Sex differences in a mouse model of diet-induced obesity: the role of the gut microbiome.

Background: Recent decades have seen an exponential rise in global obesity prevalence, with rates nearly doubling in a span of forty years. A comprehensive knowledge base regarding the systemic effects of obesity is required to create new preventative and therapeutic agents effective at combating the current obesity epidemic. Previous studies of diet-induced obesity utilizing mouse models have demonstrated a difference in bodyweight gain by sex. In such studies, female mice gained significantly less weight than male mice when given the same high fat (HF) diet, indicating a resistance to diet-induced obesity. Research has also shown sex differences in gut microbiome composition between males and females, indicated to be in part a result of sex hormones. Understanding metabolic differences between sexes could assist in the development of new measures for obesity prevention and treatment. This study aimed to characterize sex differences in weight gain, plasma lipid profiles, fecal microbiota composition, and fecal short chain fatty acid levels. We hypothesized a role for the gut microbiome in these sex differences that would be normalized following microbiome depletion. Methods: A mouse model was used to study these effects. Mice were divided into treatment groups by sex, diet, and presence/absence of an antibiotic cocktail to deplete genera in the gut microbiome. We hypothesized that sex differences would be present both in bodyweight gain and systemic measures of obesity, including hormone and circulating free fatty acid levels. Results: We determined statistically significant differences for sex and/or treatment for the outcome measures. We confirm previous findings in which male mice gained significantly more weight than female mice fed the same high fat diet. However, sex differences persisted following antibiotic administration for microbiome depletion. Conclusions: We conclude that sex differences in the gut microbiome may contribute to sex differences in obesity, but they do not explain all of the differences.

Sex differences in the fecal microbiome and hippocampal glial morphology following diet and antibiotic treatment.

Rising obesity rates have become a major public health concern within the United States. Understanding the systemic and neural effects of obesity is crucial in designing preventive and therapeutic measures. In previous studies, administration of a high fat diet has induced significant weight gain for mouse models of obesity. Interestingly, sex differences in high-fat diet-induced weight gain have been observed, with female mice gaining significantly less weight compared to male mice on the same high-fat diet. It has also been observed that consumption of a high-fat diet can increase neurogliosis, but the mechanism by which this occurs is still not fully understood. Recent research has suggested that the gut microbiome may mediate diet-induced glial activation. The current study aimed to (1) analyze changes to the gut microbiome following consumption of a high fat (HF) diet as well as antibiotic treatment, (2) evaluate hippocampal microgliosis and astrogliosis, and (3) identify sex differences within these responses. We administered a low fat (Research Diets D12450 K) or high fat diet (Research Diets D12451) to male and female C57Bl/6 mice for sixteen weeks. Mice received an antibiotic cocktail containing 0.5g/L of vancomycin, 1.0 g/L ampicillin, 1.0 g/L neomycin, and 1.0 g/L metronidazole in their drinking water during the last six weeks of the study and were compared to control mice receiving normal drinking water throughout the study. We observed a significant reduction in gut microbiome diversity for groups that received the antibiotic cocktail, as determined by Illumina next-generation sequencing. Male mice fed the HF diet (± antibiotics) had significantly greater body weights compared to all other groups. And, female mice fed the low fat (LF) diet and administered antibiotics revealed significantly decreased microgliosis and astrogliosis in the hippocampus compared to LF-fed females without antibiotics. Interestingly, male mice fed the LF diet and administered antibiotics revealed significantly increased microgliosis, but decreased astrogliosis, compared to LF-fed males without antibiotics. The observed sex differences in LF-fed mice given antibiotics brings forward questions about sex differences in nutrient metabolism, gut microbiome composition, and response to antibiotics.

High fat diet alters gut microbiota but not spatial working memory in early middle-aged Sprague Dawley rats.

As the global population ages, and rates of dementia rise, understanding lifestyle factors that play a role in the development and acceleration of cognitive decline is vital to creating therapies and recommendations to improve quality of later life. Obesity has been shown to increase risk for dementia. However, the specific mechanisms for obesity-induced cognitive decline remain unclear. One potential contributor to diet-induced cognitive changes is neuroinflammation. Furthermore, a source of diet-induced inflammation to potentially increase neuroinflammation is via gut dysbiosis. We hypothesized that a high fat diet would cause gut microbe dysbiosis, and subsequently: neuroinflammation and cognitive decline. Using 7-month old male Sprague Dawley rats, this study examined whether 8 weeks on a high fat diet could impact performance on the water radial arm maze, gut microbe diversity and abundance, and microgliosis. We found that a high fat diet altered gut microbe populations compared to a low fat, control diet. However, we did not observe any significant differences between dietary groups on maze performance (a measure of spatial working memory) or microgliosis. Our data reveal a significant change to the gut microbiome without subsequent effects to neuroinflammation (as measured by microglia characterization and counts in the cortex, hippocampus, and hypothalamus) or cognitive performance under the parameters of our study. However, future studies that explore duration of the diet, composition of the diet, age of animal model, and strain of animal model, must be explored.