.

Figure 1

Adipocyte biology in obesity. A chronic imbalance of increased energy intake and or reduced energy expenditure increases adiposity, via hypertrophy and proliferation of white adipocytes. This promotes the secretion of pro-inflammatory cytokines (i.e., tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), IL-1β, and IL-10) to aid the infiltration of pro-inflammatory immune cells into the adipose tissue and surrounding organs (16). This process promotes dyslipidemia, insulin resistance and hyperglycemia further exacerbating the dysregulation of whole-body energy homeostasis. Created with BioRender.com.

Figure 2

Adipose tissue distribution, sex hormones and metabolic disturbances of obesity. Males and post-menopausal females have increased cardiovascular risk, abdominal/visceral obesity and reduced insulin subcutaneous adipose distribution compared to pre-menopausal females. The adipose tissue within males and post-menopausal females is more pro-inflammatory than that of pre-menopausal females. Created with BioRender.com.

Figure 3

Microbial diversity, sex hormones and chromosomes in obesity. Differences in sex-based characteristics are modulated by a variety of factors. Women have a greater degree of subcutaneous fat, whereas males predominantly accumulate visceral fat. In obesity, the shift in the Firmicutes: Bacteroidetes determines disease severity. Obese males have less species richness, and testosterone was found to be associated with increased Firmicutes, thus more anti-inflammatory butyrate release. Obese females, on the other hand, despite having greater microbial diversity, have an increase estradiol and Bacteroidetes, resulting in greater LPS release, thus eliciting a greater immune response. Created with BioRender.com.

Figure 4

The “give-and-take” relationships between obesity, intestinal immunity, gut microbiome and sex. Created with BioRender.com.