17β-Estradiol supplementation changes gut microbiota diversity in intact and colorectal cancer-induced ICR male mice

Abstract

The composition of the gut microbiota is influenced by sex hormones and colorectal cancer (CRC). Previously, we reported that 17β-estradiol (E2) inhibits azoxymethane/dextran sulfate sodium (AOM/ DSS)-induced tumorigenesis in male mice. Here, we investigated whether the composition of the gut microbiota is different between male and female, and is regulated by estrogen as a secondary outcome of previous studies. We established four groups of mice based on the sex and estrogen status [ovariectomized (OVX) female and E2-treated male]. Additionally, three groups of males were established by treating them with AOM/DSS, and E2, after subjecting them to AOM/DSS treatment. The mice were sacrificed at 21 weeks old. The composition of the gut microbiota was analyzed using 16S rRNA metagenomics sequencing. We observed a significant increase in the microbial diversity (Chao1 index) in females, males supplemented with E2, and males treated with AOM/DSS/E2 compared with normal males. In normal physiological condition, sex difference and E2 treatment did not affect the ratio of Firmicutes/Bacteroidetes (F/B). However, in AOM/DSS-treated male mice, E2 supplementation showed significantly lower level of the F/B ratio. The ratio of commensal bacteria to opportunistic pathogens was higher in females and E2-treated males compared to normal males and females subjected to OVX. Unexpectedly, this ratio was higher in the AOM/DSS group than that determined in other males and the AOM/DSS/E2 group. Our findings suggest that estrogen alters the gut microbiota in ICR (CrljOri:CD1) mice, particularly AOM/DSS-treated males, by decreasing the F/B ratio and changing Shannon and Simpson index by supply of estrogen. This highlights another possibility that estrogen could cause changes in the gut microbiota, thereby reducing the risk of developing CRC. Colorectal cancer (CRC) is the third leading cause of cancer death in both men and women in the United States, with an estimation of 101,420 and 51,020 new cases of cancer and cancer-related deaths, respectively, in 2019 1. Chronic inflammation following viral or bacterial infections is considered as an important risk factor involved in human carcinogenesis, including CRC 2 and its association has been reported, particularly in infections such as viral hepatitis and hepatocellular carcinoma 3 , as well as that of Helicobacter pylori and gastric adenocarcinoma 4. Moreover, it has been reported that opportunistic pathogens play a role in colorectal carcinogenesis. Fusobacterium nucleatum, Escherichia coli, Streptococcus gallolyticus (formerly known as S. bovis), Enterococcus faecalis, and enterotoxigenic Bacteroides fragilis (a toxin-producing bacteria) have been considered as candidate microorganisms responsible for triggering the colorectal carcinogenesis 5. Additionally, results obtained from several animal experiments have suggested that these bacteria could be the causative microorganisms responsible for colorectal carcinogenesis 5. According to a recent report, infection with F. nucleatum had pr...

Selective estrogen receptor modulator lasofoxifene suppresses spondyloarthritis manifestation and affects characteristics of gut microbiota in zymosan-induced SKG mice

“…However, F/B ratio of zymosan + E2 or zymosan + Laso treated group was similar to the control group. Our study was consistent with other studies showed that estradiol supplementation showed significantly lower level of the F/B ratio compared with control group in a male mouse of colorectal cancer model 26 . E2 treatment increased the relative abundance of Bacteroidetes in leptin-deficient mice 27 .…”

“…In male mice of colorectal cancer model, α-diversity, observed OTU count, was increased in E2 supplemented male. And β-diversity was significantly distinguished based on E2 treatment 26 . Fecal microbial diversity was correlated with urinary estrogens in postmenopausal women 29 .…”

Sexual Dimorphism in Colon Cancer

“…A 2016 study using multiple mouse strains demonstrated that ovariectomy led to microbial dysbiosis although this was impacted by both strain and diet ( 149 ). More specifically, dietary supplementation with the hormone estradiol has been shown to increase microbial diversity in healthy male mice and to impact the ratio of bacteria in the microbiome of a CRC-induced mouse model ( 150 ). The potential protective effect of estrogen was examined in a recent study using the AOM/DSS mouse model of intestinal-specific ERβ deletion and induced colitis and CRC.…”

Prediagnostic use of estrogen-only therapy is associated with improved colorectal cancer survival in menopausal women: a Swedish population-based cohort study

“…ERb in normal colon epithelia has been experimentally shown to play a role in the prevention of a tumor formation in mouse models, by reducing inflammation of the gut [5]. Furthermore, in-vivo mice-models suggest exogenous estrogens impacting inflammatory markers and reducing proliferation of the crypt [5,6], and changing gut microbiota diversity in CRC-induced males [7]. As this posed link of estrogens with gut inflammation and microbiome might be modifiable, it could contribute to a reduced CRC risk [7], and potentially improved survival.…”