Changing the microbiome

The influence of hormones on the microbiome

The microbiome changes during your life. After birth, a baby is colonized with mainly facultative anaerobes which create an environment for other bacteria. In the scientific background the colonization process is described. Slowly the microbiome becomes more diverse and at an age of two to five years old children have a microbiota resembling an adult microbiota. [1]

Changes in the microbiome do not only occur during early life, but also during pregnancy. [2] A pregnant woman undergoes a lot of changes which are necessary to deliver a healthy baby. Examples of these are: the plasma volume increases with 50%; the glomerular filtration rate increases; the oxygen demand increases and she gains weight [3]. But what I find more interesting is the change in hormonal levels. Therefore, I wondered if hormones play a role in the microbiome changes and, even more, I wondered how they influence the microbiome.

Hormonal changes start right after the conception, when the embryo starts producing human chorionic gonadotropin (hCG). Due to the hCG the corpus luteum continues the production of progesterone. Estrogen is produced by the ovaries and later by the placenta, it stimulates the production of progesterone. Increasing estrogen leads to an increase in prolactin produced by the pituitary gland. Cortisol is produced by the decidua (the endometrium of a pregnant woman). Cortisol suppress the maternal immune response together with hCG. Insulin levels rise due to hyperplasia of beta-cells, this is followed by progressive insulin resistance. Finally, the follicle-stimulating hormone (FSH) and Luteinizing hormone (LH) levels drop due to the estrogen negative feedback loop, which results in stagnation of a follicle. This happens because follicle development is not wanted during pregnancy. [3][4][5] A lot more hormonal changes happen during the pregnancy but I won't address them all.

The picture shows how Estrogen, Progesterone and hCG levels rise during pregnancy. The picture is from wikipedia: https://commons.wikimedia.org/wiki/File:2919_Hormones_Initiating_Labor-02.jpg

This picture shows how cortisol levels rise, which is different when a woman caries a girl or a boy. The picture is found on http://www.pnas.org/content/109/20/E1312/1/F3.expansion.html 

A lot of literature describes the hormonal change in pregnant woman, but do they influence the microbiome? Orge, E. [6] did a study in which female mice received a gonadectomy, which is a procedure which removes the ovaries (or testicles in a male). He found that after 8 weeks the gut microbiota had changed. Female mice which underwent a gonadectomy had significantly less Akkermansia bacteria then the control group who did not undergo this procedure. This means that the gonads, and probably the hormones produced by the gonads, influence the microbiota. But has this effect also been shown in human beings?

The answer is yes, I found articles stating the effect of single hormones on the human microbiome. [7] You can read about the effects of estrogen, progesterone and cortisol in the next paragraphs.

Estrogen  

The ‘normal healthy’ vaginal microbiota should contain a low microbial diversity and four species of lactobacilli (most common are: L. crispathus, L. gasseri, L. iners and L. jensenii). See scientific background for more information. Shifts from a microbiome dominated by anaerobic bacteria, to one dominated by lactobacillus are seen during puberty and the menopause. These shifts are due to estrogen. [8]

During pregnancy levels of estrogen are high, this promotes bacterial growth. Estrogen stimulates epithelial cells to produce more glycogen, which is a nutrient for lactobacilli. Glycogen is a nutrient needed for lactobacilli to grow. The relative number of lactobacilli in the vagina increases. Lactobacilli convert sugars into lactate, the acidic lactate decrease the pH in the vagina. [9] They also produce hydrogen peroxide, which inhibits the growth of fungi. Lactobacilli form a physical barrier for pathogens by forming colonies on epithelial cells. [8] Thus the Lactobacilli a protective bacteria, for example in preventing a urine tract infection, like was mentioned in the introduction.

 

The picture shows how high and low estrogen works on the microbiome. Picture is found on:

http://www.kevinmd.com/blog/2016/08/please-dont-take-gynecological-advice-khloe-kardashian.html estrogen picture

Estrogen receptors and progesterone receptors are found in the oral cavity and have been proven to influence the oral microbiota. There is an increase found of Bacteroides intermedius during pregnancy which is associated with the increased serum levels of progesterone or estrogens. These levels are also associated with pathogenic Porphyromonas gingivalis. [10] In addition, there has been a connection between periodontal disease and preterm birth due to Fusobacterium nucleatum infection. F. nucleatum is not only able to cause a gingivitis it can also infect the placenta and cause preterm birth. [11] But Fusobacterium nucleatum abundance was not different between pregnant and non-pregnant woman. [10] This suggest that hormones are not likely to have an influence on preterm birth through an F. nucelatum bacteria.

Progesterone

In a study cariried out by Kindinger, L. M., et al [12]. vaginal progesterone was given to pregnant woman to study if it can prevent preterm birth. He specifically studied the mechanism in which progesterone may prevent preterm birth. He compared the microbiome of the pregnant woman with progesterone intervention to pregnant woman without the intervention. There was no difference found in the vaginal microbiome of the pregnant woman with and without progesterone supplement. This indicatesthat progesterone alone does not influence the vaginal microbiome.

Cortisol

Sex hormones are not the only hormones to increase. Cortisol also increases throughout the pregnancy with a peak in the third trimester. [13] Cortisol is a hormone which reduces inflammation and is also related to stress, stress is proven to be related to preterm birth [14] A cohort study has been performed to see if cortisol also is related to a changing microbiome. Where I had only focused on the possibility that hormones change the maternal microbiome, this study focusses on maternal cortisol changing the infant microbiome. And the hypothesis of the authors showed to be true, high stress or cortisol levels in the mother lead to microbial changes in their child. The children with a stressed mother had an increased abundance of Proteobacteria (e.g. E. coli) and a decreased amount of Actinobacteria in their intestines [14].  A dominance of Escherichia bacteria has been observed in preterm infants. [14] A same pattern of microbial changes due to stress was found in a likewise study with pregnant rhesus monkeys exposed to stress. [15]

How cortisol can influence the infant intestinal microbiome is not certain but the study proposes three possible mechanisms.

1.    Cortisol regulates the cholesterol and bile acid homeostasis and it controls the bile acid production. So high cortisol may lead to an increase in bile acid, and bile acid has been proven to interfere with the intestinal microbiome of the mother. This can influence the transmission from the maternal microbiota to the infant. [14] [16]

2.    Cortisol can cross the placenta. This causes an increase in fetal cortisol concentrations. The high cortisol concentrations have an effect on the immune cells of the gut, which could have an influence on the gut microbiome. [14]

3.    After birth cortisol could enter the baby via the breast milk and then affect the gut microbiome. [14]

After reading a lot of literature about hormonal influence on the microbiome, I can conclude that hormones influence the microbiome. The exact mechanism might not be clear yet and there probably are a lot more components that work together with the hormones to achieve these changes. But there is no doubt that hormones play a role. I focused mostly on estrogen and progesterone but eventually found the most interesting results when looking further into cortisol. It turns out that cortisol could possibly lead to preterm birth.

1.    Rodríguez, J. M., Murphy, K., Stanton, C., Ross, R. P., Kober, O. I., Juge, N., … Collado, M. C. (2015). The composition of the gut microbiota throughout life, with an emphasis on early life. Microbial Ecology in Health and Disease, 26, 10.3402/mehd.v26.26050. http://doi.org/10.3402/mehd.v26.26050

2.    Nuriel-Ohayon, M., Neuman, H., Koren, O., (2016). Microbial Chages during Pregnancy, Birth, and Infancy. Frontiers in Microbiology Microbial Symbioses. https://doi.org/10.3389/fmicb.2016.01031

3.    Soma-Pillay, P., Catherine, N.-P., Tolppanen, H., Mebazaa, A., Tolppanen, H., & Mebazaa, A. (2016). Physiological changes in pregnancy. Cardiovascular Journal of Africa, 27(2), 89–94. http://doi.org/10.5830/CVJA-2016-021

4.    Feldt-Rsmussen, U., Mathiesen E. R.,(2011). Endocrine disorders in pregnancy: Physiological and hormonal aspects of pregnancy. Clinical Endocrionlogy & Metabolism. Volume 25, issue 6, pages 875-884. http://dx.doi.org/10.1016/j.beem.2011.07.004

5.    Kumar, P., & Magon, N. (2012). Hormones in pregnancy. Nigerian Medical Journal : Journal of the Nigeria Medical Association, 53(4), 179–183. http://doi.org/10.4103/0300-1652.107549

6.    Org, E., Mehrabian, M., Parks, B. W., Shipkova, P., Liu, X., Drake, T. A., & Lusis, A. J. (2016). Sex differences and hormonal effects on gut microbiota composition in mice. Gut Microbes, 7(4), 313–322. http://doi.org/10.1080/19490976.2016.1203502 

7.      Neuman, H., Debelius, J. W., Knight, R., Koren, O., (2015). Microbial endocrinology: the interplay between the microbiota and the endocrine system.  FEMS microbiology reviews. Volume 39, issue 4, pages 509-521. https://doi.org/10.1093/femsre/fuu010

8.    Vitali, D., Wessels, J. M., & Kaushic, C. (2017). Role of sex hormones and the vaginal microbiome in susceptibility and mucosal immunity to HIV-1 in the female genital tract. AIDS Research and Therapy, 14, 39. http://doi.org/10.1186/s12981-017-0169-4

9.    Kumar, P. S. (2013), Sex and the subgingival microbiome: Do female sex steroids affect periodontal bacteria?. Periodontology 2000, 61: 103–124. doi:10.1111/j.1600-0757.2011.00398.x

10.  Wu, M., Chen, S.-W., & Jiang, S.-Y. (2015). Relationship between Gingival Inflammation and Pregnancy. Mediators of Inflammation, 2015, 623427. http://doi.org/10.1155/2015/623427

11.  Indira, U., Mysorekar, Cao, B., (2014). Microbiome in Parturition and Preterm Birth.  Thieme Seminars in Reproductive Medicine. 32(01):050-055 https://www-thieme-connect-com.ezproxy.leidenuniv.nl:2443/products/ejournals/html/10.1055/s-0033-1361830#JR00858-18

12.  Kindinger, L. M., Bennett, P. R., Lee, Y. S., Marchesi, J. R., Smith, A., Cacciatore, S., … MacIntyre, D. A. (2017). The interaction between vaginal microbiota, cervical length, and vaginal progesterone treatment for preterm birth risk. Microbiome, 5, 6. http://doi.org/10.1186/s40168-016-0223-9

13.  Jung, C., Ho, J. T., Torpy, D. J., Rogers, A., Doogue, M., Lewis, J. G., Czajko, R. J., Inder, W. J., (2011). A longitudinal Study of Plasma and Urinary Cortisol in Pregnancy and Postpartum. The Journal of Clinical Endocrinology and Metabolism. 96(5). http://dx.doi.org/10.1210/jc.2010-2395

14.  Zijlman, M. A. C., Korpela, K., Riksen-Walraven, J. M., de Vos, W. M., de Weerth, C., (2015). Maternal prenatal stress is associated with the infant intestinal microbiota. Psychoneuroendocrinology, Volume 53, pages 233-245. http://dx.doi.org/10.1016/j.psyneuen.2015.01.006

15.  Bailey, M. T., Lubach, G. R., Coe, C. L., Prenatal stress alters bacterial colonization of the gut in infant monkeys. Journal of Pediatric Gastroenterology and Nutritio . 38(4): 414-21. https://insights.ovid.com/pubmed?pmid=15085020

16.  Islam, K. B. M. S., Fukiya, S., Hagio, M., Fujii, N., Ishizuka, S., Ooka, T., Ogura, Y., Hayashi, T., Yokota, A., Bile Acid is a Host Factor That Regulates the Composition of the Cecal Microbiota in Rats. Gastroenterology. 141(5):1773-1781 : http://dx.doi.org/10.1053/j.gastro.2011.07.046