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Reproductive Senescence and Ischemic Stroke Remodel the Gut Microbiome and Modulate the Effects of Estrogen Treatment in Female Rats

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Abstract

Our previous work has shown that reproductively senescent (or middle-aged; 10–12-month-old) Sprague–Dawley female rats, that are naturally estrogen-deficient, have worse stroke outcomes as compared to normally estrous-cycling adult (5–6-month-old) females. Paradoxically, estrogen replacement to this middle-aged group exacerbates stroke outcomes, while it is neuroprotective in adult females. Recent studies reveal an important role for the gut microbiome and gut metabolites in cardiovascular health, including stroke outcomes. To determine whether gut dysbiosis underlies stroke severity in reproductive senescent females, and underlies the anomalous effects of estrogen on stroke, we compared the gut microbiota and gut metabolites pre and post stroke in (a) gonadally intact adult and middle-aged females, (b) in ovariectomized and estrogen-treated (OVX+E) adult and OVX+E middle-aged females, and (c) in middle-aged OVX+E females after fecal microbiome transfer. Our data show significant gut dysbiosis in reproductive senescent females at baseline and after stroke as indicated by an elevated ratio of the major phyla, Firmicutes/Bacteroidetes (F:B), reduced alpha diversity, and significant shifts in beta diversity as compared with adult females. Specific bacterial families were also altered as a result of reproductive aging, as well as gut metabolites, including elevated serum endotoxin levels and decreased short-chain fatty acids (SCFAs), with a concomitant increase in IL-17A, indicating that reproductive senescence significantly affects gut communities under pathologic conditions. Despite the differences in gonadally intact adult and middle-aged females, estrogen-treated ovariectomized (OVX+E) females of either age group displayed no differences in the major phyla, but there was increased abundance in specific bacterial taxa, including Prevotella and Lactobacillus. The SCFA butyrate was significantly reduced at baseline in the middle-aged OVX+E females, while circulating endotoxin LPS were elevated in this group after stroke, suggesting that gut metabolites were differently affected by estrogen treatment in the two age groups. A fecal transfer from adult OVX+E females to middle-aged OVX+E females significantly reduced infarct volume, improved behavioral recovery and transiently reduced IL-17A expression. These data provide the first evidence that microbial gut communities and metabolites are altered by reproductive senescence in female rats at baseline and after stroke, and suggest that estrogen may impact stroke recovery differently in adult and reproductive senescent females due to an age-specific effect on gut microbiota and metabolites.

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Acknowledgments

The authors thank Yumna El-Hakim, Dr. Amanda Mahnke and Dr. Rajesh Miranda for careful reading and comments. Dr. Park’s current address: Brain Research Institute, Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.

Funding

This study was supported by funding from NIH/NS074895 and AG042189 to FS.

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Author notes

  1. Min Jung Park and Rachel Pilla contributed equally to this work.

Authors and Affiliations

  1. Women’s Health in Neuroscience Program, Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, College of Medicine, 8447 Riverside Pkwy, Bryan, TX, 77807, USA

    Min Jung Park, Aditya Panta, Sivani Pandey & Farida Sohrabji

  2. Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, Texas A&M University, College Station, TX, USA

    Rachel Pilla, Benjamin Sarawichitr & Jan Suchodolski

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  1. Min Jung Park
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Contributions

MJP and RP are co-first authors. MJP: conceptualized/hypothesized, designed, performed the experiments; analyzed data and prepared figures; and wrote the manuscript. RP: performed metagenomic analyses, assisted with data interpretation, prepared figures, and wrote the manuscript. BS: assisted with metagenomic analysis. AP: performed the FMT experiments. SP: assisted with experiments and performed behavioral tests. JS: assisted with experimental design and data interpretation. FS: refined hypothesis and experimental design, data analysis and interpretation, and wrote the manuscript.

Corresponding author

Correspondence to Farida Sohrabji.

Ethics declarations

All experimental protocols were approved by Texas A&M University Institutional Animal Care and Use Committee. All animal care and use was conducted in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council).

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The authors declare that they have no conflict of interest.

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Electronic supplementary material

Supplementary Fig. 1

Reproductive aging affects behavioral outcomes after stroke. The latency (in seconds) to tape removal from the forepaw was evaluated by the adhesive tape test before (pre) or after (2d and 5d) MCAO. Post-stroke performance in both adult and middle-aged animals was not significantly impaired in the ipsilesional forepaw. a. In adult females, there was no detectable change in latency due to stroke. b. In middle-aged females, latency for adhesive removal was severely affected on the contralesional side after stroke. N = 5, All graphs represent mean ± S.E.M. a, main effect of side, p < 0.0001; b, main effect of stroke, p = 0.0028; c, interaction, p = 0.015. Key: Ipsi: ipsilesional paw, contra: contralesional paw. (PNG 519 kb)

High resolution image (TIFF 1142 kb)

Supplementary Fig. 2

Estrogen replacement to ovariectomized adult and middle-aged females. a. Estrogen replacement (OVX + E) to ovariectomized females significantly increased uterine weight as compared to ovariectomized (OVX) females in both adult and middle-aged female groups. b. Normalized feed consumption was similar in adult and middle-aged rats. a: main effect of treatment. (PNG 396 kb)

High resolution image (TIFF 1142 kb)

Supplementary Fig 3

The latency (in seconds) to tape removal from the forepaw was evaluated by the adhesive tape test before (0 day) or after (2 days and 5 days) MCAO. Post-stroke performance in both adult and middle-aged animals was not significantly impaired in the ipsilesional forepaw a. In adult females, both OVX + Placebo and OVX + Estrogen groups displayed a significant increase in latency on the contralesional paw after stroke, however at 5d after stroke latency in both groups was lower than at 2d after stroke. b. In middle-aged females, both OVX + Placebo and OVX + Estrogen groups displayed a significant increase in latency on the contralesional paw after stroke, however there was no improvement in latency between 2d and 5d in either group. Key: Ipsi: ipsilesional paw, contra: contralesional paw, OVX + Pl: ovariectomized with placebo pellet, OVX + E: ovariectomized with estradiol pellet. All graphs represent mean ± S.E.M. * p < 0.05; ns: not significant. (PNG 632 kb)

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Supplementary Fig. 4

Timeline for procedures related to the Fecal Microbiome Transfer study. OVX + E: ovariectomized females treated with estrogen, MCAo: middle cerebral artery occlusion. (PNG 306 kb)

High resolution image (TIFF 1142 kb)

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Park, M.J., Pilla, R., Panta, A. et al. Reproductive Senescence and Ischemic Stroke Remodel the Gut Microbiome and Modulate the Effects of Estrogen Treatment in Female Rats. Transl. Stroke Res. 11, 812–830 (2020). https://doi.org/10.1007/s12975-019-00760-5

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  • DOI: https://doi.org/10.1007/s12975-019-00760-5

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