Why does Rheumatoid Arthritis improve during a woman’s period or when pregnant?

Why does Rheumatoid Arthritis improve during a

woman’s period or when pregnant?

By Richard Matthews DC DACNB

By Richard Matthews DC DACNB

This is an article that I wrote for Clint Paddison, to use for his Paddison Program for Rheumatoid Arthritis. Clint successfully healed himself from RA, and took the extraordinary step of teaching other people how to do it!  I’m sharing the article here for my own blog readers.
Rheumatoid Arthritis is a progressive, debilitating autoimmune inflammatory arthritis. The site of actual damage is the synovial membrane of the joint itself, often causing severe angulation deformities of the joint when not controlled. Hands are the most commonly affected area, often in a symmetrical pattern. As it is an inflammatory disorder, the inflammation can also affect the heart, lungs, or other areas of the body. The portions of the immune system that have been identified are the cytokine (inflammatory immune factor) Tumor Necrosis Alpha or TNF-α, Interleukin-6 or IL-6 and Interleukin-17 or IL-17. There are others involved of course but these are the major therapeutic targets for the condition.

It is best to refer to the accompanying drawing to understand the relationship between these factors, as immune function is complex. We have a type of T-cell in our immune system which is called a T-Regulatory cell or Treg. These cells regulate the activity of T-helper cells or Th. The T-helper cells produce cytokines, such as TNF-α, IL-6 and IL-17, which in this case are the prime suspects in this crime!

Our immune system, and the T cells in particular, receive much of their instruction from the microbiome in our gut. Our gut bacteria directly interact with Treg cells, and through that mechanism help to regulate the cytokine system. This interaction has been quite specifically studied down to the genus and species involved.

The species of gut bacteria found to regulate the immune system and reduce inflammation by reducing IL-6, TNF-α and IL-17 include Lactobacillus and Bifidobacterium genus. These organisms have been found to grow well when our gut is reasonably active, a condition that results when we are not in a highly stressed state. They grow well when we have a diet that includes fruits, vegetables and fish. It should not be surprising that this same diet is known to be good for the heart and blood vessels, as atherosclerosis and heart disease are promoted by inflammation.

At least one species, Prevotella copri, is strongly associated with RA. This organism drives the levels of inflammatory IL-17 higher. It thrives in a high-carbohydrate diet, so make sure that your diet includes healthy anti-inflammatory fats and good protein! Also, its growth can be suppressed by seeding and feeding with probiotics, prebiotics, and diet. Another category of organism, segmented filamentous bacteria or SFB, is what initiates the function of the IL-17 cytokine. While getting it started is important, too much SFB can also keep IL-17 levels too high.

Now having identified the immune factors, let’s look at what affects them!
-Progesterone suppresses IL-6 and IL-17
-Estrogen suppresses IL-6 and IL-17
-Microbiome also influences both

Both hormones are elevated around the time of ovulation until the onset of menstruation; essentially during the interval of a woman’s period when she is fertile. Both of these hormones drop off at the onset of menstruation, triggering the sloughing of endometrial lining and blood. Both hormones increase in concentrations during pregnancy, only dropping precipitously at childbirth. It is important to consider that one of the things a woman’s body does in preparation for pregnancy and during pregnancy is to create an increased immune tolerance. If this were not the case, the immune system could treat the developing child as a tumor and attack it, something which actually does happen sometimes and results in miscarriage. It should also be noted that another thing that progesterone does is to reduce inflammation, which is great prior to childbirth, but also may reduce the symptoms of RA during menses or pregnancy—providing a second pathway that explains the relief.

What options does that leave, other than enjoying the brief hormone-induced RA interlude or having another child? Well, progesterone and vitamin D have been used to treat brain inflammation. Certainly a woman should consider using some of the natural and OTC progesterone preparations such as wild yam extract, particularly if evaluation of her existing hormone levels show that there is room for addition of progesterone without levels becoming unnaturally high. Now for the shocker: men also have progesterone, in levels comparable to women during the follicular phase of ovulation. It is converted into testosterone in men, and inhibits the conversion of testosterone into DHT—that nasty little product that causes male pattern baldness and gynecomastia (aka “man-boobs”). Does that mean that men should use low levels of progesterone? Quite possibly! It isn’t the “feminizing hormone” that estrogen is, and its use in men has some precedent already.

Systemic inflammation has the effect of making hormone receptors on the actual cells less functional, so that the hormones do not work as well. Reducing inflammation should therefore also make your existing hormones (progesterone and estrogen in this example) work more effectively. Of course, reducing inflammation helps RA directly as well, since it is an inflammatory condition. Cultivating a diverse and healthy microbiome is at the top of that list, and involves probiotics, prebiotics, diet, lifestyle, stress levels, and avoidance of toxins.

In summary, the sex hormones estrogen and progesterone both inhibit inflammation via inhibition of the IL-6 and IL-17 cytokines. These are the immune molecules that target the actual joint tissue in RA, and they are produced by T-helper cells, which are regulated by T-regulatory cells, which talk to gut bacteria across the intestinal wall to get their instructions. So, healthier gut bacteria means better immune control. Healthier gut bacteria also means better hormone levels and better hormone sensitivity, so it’s a win-win. If getting pregnant is not in your immediate future, and the brief hormone boost afforded by menses is insufficient, supplementation with progesterone may be worth considering in addition to a microbiome-healthy diet with good prebiotics and probiotics. Of course, all of these decisions are best made with the help of some labwork when possible. Identifying your existing microbiome can help to point the direction for improvement whether that means growing more Bifidobacteria or inhibiting the growth of Prevotella copri. In any case, optimize your hormones, and get those symbionts in shape so they can retrain your immune system!
References:
1: Andersson A, Grahnemo L, Engdahl C, Stubelius A, Lagerquist MK, Carlsten H,
Islander U. IL-17-producing γδT cells are regulated by estrogen during
development of experimental arthritis. Clin Immunol. 2015 Sep 28;161(2):324-332.
doi: 10.1016/j.clim.2015.09.014. [Epub ahead of print] PubMed PMID: 26423309.
http://www.ncbi.nlm.nih.gov/pubmed/26423309
2: Kim KW, Kim HR, Kim BM, Cho ML, Lee SH. Th17 Cytokines Regulate
Osteoclastogenesis in Rheumatoid Arthritis. Am J Pathol. 2015 Sep 8. pii:
S0002-9440(15)00445-9. doi: 10.1016/j.ajpath.2015.07.017. [Epub ahead of print]
PubMed PMID: 26362732.
http://www.ncbi.nlm.nih.gov/pubmed/26362732
3: Mortaz E, Adcock IM, Ricciardolo FL, Varahram M, Jamaati H, Velayati AA,
Folkerts G, Garssen J. Anti-Inflammatory Effects of Lactobacillus Rahmnosus and
Bifidobacterium Breve on Cigarette Smoke Activated Human Macrophages. PLoS One.
2015 Aug 28;10(8):e0136455. doi: 10.1371/journal.pone.0136455. eCollection 2015.
PubMed PMID: 26317628; PubMed Central PMCID: PMC4552661.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4552661/

4: Gluhovschi C, Gluhovschi G, Petrica L, Velciov S, Gluhovschi A. Pregnancy
Associated with Systemic Lupus Erythematosus: Immune Tolerance in Pregnancy and
Its Deficiency in Systemic Lupus Erythematosus–An Immunological Dilemma. J
Immunol Res. 2015;2015:241547. doi: 10.1155/2015/241547. Epub 2015 May 18.
Review. PubMed PMID: 26090485; PubMed Central PMCID: PMC4451247.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451247/
5: Tang H, Hua F, Wang J, Yousuf S, Atif F, Sayeed I, Stein DG. Progesterone and
vitamin D combination therapy modulates inflammatory response after traumatic
brain injury. Brain Inj. 2015 Jun 17:1-10. [Epub ahead of print] PubMed PMID:
26083048.
http://www.ncbi.nlm.nih.gov/pubmed/26083048

6: Carasi P, Racedo SM, Jacquot C, Romanin DE, Serradell MA, Urdaci MC. Impact of
kefir derived Lactobacillus kefiri on the mucosal immune response and gut
microbiota. J Immunol Res. 2015;2015:361604. doi: 10.1155/2015/361604. Epub 2015
Feb 24. PubMed PMID: 25811034; PubMed Central PMCID: PMC4355334.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4355334/

7: Garling RJ, Watts LT, Sprague S, Fletcher L, Jimenez DF, Digicaylioglu M. Does
progesterone show neuroprotective effects on traumatic brain injury through
increasing phosphorylation of Akt in the hippocampus? Neural Regen Res. 2014 Nov
1;9(21):1891-6. doi: 10.4103/1673-5374.145355. PubMed PMID: 25558238; PubMed
Central PMCID: PMC4281427.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281427/
8: Moreno J. Prevotella copri and the microbial pathogenesis of rheumatoid
arthritis. Reumatol Clin. 2015 Mar-Apr;11(2):61-3. doi:
10.1016/j.reuma.2014.11.001. Epub 2014 Dec 30. English, Spanish. PubMed PMID:
25555460.
http://www.reumatologiaclinica.org/en/prevotella-copri-microbial-pathogenesis-rheumatoid/articulo/S1699258X1400223X/

9: Furusawa Y, Obata Y, Hase K. Commensal microbiota regulates T cell fate
decision in the gut. Semin Immunopathol. 2015 Jan;37(1):17-25. doi:
10.1007/s00281-014-0455-3. Epub 2014 Oct 15. Review. PubMed PMID: 25315350.
http://www.ncbi.nlm.nih.gov/pubmed/25315350

10: Si D, Li J, Liu J, Wang X, Wei Z, Tian Q, Wang H, Liu G. Progesterone
protects blood-brain barrier function and improves neurological outcome following
traumatic brain injury in rats. Exp Ther Med. 2014 Sep;8(3):1010-1014. Epub 2014
Jul 11. PubMed PMID: 25120639; PubMed Central PMCID: PMC4113529.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113529/

11: Sudo N. Microbiome, HPA axis and production of endocrine hormones in the gut.
Adv Exp Med Biol. 2014;817:177-94. doi: 10.1007/978-1-4939-0897-4_8. PubMed PMID:
24997034.
http://www.ncbi.nlm.nih.gov/pubmed/24997034

12: Scher JU, Sczesnak A, Longman RS, Segata N, Ubeda C, Bielski C, Rostron T,
Cerundolo V, Pamer EG, Abramson SB, Huttenhower C, Littman DR. Expansion of
intestinal Prevotella copri correlates with enhanced susceptibility to arthritis.
Elife. 2013 Nov 5;2:e01202. doi: 10.7554/eLife.01202. PubMed PMID: 24192039;
PubMed Central PMCID: PMC3816614.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816614/

13: Shapira I, Sultan K, Lee A, Taioli E. Evolving concepts: how diet and the
intestinal microbiome act as modulators of breast malignancy. ISRN Oncol. 2013
Sep 25;2013:693920. doi: 10.1155/2013/693920. Review. PubMed PMID: 24187630;
PubMed Central PMCID: PMC3800670.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800670/

14: Tanabe S. The effect of probiotics and gut microbiota on Th17 cells. Int Rev
Immunol. 2013 Oct-Dec;32(5-6):511-25. doi: 10.3109/08830185.2013.839665. Epub
2013 Oct 4. Review. PubMed PMID: 24094077.
http://www.ncbi.nlm.nih.gov/pubmed/24094077
15: Xu L, Dong B, Wang H, Zeng Z, Liu W, Chen N, Chen J, Yang J, Li D, Duan Y.
Progesterone suppresses Th17 cell responses, and enhances the development of
regulatory T cells, through thymic stromal lymphopoietin-dependent mechanisms in
experimental gonococcal genital tract infection. Microbes Infect. 2013
Nov;15(12):796-805. doi: 10.1016/j.micinf.2013.06.012. Epub 2013 Jul 5. PubMed
PMID: 23835188.
http://www.ncbi.nlm.nih.gov/pubmed/23835188

16: Wang HY, Gao WT, He QH, Yang C, Gu W, Yan J, Jiang JX. Endogenous
glucocorticoid increases the basal level of Treg-Th17 balance under early phase
of stress. Chin J Traumatol. 2012;15(6):323-8. PubMed PMID: 23186919.
http://www.ncbi.nlm.nih.gov/pubmed/23186919

17: Ghadimi D, Helwig U, Schrezenmeir J, Heller KJ, de Vrese M. Epigenetic
imprinting by commensal probiotics inhibits the IL-23/IL-17 axis in an in vitro
model of the intestinal mucosal immune system. J Leukoc Biol. 2012
Oct;92(4):895-911. doi: 10.1189/jlb.0611286. Epub 2012 Jun 22. PubMed PMID:
22730546.
http://www.ncbi.nlm.nih.gov/pubmed/22730546

18: Campeau JL, Salim SY, Albert EJ, Hotte N, Madsen KL. Intestinal epithelial
cells modulate antigen-presenting cell responses to bacterial DNA. Infect Immun.
2012 Aug;80(8):2632-44. doi: 10.1128/IAI.00288-12. Epub 2012 May 21. PubMed PMID:
22615241; PubMed Central PMCID: PMC3434593.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3434593/

19: Ait-Belgnaoui A, Durand H, Cartier C, Chaumaz G, Eutamene H, Ferrier L,
Houdeau E, Fioramonti J, Bueno L, Theodorou V. Prevention of gut leakiness by a
probiotic treatment leads to attenuated HPA response to an acute psychological
stress in rats. Psychoneuroendocrinology. 2012 Nov;37(11):1885-95. doi:
10.1016/j.psyneuen.2012.03.024. Epub 2012 Apr 26. PubMed PMID: 22541937.
http://www.ncbi.nlm.nih.gov/pubmed/22541937

20: Ekmekcioglu C. Are proinflammatory cytokines involved in an increased risk
for depression by unhealthy diets? Med Hypotheses. 2012 Feb;78(2):337-40. doi:
10.1016/j.mehy.2011.11.015. Epub 2011 Dec 6. PubMed PMID: 22153575.
http://www.ncbi.nlm.nih.gov/pubmed/22153575

21: López P, González-Rodríguez I, Gueimonde M, Margolles A, Suárez A. Immune
response to Bifidobacterium bifidum strains support Treg/Th17 plasticity. PLoS
One. 2011;6(9):e24776. doi: 10.1371/journal.pone.0024776. Epub 2011 Sep 22.
PubMed PMID: 21966367; PubMed Central PMCID: PMC3178565.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178565/

22: Reading NC, Kasper DL. The starting lineup: key microbial players in
intestinal immunity and homeostasis. Front Microbiol. 2011 Jul 7;2:148. doi:
10.3389/fmicb.2011.00148. eCollection 2011. PubMed PMID: 21779278; PubMed Central
PMCID: PMC3133820.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3133820/

23: Meyer J, Döring A, Herder C, Roden M, Koenig W, Thorand B. Dietary patterns,
subclinical inflammation, incident coronary heart disease and mortality in
middle-aged men from the MONICA/KORA Augsburg cohort study. Eur J Clin Nutr. 2011
Jul;65(7):800-7. doi: 10.1038/ejcn.2011.37. Epub 2011 Apr 6. PubMed PMID:
21468094.
http://www.ncbi.nlm.nih.gov/pubmed/21468094

24: Weinberg A, Enomoto L, Marcus R, Canniff J. Effect of menstrual cycle
variation in female sex hormones on cellular immunity and regulation. J Reprod
Immunol. 2011 Apr;89(1):70-7. doi: 10.1016/j.jri.2010.11.009. Epub 2011 Mar 22.
PubMed PMID: 21429588.
http://www.ncbi.nlm.nih.gov/pubmed/21429588

25: Srirangan S, Choy EH. The role of interleukin 6 in the pathophysiology of
rheumatoid arthritis. Ther Adv Musculoskelet Dis. 2010 Oct;2(5):247-56. doi:
10.1177/1759720X10378372. PubMed PMID: 22870451; PubMed Central PMCID:
PMC3383508.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383508/

26: Yates MA, Li Y, Chlebeck P, Proctor T, Vandenbark AA, Offner H. Progesterone
treatment reduces disease severity and increases IL-10 in experimental autoimmune
encephalomyelitis. J Neuroimmunol. 2010 Mar 30;220(1-2):136-9. doi:
10.1016/j.jneuroim.2010.01.013. Epub 2010 Feb 11. PubMed PMID: 20153059; PubMed
Central PMCID: PMC2835841.
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27: Ozdemir C, Akdis M, Akdis CA. T regulatory cells and their counterparts:
masters of immune regulation. Clin Exp Allergy. 2009 May;39(5):626-39. Review.
PubMed PMID: 19422105.
http://www.ncbi.nlm.nih.gov/pubmed/19422105

28: Lubberts E. IL-17/Th17 targeting: on the road to prevent chronic destructive
arthritis? Cytokine. 2008 Feb;41(2):84-91. Epub 2007 Nov 26. Review. PubMed PMID:
18039580.
http://www.ncbi.nlm.nih.gov/pubmed/18039580

29: Leite RS, Brown AG, Strauss JF 3rd. Tumor necrosis factor-alpha suppresses
the expression of steroid receptor coactivator-1 and -2: a possible mechanism
contributing to changes in steroid hormone responsiveness. FASEB J. 2004
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http://www.ncbi.nlm.nih.gov/pubmed/15231721

30: http://sbi4u3.weebly.com/endocrine-hormones-basic-mechanisms-and-the-menstrual-cycle.html

31: http://www.medicine.mcgill.ca/physio/vlab/other_exps/endo/reprod_horm.htm

32: https://en.wikipedia.org/wiki/Progesterone

33: http://www.hairloss-research.org/UpdateProgesterone5-08.html

In summary, the sex hormones estrogen and progesterone both inhibit inflammation via inhibition of the IL-6 and IL-17 cytokines. These are the immune molecules that target the actual joint tissue in RA, and they are produced by T-helper cells, which are regulated by T-regulatory cells, which talk to gut bacteria across the intestinal wall to get their instructions. So, healthier gut bacteria means better immune control. Healthier gut bacteria also means better hormone levels and better hormone sensitivity, so it’s a win-win. If getting pregnant is not in your immediate future, and the brief hormone boost afforded by menses is insufficient, supplementation with progesterone may be worth considering in addition to a microbiome-healthy diet with good prebiotics and probiotics. Of course, all of these decisions are best made with the help of some labwork when possible. Identifying your existing microbiome can help to point the direction for improvement whether that means growing more Bifidobacteria or inhibiting the growth of Prevotella copri. In any case, optimize your hormones, and get those symbionts in shape so they can retrain your immune system!

References:

1: Andersson A, Grahnemo L, Engdahl C, Stubelius A, Lagerquist MK, Carlsten H,

Islander U. IL-17-producing γδT cells are regulated by estrogen during

development of experimental arthritis. Clin Immunol. 2015 Sep 28;161(2):324-332.

doi: 10.1016/j.clim.2015.09.014. [Epub ahead of print] PubMed PMID: 26423309.

http://www.ncbi.nlm.nih.gov/pubmed/26423309

2: Kim KW, Kim HR, Kim BM, Cho ML, Lee SH. Th17 Cytokines Regulate

Osteoclastogenesis in Rheumatoid Arthritis. Am J Pathol. 2015 Sep 8. pii:

S0002-9440(15)00445-9. doi: 10.1016/j.ajpath.2015.07.017. [Epub ahead of print]

PubMed PMID: 26362732.

http://www.ncbi.nlm.nih.gov/pubmed/26362732

3: Mortaz E, Adcock IM, Ricciardolo FL, Varahram M, Jamaati H, Velayati AA,

Folkerts G, Garssen J. Anti-Inflammatory Effects of Lactobacillus Rahmnosus and

Bifidobacterium Breve on Cigarette Smoke Activated Human Macrophages. PLoS One.

2015 Aug 28;10(8):e0136455. doi: 10.1371/journal.pone.0136455. eCollection 2015.

PubMed PMID: 26317628; PubMed Central PMCID: PMC4552661.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4552661/

4: Gluhovschi C, Gluhovschi G, Petrica L, Velciov S, Gluhovschi A. Pregnancy

Associated with Systemic Lupus Erythematosus: Immune Tolerance in Pregnancy and

Its Deficiency in Systemic Lupus Erythematosus–An Immunological Dilemma. J

Immunol Res. 2015;2015:241547. doi: 10.1155/2015/241547. Epub 2015 May 18.

Review. PubMed PMID: 26090485; PubMed Central PMCID: PMC4451247.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451247/

5: Tang H, Hua F, Wang J, Yousuf S, Atif F, Sayeed I, Stein DG. Progesterone and

vitamin D combination therapy modulates inflammatory response after traumatic

brain injury. Brain Inj. 2015 Jun 17:1-10. [Epub ahead of print] PubMed PMID:

26083048.

http://www.ncbi.nlm.nih.gov/pubmed/26083048

6: Carasi P, Racedo SM, Jacquot C, Romanin DE, Serradell MA, Urdaci MC. Impact of

kefir derived Lactobacillus kefiri on the mucosal immune response and gut

microbiota. J Immunol Res. 2015;2015:361604. doi: 10.1155/2015/361604. Epub 2015

Feb 24. PubMed PMID: 25811034; PubMed Central PMCID: PMC4355334.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4355334/

7: Garling RJ, Watts LT, Sprague S, Fletcher L, Jimenez DF, Digicaylioglu M. Does

progesterone show neuroprotective effects on traumatic brain injury through

increasing phosphorylation of Akt in the hippocampus? Neural Regen Res. 2014 Nov

1;9(21):1891-6. doi: 10.4103/1673-5374.145355. PubMed PMID: 25558238; PubMed

Central PMCID: PMC4281427.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281427/

8: Moreno J. Prevotella copri and the microbial pathogenesis of rheumatoid

arthritis. Reumatol Clin. 2015 Mar-Apr;11(2):61-3. doi:

10.1016/j.reuma.2014.11.001. Epub 2014 Dec 30. English, Spanish. PubMed PMID:

25555460.

http://www.reumatologiaclinica.org/en/prevotella-copri-microbial-pathogenesis-rheumatoid/articulo/S1699258X1400223X/

9: Furusawa Y, Obata Y, Hase K. Commensal microbiota regulates T cell fate

decision in the gut. Semin Immunopathol. 2015 Jan;37(1):17-25. doi:

10.1007/s00281-014-0455-3. Epub 2014 Oct 15. Review. PubMed PMID: 25315350.

http://www.ncbi.nlm.nih.gov/pubmed/25315350

10: Si D, Li J, Liu J, Wang X, Wei Z, Tian Q, Wang H, Liu G. Progesterone

protects blood-brain barrier function and improves neurological outcome following

traumatic brain injury in rats. Exp Ther Med. 2014 Sep;8(3):1010-1014. Epub 2014

Jul 11. PubMed PMID: 25120639; PubMed Central PMCID: PMC4113529.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113529/

11: Sudo N. Microbiome, HPA axis and production of endocrine hormones in the gut.

Adv Exp Med Biol. 2014;817:177-94. doi: 10.1007/978-1-4939-0897-4_8. PubMed PMID:

24997034.

http://www.ncbi.nlm.nih.gov/pubmed/24997034

12: Scher JU, Sczesnak A, Longman RS, Segata N, Ubeda C, Bielski C, Rostron T,

Cerundolo V, Pamer EG, Abramson SB, Huttenhower C, Littman DR. Expansion of

intestinal Prevotella copri correlates with enhanced susceptibility to arthritis.

Elife. 2013 Nov 5;2:e01202. doi: 10.7554/eLife.01202. PubMed PMID: 24192039;

PubMed Central PMCID: PMC3816614.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816614/

13: Shapira I, Sultan K, Lee A, Taioli E. Evolving concepts: how diet and the

intestinal microbiome act as modulators of breast malignancy. ISRN Oncol. 2013

Sep 25;2013:693920. doi: 10.1155/2013/693920. Review. PubMed PMID: 24187630;

PubMed Central PMCID: PMC3800670.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800670/

14: Tanabe S. The effect of probiotics and gut microbiota on Th17 cells. Int Rev

Immunol. 2013 Oct-Dec;32(5-6):511-25. doi: 10.3109/08830185.2013.839665. Epub

2013 Oct 4. Review. PubMed PMID: 24094077.

http://www.ncbi.nlm.nih.gov/pubmed/24094077

15: Xu L, Dong B, Wang H, Zeng Z, Liu W, Chen N, Chen J, Yang J, Li D, Duan Y.

Progesterone suppresses Th17 cell responses, and enhances the development of

regulatory T cells, through thymic stromal lymphopoietin-dependent mechanisms in

experimental gonococcal genital tract infection. Microbes Infect. 2013

Nov;15(12):796-805. doi: 10.1016/j.micinf.2013.06.012. Epub 2013 Jul 5. PubMed

PMID: 23835188.

http://www.ncbi.nlm.nih.gov/pubmed/23835188

16: Wang HY, Gao WT, He QH, Yang C, Gu W, Yan J, Jiang JX. Endogenous

glucocorticoid increases the basal level of Treg-Th17 balance under early phase

of stress. Chin J Traumatol. 2012;15(6):323-8. PubMed PMID: 23186919.

http://www.ncbi.nlm.nih.gov/pubmed/23186919

17: Ghadimi D, Helwig U, Schrezenmeir J, Heller KJ, de Vrese M. Epigenetic

imprinting by commensal probiotics inhibits the IL-23/IL-17 axis in an in vitro

model of the intestinal mucosal immune system. J Leukoc Biol. 2012

Oct;92(4):895-911. doi: 10.1189/jlb.0611286. Epub 2012 Jun 22. PubMed PMID:

22730546.

http://www.ncbi.nlm.nih.gov/pubmed/22730546

18: Campeau JL, Salim SY, Albert EJ, Hotte N, Madsen KL. Intestinal epithelial

cells modulate antigen-presenting cell responses to bacterial DNA. Infect Immun.

2012 Aug;80(8):2632-44. doi: 10.1128/IAI.00288-12. Epub 2012 May 21. PubMed PMID:

22615241; PubMed Central PMCID: PMC3434593.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3434593/

19: Ait-Belgnaoui A, Durand H, Cartier C, Chaumaz G, Eutamene H, Ferrier L,

Houdeau E, Fioramonti J, Bueno L, Theodorou V. Prevention of gut leakiness by a

probiotic treatment leads to attenuated HPA response to an acute psychological

stress in rats. Psychoneuroendocrinology. 2012 Nov;37(11):1885-95. doi:

10.1016/j.psyneuen.2012.03.024. Epub 2012 Apr 26. PubMed PMID: 22541937.

http://www.ncbi.nlm.nih.gov/pubmed/22541937

20: Ekmekcioglu C. Are proinflammatory cytokines involved in an increased risk

for depression by unhealthy diets? Med Hypotheses. 2012 Feb;78(2):337-40. doi:

10.1016/j.mehy.2011.11.015. Epub 2011 Dec 6. PubMed PMID: 22153575.

http://www.ncbi.nlm.nih.gov/pubmed/22153575

21: López P, González-Rodríguez I, Gueimonde M, Margolles A, Suárez A. Immune

response to Bifidobacterium bifidum strains support Treg/Th17 plasticity. PLoS

One. 2011;6(9):e24776. doi: 10.1371/journal.pone.0024776. Epub 2011 Sep 22.

PubMed PMID: 21966367; PubMed Central PMCID: PMC3178565.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178565/

22: Reading NC, Kasper DL. The starting lineup: key microbial players in

intestinal immunity and homeostasis. Front Microbiol. 2011 Jul 7;2:148. doi:

10.3389/fmicb.2011.00148. eCollection 2011. PubMed PMID: 21779278; PubMed Central

PMCID: PMC3133820.

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