Skip to main content
SpringerLink
Log in

Lactic acid alleviates stress: good for female genital tract homeostasis, bad for protection against malignancy

  • Perspective and Reflection Article
  • Published:
Cell Stress and Chaperones Aims and scope

Abstract

Women are unique from all other mammals in that lactic acid is present at high levels in the vagina during their reproductive years. This dominance may have evolved in response to the unique human lifestyle and a need to optimally protect pregnant women and their fetuses from endogenous and exogenous insults. Lactic acid in the female genital tract inactivates potentially pathogenic bacteria and viruses, maximizes survival of vaginal epithelial cells, and inhibits inflammation that may be damaging to the developing fetus and maintenance of the pregnancy. In an analogous manner, lactic acid production facilitates survival of malignantly transformed cells, inhibits activation of immune cells, and prevents the release of pro-inflammatory mediators in response to tumor-specific antigens. Thus, the same stress-reducing properties of lactic acid that promote lower genital tract health facilitate malignant transformation and progression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Alakomi H-L, Skytta E, Saarela M, Mattila-Sandholm T, Latva-Kala K, Helander IM (2000) Lactic acid permeabilizes gram-negative bacteria by disrupting the outer membrane. Appl Environ Microbiol 66:2001–2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aldunate M, Tyssen D, Johnson A, Zakir T, Sonza S, Moench T, Cone R, Tachedijan G (2013) Vaginal concentrations of lactic acid potently inactivate HIV. J Antimicrob Chemother 68:2015–2025

  • Aldunate M, Sribinovski D, Hearps AC, Latham CF, Ramsland PA, Gugasyan R, Cone RA, Tachedijan G (2015) Antimicrobial and immune modulatory effects of lactic acid and short chain fatty acids produced by vaginal microbiota associated with eubiosis and bacterial vaginosis. Front Physiol 6:164

    Article  PubMed  PubMed Central  Google Scholar 

  • Ayre WB (1951) The glycogen-estrogen relationship in the vaginal tract. J Clin Endocrinol Metab 11:103–110

  • Bhaskara S (2015) Histone deacetylases 1 and 2 regulate DNA replication and DNA repair: potential targets for genome stability-mechanism-based therapeutics for a subset of cancers. Cell Cycle 14:1779–1785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bo WJ (1970) The effect of progesterone and progesterone-estrogen on the glycogen deposition in the vagina of the squirrel monkey. Am J Obstet Gynecol 107:524–530

    Article  CAS  PubMed  Google Scholar 

  • Boskey ER, Cone RA, Whaley KJ, Moench TR (2001) Origins of vaginal acidity: high D/L lactate ratio is consistent with bacteria being the primary source. Hum Reprod 16:1809–1813

  • Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, Matos C et al (2016) LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab 24:657–671

    Article  CAS  PubMed  Google Scholar 

  • Bronte V (2014) Tumor cells hijack macrophages via lactic acid. Immunol Cell Biol 92:647–649

    Article  CAS  PubMed  Google Scholar 

  • Chang C-H, Qiu J, O’Sullivan D, Buck MD, Noguchi T, Curtis JD (2015) Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162:1229–1241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng Y, Chen G, Hong L, Zhou L, Hu M, Li B, Huang J, Xia L, Li C (2013) How does hypoxia inducible factor-1α participate in enhancing the glycolysis activity in cervical cancer? Ann Diagn Pathol 17:305–311

    Article  PubMed  Google Scholar 

  • Choi SYC, Collins CC, Gout PW, Wang Y (2013) Cancer-generated lactic acid: a regulatory, immunosuppressive metabolite? J Pathol 230:350–355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clark GN (2009) Etiology of sperm immunity in women. Fertil Steril 91:639–643

    Article  Google Scholar 

  • Colegio OR (2015) Lactic acid polarizes macrophages to a tumor-promoting state. Oncoimmunology 5:e1014774

    Article  PubMed  PubMed Central  Google Scholar 

  • Colegio OR, Chu N-Q, Szabo AL, Chu T, Rhebergen AM, Jairam V, Cyrus N et al (2014) Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513:559–563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Conti C, Malacrino C, Mastromarino P (2009) Inhibition of herpes simplex virus type 2 by vaginal lactobacilli. J Physiol Pharmacol 60(Suppl 6):19–26

    PubMed  Google Scholar 

  • Dietl K, Renner K, Dettmer K, Timischi B, Eberhart K, Dorn C, Hellerbrand C et al (2010) Lactic acid and acidification inhibit TNF secretion and glycolysis of human monocytes. J Immunol 184:1200–1209

  • Eckert LO, Moore DE, Patton DL, Agnew KJ, Eschenbach DA (2003) Relationship of vaginal bacteria and inflammation with conception and early pregnancy loss following in-vitro fertilization. Infect Dis Obstet Gynecol 11:11–17

    Article  PubMed  PubMed Central  Google Scholar 

  • Fantin VR, St-Pierre J, Leder P (2006) Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9:425–434

    Article  CAS  PubMed  Google Scholar 

  • Feng D, Wu J, Tian Y, Zhou H, Zhou Y, Hu W, Zhao W et al (2013) Targeting of histone deacetylases to reactivate tumour suppressor genes and its therapeutic potential in a human cervical cancer xenograft model. PLoS One 8(11):e80657

    Article  PubMed  PubMed Central  Google Scholar 

  • Fischer K, Hoffmann P, Voelkl S, Meichenbauer N, Ammer J, Edinger M, Gottfried E et al (2007) Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109:3812–3819

    Article  CAS  PubMed  Google Scholar 

  • Ghadimi D, de Vrese M, Heller KJ, Schrezenmeir J (2010) Lactic acid bacteria enhance autophagic activity of mononuclear phagocytes by increasing Th1 autophagy-promoting cytokine (IFN-g) and nitric oxide (NO) levels and reducing Th2 autophagy-restraining cytokines (IL-4 and IL-13) in response to Mycobacterium tuberculosis antigen. Int Immunopharmacol 10:694–706

    Article  CAS  PubMed  Google Scholar 

  • Gong Z, Luna Y, Yu P, Fan H (2014) Lactobacilli inactivate Chlamydia trachomatis through lactic acid but not H2O2. PLoS One 9(9):e107758

    Article  PubMed  PubMed Central  Google Scholar 

  • Graver MA, Wade JJ (2011) The role of acidification in the inhibition of Neisseria gonorrhoeae by vaginal lactobacilli during anaerobic growth. Ann Clin Microbiol Antimicrob 10:8

  • Gross M (1961) Biochemical changes in the reproductive cycle. Fertil Steril 12:245–262

    Article  CAS  PubMed  Google Scholar 

  • Haas R, Smith J, Rocher-Ros V, Nadkarni S, Montero-Melendez T, D’Acquiisto F, Bland EJ et al (2015) Lactate regulates metabolic and pro-inflammatory circuits in control of T cell migration and effector functions. PLoS Biol 13(7):e1002202

    Article  PubMed  PubMed Central  Google Scholar 

  • Hearps AC, Tyssen D, Srbinovski D, Bayigga L, Diaz DJD, Aldunate M, Cone RA et al (2017) Vaginal lactic acid elicits an anti-inflammatory response from human cervicovaginal epithelial cells and inhibits production of pro-inflammatory mediators associated with HIV acquisition. Mucosal Immunol. https://doi.org/10.1038/mi2017/27

  • Hsu PP, Sabatini DM (2008) Cancer cell metabolism: Warburg and beyond. Cell 134:703–707

    Article  CAS  PubMed  Google Scholar 

  • Huggins GR, Preti G (1976) Volatile constituents of human vaginal secretions. Am J Obstet Gynecol 126:129–136

  • Jang SE, Hyam SR, Han MJ, Kim SY, Lee BG, Kim DH (2013) Lactobacillus brevis G-101 ameliorates colitis in mice by inhibiting NF-kappaB, MAPK and AKT pathways and by polarizing M1 macrophages to M2-like macrophages. J Appl Microbiol 115:888–896

  • Kelly RDW, Cowley SM (2013) The physiological roles of histone deacetylase (HDAC) 1 and 2: complex co-stars with multiple leading parts. Biochem Soc Trans 41:741–749

    Article  CAS  PubMed  Google Scholar 

  • Lardner A (2001) The effect of extracellular pH on immune function. J Leukoc Biol 69:522–530

    CAS  PubMed  Google Scholar 

  • Latham T, Mackay L, Sprout D, Karim M, Culley J, Harrison DJ, Hayward L et al (2012) Lactate, a product of glycolytic metabolism, inhibits histone deacetylase activity and promotes changes in gene expression. Nucleic Acid Res 40:4794–4803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leizer J, Nasioudis D, Forney LJ, Schneider GM, Gliniewicz K, Boester A, Witkin SS (2017) Properties of epithelial cells and vaginal secretions in pregnant women when Lactobacillus crispatus or Lactobacillus iners dominate the vaginal microbiome. Reprod Sci. https://doi.org/10.1177/1933719117698583

  • Lin AE, Beasley FC, Olson J, Keller N, Shalwitz RA, Hannan TJ, Hultgren SJ, Nizet V (2015) Role of hypoxia inducible factor-1α (HIF-1α) in innate defense against uropathogenic Escherichia coli infection. PLoS Pathog 11(4):e1004818

    Article  PubMed  PubMed Central  Google Scholar 

  • Linhares IM, Summers PR, Larsen B, Giraldo PC, Witkin SS (2011) Contemporary perspectives on vaginal pH and lactobacilli. Am J Obstet Gynecol 204:120.e1–120.e5

    Article  Google Scholar 

  • Lynch SV, Pedersen O (2016) The human intestinal microbiome in health and disease. N Engl J Med 375:2369–2379

    Article  CAS  PubMed  Google Scholar 

  • Ma P, Schultz RM (2008) Histone deacetylase 1 (HDAC1) regulates histone acetylation, development, and gene expression in preimplantation mouse embryos. Dev Biol 319:110–120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Masson L, Salkinder AL, Olivier AJ, Mckinnon LR, Gamieldien H, Mlisana K, Scriba TJ et al (2015) Relationship between female genital tract infections, mucosal interleukin-17 production and local T helper type 17 cells. Immunology 146:557–567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McInturff AM, Cody MJ, Elliott EA, Glenn JW, Rowley JW, Rondina MT, Yost CC (2012) Mammalian target of rapamycin regulates neutrophil extracellular trap formation via induction of hypoxia-inducible factor 1α. Blood 120:3118–3125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Montezuma D, Henrique R, Jeronimo C (2015) Altered expression of histone deacetylases in cancer. Crit Rev Oncog 20:19–34

    Article  PubMed  Google Scholar 

  • Nasioudis D, Beghini J, Bongiovanni AM, Giraldo PC, Linhares IM, Witkin SS (2015) α amylase in vaginal fluid: association with conditions favorable to dominance of lactobacillus. Reprod Sci 22:393–398

    Article  Google Scholar 

  • O’Hanlon DE, Moench TR, Cone RA (2011) In vaginal fluid, bacteria associated with bacterial vaginosis can be suppressed with lactic acid but not hydrogen peroxide. BMC Infect Dis 11:200

    Article  PubMed  PubMed Central  Google Scholar 

  • Orfanelli T, Jeong JM, Doulaveris G, Holcomb K, Witkin SS (2014) Involvement of autophagy in cervical, endometrial and ovarian cancer. Int J Cancer 135:519–528

    Article  CAS  PubMed  Google Scholar 

  • Preti G, Huggins GR (1975) Cyclic changes in volatile acidic metabolites of human vaginal secretions and their relation to ovulation. J Chem Ecol 1:361–376

    Article  CAS  Google Scholar 

  • Ramos BR, Witkin SS (2016) The influence of oxidative stress and autophagy cross regulation on pregnancy outcome. Cell Stress Chaperones 21:755–762

    Article  Google Scholar 

  • Romero R, Hassan SS, Gajer P, Tarca AL, Fadrosh DW, Nikita L, Galuppi M et al (2014) The composition and stability of the vaginal microbiota of normal pregnant women is different from that of non-pregnant women. Microbiome 2:4

    Article  PubMed  PubMed Central  Google Scholar 

  • Shime H, Yabu M, Akazawa T, Kodama K, Matsumoto M, Seya T, Inoue N (2008) Tumor-secreted lactic acid promotes IL-23/IL-17 proinflammatory pathway. J Immunol 180:7175–7183

  • Spear GT, French AL, Gilbert D, Zaniffard MR, Mirmonsef P, Sullivan TH, Spear WW et al (2014) Human α-amylase present in lower-genital-tract mucosal fluid processes glycogen to support vaginal colonization by lactobacillus. J Infect Dis 210:1019–1028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stern R, Shuster S, Neudecker BA, Formby B (2002) Lactate stimulates fibroblast expression of hyaluronan and CD44: the Warburg effect revisited. Exp Cell Res 276:24–31

    Article  CAS  PubMed  Google Scholar 

  • Stumpf RM, Wilson BA, Rivera A, Yildirim S, Yeoman CJ, Polk JD, White BA, Leigh SR (2013) The primate vaginal microbiome: comparative context and implications for human health and disease. Am J Phys Anthropol 57:119–134

    Article  Google Scholar 

  • Wagner W, Ciszewski WM, Kania KD (2015) L- and D- lactate enhance DNA repair and modulate the resistance of cervical carcinoma cells to anticancer drugs via histone deacetylase inhibition and hydroxycarboxylic acid receptor 1 activation. Cell Commun Signal 13:36

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang C-W, Klionsky DJ (2003) The molecular mechanism of autophagy. Mol Med 9:65–76

    PubMed  PubMed Central  Google Scholar 

  • Warburg O (1956) On the origin of cancer cells. Science 324:1029–1033

    Google Scholar 

  • Webb BA, Chimenti M, Jacobson MP, Barber DL (2011) Disregulated pH: a perfect storm for cancer progression. Nat Rev Cancer 11:671–677

    Article  CAS  PubMed  Google Scholar 

  • Witkin SS (2015) The vaginal microbiome, vaginal anti-microbial defence mechanisms and the clinical challenge of reducing infection-related preterm birth. BJOG 122:213–218

    Article  CAS  PubMed  Google Scholar 

  • Witkin SS, Ledger WJ (2012) Complexities of the uniquely human vagina. Sci Transl Med 4:132fs11

  • Witkin SS, Linhares IM (2017) Why do lactobacilli dominate the human vaginal microbiota? BJOG 124:606–611

    Article  CAS  PubMed  Google Scholar 

  • Witkin SS, Alvi S, Bongiovanni AM, Linhares IM, Ledger WJ (2011) Lactic acid stimulates interleukin-23 production by peripheral blood mononuclear cells exposed to bacterial liposaccharide. FEMS Immunol Med Microbiol 61:153–158

    Article  CAS  PubMed  Google Scholar 

  • Witkin SS, Mendes-Soares H, Linhares IM, Jayaram A, Ledger WJ, Forney LJ (2013) Influence of vaginal bacteria and D- and L- lactic acid isomers on vaginal extracellular matrix metalloproteinase inducer: implications for protection against upper genital tract infections. MBio 4:e00460–e00413

  • Xu L, Zhang X, Li Y, Lu S, Lu S, Li J, Wang Y et al (2016) Neferine induces autophagy of human ovarian cancer cells via p38 MAPK/JNK activation. Tumour Biol 37:8721–8729

    Article  CAS  PubMed  Google Scholar 

  • Yabu M, Shime H, Hara H, Saito T, Matsumoto M, Seya T, Akazawa T, Inoue N (2011) IL-12-dependent and -independent enhancement pathways of IL-17A production by lactic acid. Int Immunol 23:29–41

    Article  CAS  PubMed  Google Scholar 

  • Yildirim S, Yeoman CJ, Janga SC, Thomas SM, Ho M, Leigh SR et al (2014) Primate vaginal microbiomes exhibit species specificity without universal Lactobacillus dominance. ISME J 8:2431–2444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou X, Bent SJ, Schneider MG, Davis CC, Islam MR, Forney LJ (2004) Characterization of vaginal microbial communities in adult healthy women using cultivation-independent methods. Microbiology 150:2565–2573

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Immunology and Infectious Diseases, Department of Obstetrics and Gynecology, Weill Cornell Medicine, 1300 York Avenue, Box 35, New York, NY, 10065, USA

    Steven S. Witkin

Authors
  1. Steven S. Witkin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Steven S. Witkin.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Witkin, S.S. Lactic acid alleviates stress: good for female genital tract homeostasis, bad for protection against malignancy. Cell Stress and Chaperones 23, 297–302 (2018). https://doi.org/10.1007/s12192-017-0852-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12192-017-0852-3

Keywords

Search

Navigation