Sex differences matter in the gut: Effect on mucosal immune activation and inflammation

Sumathi Sankaran-Walters, Monica Macal, Irina Grishina, Lauren Nagy, Larissa Goulart, Kathryn Coolidge, Jay Li, Anne Fenton, Theodore Williams, Mary K. Miller, Jason Flamm, Thomas P Prindiville, Michael George, Satya Dandekar

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Background: Women and men have diverse responses to many infectious diseases. These differences are amplified following menopause. However, despite extensive information regarding the effects of sex hormones on immune cells, our knowledge is limited regarding the effects of sex and gender on the function of the mucosal immune system. Sex differences also manifest in the prevalence of gut associated inflammatory and autoimmune disorders, including Crohn's disease, ulcerative colitis and Celiac disease. It is thus hypothesized that a baseline sex-associated difference in immune activation may predispose women to inflammation-associated disease. Methods: Peripheral blood samples and small intestinal biopsies were obtained from 34 healthy men and women. Immunophenotypic analysis of isolated lymphocytes was performed by flow cytometry. Oligonucleotide analysis was used to study the transcriptional profile in the gut mucosal microenvironment while real-time PCR analysis was utilized to identify differential gene expression in isolated CD4+ T cells. Transcriptional analysis was confirmed by protein expression levels for genes of interest using fluorescent immunohistochemistry. Data was analyzed using the GraphPad software package. Results: Women had higher levels of immune activation and inflammation-associated gene expression in gut mucosal samples. CD4+ and CD8+ T cells had a significantly higher level of immune activation-associated phenotype in peripheral blood as well as in gut associated lymphoid tissue along with higher levels of proliferating T cells. CD4+ T cells that showed upregulation of IL1β as well as the TH17 pathway-associated genes contributed a large part of the inflammatory profile. Conclusion: In this study, we demonstrated an upregulation in gene expression related to immune function in the gut microenvironment of women compared to men, in the absence of disease or pathology. Upon closer investigation, CD4+ T cell activation levels were higher in the LPLs in women than in men. Sex differences in the mucosal immune system may predispose women to inflammation-associated diseases that are exacerbated following menopause. Our study highlights the need for more detailed analysis of the effects of sex differences in immune responses at mucosal effector sites.

Original languageEnglish (US)
Article number10
JournalBiology of Sex Differences
Volume4
Issue number1
DOIs
StatePublished - 2013

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Sex Characteristics
activation
Inflammation
Disease
T-Lymphocytes
Gene Expression
menopause
Menopause
Immune System
Up-Regulation
Mucosal Immunity
Gonadal Steroid Hormones
Celiac Disease
Lymphoid Tissue
Ulcerative Colitis
pathology
Oligonucleotides
Crohn Disease
contagious disease
Communicable Diseases

ASJC Scopus subject areas

  • Endocrinology
  • Gender Studies

Cite this

Sex differences matter in the gut : Effect on mucosal immune activation and inflammation. / Sankaran-Walters, Sumathi; Macal, Monica; Grishina, Irina; Nagy, Lauren; Goulart, Larissa; Coolidge, Kathryn; Li, Jay; Fenton, Anne; Williams, Theodore; Miller, Mary K.; Flamm, Jason; Prindiville, Thomas P; George, Michael; Dandekar, Satya.

In: Biology of Sex Differences, Vol. 4, No. 1, 10, 2013.

Research output: Contribution to journalArticle

Sankaran-Walters, S, Macal, M, Grishina, I, Nagy, L, Goulart, L, Coolidge, K, Li, J, Fenton, A, Williams, T, Miller, MK, Flamm, J, Prindiville, TP, George, M & Dandekar, S 2013, 'Sex differences matter in the gut: Effect on mucosal immune activation and inflammation', Biology of Sex Differences, vol. 4, no. 1, 10. https://doi.org/10.1186/2042-6410-4-10
Sankaran-Walters, Sumathi ; Macal, Monica ; Grishina, Irina ; Nagy, Lauren ; Goulart, Larissa ; Coolidge, Kathryn ; Li, Jay ; Fenton, Anne ; Williams, Theodore ; Miller, Mary K. ; Flamm, Jason ; Prindiville, Thomas P ; George, Michael ; Dandekar, Satya. / Sex differences matter in the gut : Effect on mucosal immune activation and inflammation. In: Biology of Sex Differences. 2013 ; Vol. 4, No. 1.
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abstract = "Background: Women and men have diverse responses to many infectious diseases. These differences are amplified following menopause. However, despite extensive information regarding the effects of sex hormones on immune cells, our knowledge is limited regarding the effects of sex and gender on the function of the mucosal immune system. Sex differences also manifest in the prevalence of gut associated inflammatory and autoimmune disorders, including Crohn's disease, ulcerative colitis and Celiac disease. It is thus hypothesized that a baseline sex-associated difference in immune activation may predispose women to inflammation-associated disease. Methods: Peripheral blood samples and small intestinal biopsies were obtained from 34 healthy men and women. Immunophenotypic analysis of isolated lymphocytes was performed by flow cytometry. Oligonucleotide analysis was used to study the transcriptional profile in the gut mucosal microenvironment while real-time PCR analysis was utilized to identify differential gene expression in isolated CD4+ T cells. Transcriptional analysis was confirmed by protein expression levels for genes of interest using fluorescent immunohistochemistry. Data was analyzed using the GraphPad software package. Results: Women had higher levels of immune activation and inflammation-associated gene expression in gut mucosal samples. CD4+ and CD8+ T cells had a significantly higher level of immune activation-associated phenotype in peripheral blood as well as in gut associated lymphoid tissue along with higher levels of proliferating T cells. CD4+ T cells that showed upregulation of IL1β as well as the TH17 pathway-associated genes contributed a large part of the inflammatory profile. Conclusion: In this study, we demonstrated an upregulation in gene expression related to immune function in the gut microenvironment of women compared to men, in the absence of disease or pathology. Upon closer investigation, CD4+ T cell activation levels were higher in the LPLs in women than in men. Sex differences in the mucosal immune system may predispose women to inflammation-associated diseases that are exacerbated following menopause. Our study highlights the need for more detailed analysis of the effects of sex differences in immune responses at mucosal effector sites.",
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AU - Li, Jay

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