Sex Differences in Gut Microbiota and Metabolism

Educational Objectives

The goal of this program is to increase knowledge about the interaction of gut microbiota and sex hormones in chronic disease. After hearing and assimilating this program, the clinician will be better able to:

1. Provide examples that highlight the relationship between the gut microbiota and chronic disease.
2. Summarize the role of the gut microbiota on sex hormone functionality and phenotypic expression.

Summary

Sexual dimorphism: obesity — more overweight men than women; however, women dominate categories of obesity and extreme obesity (global trend); sex hormones — women protected against certain diseases (eg, cardiometabolic) until after menopause; without estrogen, risk normalizes for men and women; women experience increased weight gain after 45 yr of age; men more susceptible to type 2 diabetes; gastrointestinal (GI)-associated diseases (irritable bowel syndrome, inflammatory bowel disease) generally more severe in women; symptoms can fluctuate with estrous cycle

Sex hormones: estradiol — predominant female hormone involved in GI homeostasis; estradiol can signal through membrane receptors (eg, G-coupled protein receptors); differences in expression of protein receptors observed in states of inflammation; mouse model — female rats resist intestinal injury and inflammation; intestinal permeability fluctuates during estrous cycle; oophorectomy eliminates sex differences; sex hormones broadly influence molecular metabolism and exert different effects on key metabolic outcomes in men and women

Gut microbiota: mouse model — germ-free mice exhibit differential hormone levels and resist diet-induced obesity compared with conventionally raised mice with gut microbiota; when germ-free and conventionally raised mice given same diet (low-fat or high-fat), conventionally raised mice develop obesity but germ-free mice remain lean; gut microbiota play key role in driving certain phenotypes

Microbial communities: use sequencing-based technology to characterize microbial communities; 16S ribosomal RNA (rRNA) gene conserved across all bacteria; variable regions across gene targeted with primers to identify differences between microbial members in communities (“thumbprint”); shotgun metagenomic sequencing allows examination at strain level for certain genomes

Mouse studies: sexual dimorphism — occurs in nonobese diabetic mice raised under germ-free and conventional conditions; among conventionally raised mice, increased percentage of type 1 diabetes observed among female mice compared with male mice; among germ-free mice, difference between sexes disappears; role for gut microbiota and sex hormones driving onset of disease; testosterone — among conventionally raised and germ-free female mice, testosterone levels higher in germ-free mice; among conventionally raised and germ-free male mice, testosterone levels higher in conventionally raised mice; gut microbiota influence levels of sex hormones; microbiota — among 3-wk-old male and female mice, no significant differences noted; differences in microbiota begin to appear by 6 wk of age; after castration, microbiota of male mice resemble those of female mice; microbes transferred from female to male germ-free mice differentiate according to recipient’s milieu of sex hormones; transplantation of microbiota from male to female mice forces germ-free recipient to make more testosterone; increased testosterone changes microbial community; protects against onset of type 1 diabetes and autoimmune disease; diet — different diets support different microbial communities; manipulation of sex hormones drives differences in microbiota

Disease presentation: sex hormones impact complex diseases; estrogen influences functionality of GI tract; level of sex hormones impacts gut membership and function of microbial community; microbiota interacting with sex hormones — gut microbiota directly modulate conjugated estrogens in gut; estradiol converted from testosterone and made primarily in ovaries; most abundant in premenopausal women; estrone converted from estradiol (E2) or androstenedione; estrone made in adipose tissue and constitutes main estrogen in postmenopausal women; estriol made in placenta during pregnancy; sex hormones secreted into gut by liver or reabsorbed by enterohepatic circulation; gut hormones directly transformed in intestine; modifications impact whether hormone reabsorbed or excreted; specific gut microbes within GI tract transform estrogens and impact whether secretion or recirculation of sex hormones occurs

Suggested Readings

Caricilli AM, Saad MJ: Gut microbiota composition and its effects on obesity and insulin resistance. Curr Opin Clin Nutr Metab Care. 2014 Jul;17(4):312-8; Markle JG et al: Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science. 2013 Mar;339(6123):1084-8; Org E et al: Sex differences and hormonal effects on gut microbiota composition in mice. Gut Microbes. 2016 Jul;7(4):313-22; Shin JH et al: Serum level of sex steroid hormone is associated with diversity and profiles of human gut microbiome. Res Microbiol. 2019 Jun-Aug;170(4-5):192-201; Ticinesi A et al: The impact of intestinal microbiota on bio-medical research: definitions, techniques and physiology of a “new frontier”. Acta Biomed. 2018 Dec;89(9-S):52-9; Yurkovetskiy L et al: Gender bias in autoimmunity is influenced by microbiota. Immunity. 2013 Aug;39(2):400-12; Ziesemer KA et al: Intrinsic challenges in ancient microbiome reconstruction using 16S rRNA gene amplification. Sci Rep. 2015 Nov;5:16498.

Readings

Disclosures

For this program, members of the faculty and planning committee reported nothing to disclose.

Acknowledgements

Dr. Leone was recorded at Women in Digestive Diseases: At the Forefront, held March 9, 2019, in Chicago, IL, and presented by the University of Chicago Pritzker School of Medicine. For information about upcoming CME activities sponsored by the University of Chicago Pritzker School of Medicine, please visit: cme.uchicago.edu. The Audio Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

GE340503

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.