title: Sex differences matter in the gut: effect on mucosal immune activation and inflammation.
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.
  
  
  CONCLUSIONS
  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.
authors: Department of Medical Microbiology and Immunology, University of CA Davis Health System, 5605A GBSF, 451 Health Sciences Drive, Davis, CA 95616, USA. ssankara@ucdavis.edu.
authors: Sumathi
authors: S
authors: Sankaran-Walters
authors: Monica
authors: M
authors: Macal
authors: Irina
authors: I
authors: Grishina
authors: Lauren
authors: L
authors: Nagy
authors: Larissa
authors: L
authors: Goulart
authors: Kathryn
authors: K
authors: Coolidge
authors: Jay
authors: J
authors: Li
authors: Anne
authors: A
authors: Fenton
authors: Theodore
authors: T
authors: Williams
authors: Mary K
authors: MK
authors: Miller
authors: Jason
authors: J
authors: Flamm
authors: Thomas
authors: T
authors: Prindiville
authors: Michael
authors: M
authors: George
authors: Satya
authors: S
authors: Dandekar
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