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. 2018 Jun 13;32(12):fj201800560R.
doi: 10.1096/fj.201800560R. Online ahead of print.

Sex differences in NSAID-induced perturbation of human intestinal barrier function and microbiota

Shoko Edogawa  1 , Stephanie A Peters  1 , Gregory D Jenkins  2   3 , Sakteesh V Gurunathan  1 , Wendy J Sundt  1 , Stephen Johnson  2   3 , Ryan J Lennon  2 , Roy B Dyer  4 , Michael Camilleri  1 , Purna C Kashyap  1 , Gianrico Farrugia  5 , Jun Chen  2 , Ravinder J Singh  4 , Madhusudan Grover  1
Affiliations

Sex differences in NSAID-induced perturbation of human intestinal barrier function and microbiota

Shoko Edogawa et al. FASEB J. .

Abstract

Intestinal barrier function and microbiota are integrally related and play critical roles in maintenance of host physiology. Sex is a key biologic variable for several disorders. Our aim was to determine sex-based differences in response to perturbation and subsequent recovery of intestinal barrier function and microbiota in healthy humans. Twenty-three volunteers underwent duodenal biopsies, mucosal impedance, and in vivo permeability measurement. Permeability testing was repeated after administration of indomethacin, then 4 to 6 wk after its discontinuation. Duodenal and fecal microbiota composition was determined using 16S rRNA amplicon sequencing. Healthy women had lower intestinal permeability and higher duodenal and fecal microbial diversity than healthy men. Intestinal permeability increases after indomethacin administration in both sexes. However, only women demonstrated decreased fecal microbial diversity, including an increase in Prevotella abundance, after indomethacin administration. Duodenal microbiota composition did not show sex-specific changes. The increase in permeability and microbiota changes normalized after discontinuation of indomethacin. In summary, women have lower intestinal permeability and higher microbial diversity. Intestinal permeability is sensitive to perturbation but recovers to baseline. Gut microbiota in women is sensitive to perturbation but appears to be more stable in men. Sex-based differences in intestinal barrier function and microbiome should be considered in future studies.-Edogawa, S., Peters, S. A., Jenkins, G. D., Gurunathan, S. V., Sundt, W. J., Johnson, S., Lennon, R. J., Dyer, R. B., Camilleri, M., Kashyap, P. C., Farrugia, G., Chen, J., Singh, R. J., Grover, M. Sex differences in NSAID-induced perturbation of human intestinal barrier function and microbiota.

Keywords: gender; indomethacin; lactulose; microbiome; permeability.

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Conflict of interest statement

The authors thank L. Anderson (Mayo Clinic) for administrative assistance. This project was funded by grants from the Mayo Clinic Department of Laboratory Medicine and Pathology, Mayo Clinic Division of Gastroenterology and Hepatology, and by the U.S. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grant K23 DK103911 (to M.G.). J.C. is supported by Mayo Clinic Center for Individualized Medicine. M.G. has served on the advisory board or received research support from Takeda, DongA, Ironwood, and Napo. The remaining authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Sex-based differences in permeability and microbiome of proximal small intestine. A) Healthy women have significantly lower in vivo proximal small intestinal permeability (0–2 h lactulose excretion) than healthy men. B) Healthy women have higher duodenal TMR compared to healthy men. C) Duodenal impedance measured in vivo using endoscopic catheter; results indicated women had tendency to have higher duodenal impedance compared to men. D) Healthy women have greater microbial diversity than healthy men. Data are presented as means ± sd; n = 10–12/group.
Figure 2
Figure 2
Sex-based differences in permeability of distal small intestine/colon and fecal microbiome. A) Healthy women showed significantly lower in vivo distal small intestinal and colonic permeability (2–24 h lactulose excretion) than healthy men. B) Alpha diversity [observed (P = 0.026), Chao1 estimator (P = 0.044), Shannon index (P = 0.011), Inverse Simpson index (P = 0.053), unpaired t test] was higher in women. C) β diversity [UniFrac (P = 0.005), GUniFrac (P = 0.001), WUniFrac (P = 0.001), Bray Curtis (P = 0.030), PERMANOVA] was higher in women compared to men.
Figure 3
Figure 3
Sex-based differences in fecal microbial composition. Taxa with differences in abundance between healthy women and men (q < 0.05)
Figure 4
Figure 4
Effect of indomethacin on proximal small intestinal permeability and microbiome. Lactose excretion at 0–2 h was significantly higher after indomethacin administration (visit 2) compared to baseline (visit 1) and returned to baseline at recovery (visit 3). A) Women. B). Men. Data are presented as paired comparisons. Means ± sd; n = 10–11/group. C) β diversity decreased after indomethacin administration. Overall group [UniFrac (P < 0.001), PERMANOVA]; women [UniFrac (P = 0.016)]; men [UniFrac (P = 0.004), PERMANOVA].
Figure 5
Figure 5
Effect of indomethacin on distal small intestinal/colonic permeability and fecal microbiome. Lactulose excretion (2–24 h) was significantly higher after indomethacin administration (visit 2) compared to baseline (visit 1) and returned to baseline at recovery (visit 3). A) Women. B) Men. Data are presented as paired comparisons. Means ± sd; n = 10–11/group. C). After indomethacin administration, healthy women have evidence of decreased species richness and overall diversity compared to baseline. Observed OTU decreased in women after indomethacin administration (P = 0.012), but not in men. Chao1 estimator decreased in women after indomethacin administration (P = 0.041), but not in men. Shannon index decreased in women after indomethacin administration (P = 0.019), but not in men.
Figure 6
Figure 6
Effect of indomethacin on fecal Prevotella abundance. Prevotella abundance increases after indomethacin administration in women but not men.
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