Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Mar 15:15:1336496.
doi: 10.3389/fendo.2024.1336496. eCollection 2024.

High-fat diets promote peritoneal inflammation and augment endometriosis-associated abdominal hyperalgesia

Tristin Herup-Wheeler #  1 , Mingxin Shi #  1 , Madeleine E Harvey  1 , Chandni Talwar  2   3 , Ramakrishna Kommagani  2   3 , James A MacLean 2nd  1 , Kanako Hayashi  1
Affiliations

High-fat diets promote peritoneal inflammation and augment endometriosis-associated abdominal hyperalgesia

Tristin Herup-Wheeler et al. Front Endocrinol (Lausanne). .

Abstract

Immune dysfunction is one of the central components in the development and progression of endometriosis by establishing a chronic inflammatory environment. Western-style high-fat diets (HFD) have been linked to greater systemic inflammation to cause metabolic and chronic inflammatory diseases, and are also considered an environmental risk factor for gynecologic diseases. Here, we aimed to examine how HFD cause an inflammatory environment in endometriosis and discern their contribution to endometriotic-associated hyperalgesia. Our results showed that HFD-induced obesity enhanced abdominal hyperalgesia that was induced by endometriotic lesions. Peritoneal inflammatory macrophages and cytokine levels increased by lesion induction were elevated by chronic exposure to HFD. Increased expression of pain-related mediators in the dorsal root ganglia was observed after lesion induction under the HFD condition. Although HFD did not affect inflammatory macrophages in the peritoneal cavity without lesion induction, the diversity and composition of the gut microbiota were clearly altered by HFD as a sign of low-grade systemic inflammation. Thus, HFD alone might not establish a local inflammatory environment in the pelvic cavity, but it can contribute to further enhancing chronic inflammation, leading to the exacerbation of endometriosis-associated abdominal hyperalgesia following the establishment and progression of the disease.

Keywords: endometriosis; high-fat diets; inflammation; macrophages; microbiota; pain.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Diet-induced obesity in the mouse model of endometriosis. (A) Experimental study design as described in Material and Methods. (B) Body weight (BW) changes in mice during the feeding of standard diets (SD) or 45% high-fat diets (HFD) for the baseline study or the endometriosis study. Female mice were fed either SD or HFD starting at the age of 5 weeks (defined as Week 0 of the 12-week as a baseline study or 18-week as an endometriosis study). Two-way ANOVA was used to determine the significance between times and groups. (C) Blood glucose levels by cardiac puncture were measured by Contour Next (n=5 in each group). (D) Plasma insulin levels were quantified by ELISA (n=5 in each group). Data at 12 weeks were analyzed by two-tailed Student’s t-test comparing SD and HFD. Data at 18 weeks were analyzed through one-way ANOVA and Tukey’s post hoc test. Values in graphs are expressed as the mean ± SEM. Different letters indicated significant differences among the groups (P<0.05). ELL: endometrial-like lesion.
Figure 2
Figure 2
Diet-induced obesity increases macrophage infiltration in the lesion. (A) Lesion number (n=18 per group). (B) CD68 was stained to determine macrophage infiltration in the lesion. (C) The quantification of the percentage of CD68+ cells per total cells (n=5). Data were analyzed with the student t-test and are shown as mean ± SEM. Different letters indicated significant differences among the groups (P<0.05). SD: standard diets, and HFD: high-fat diets.
Figure 3
Figure 3
HFD accelerates endometriosis-associated abdominal hyperalgesia. Von Frey tests were performed on mice to the lower abdomen and hind paw in the bseline study after 12 weeks of SD or HFD feeding (A and C, n=10), or 6 weeks post-lesion induction in the endometriosis study (B, D, a total of 18 weeks of SD or HFD feeding, n=8 for Sham and n=18 for ELL groups). Data are shown as mean ± SEM. Statistical significance was determined by student t-test (A, C), or one-way ANOVA followed by Tukey’s post hoc test (B, D). Different letters indicated significant differences among the groups (P<0.05). ELL: endometrial-like lesion, SD: standard diets, and HFD: high-fat diets.
Figure 4
Figure 4
HFD increases Ly6C+ macrophages (MΦ) in the peritoneal fluid (PF) of ELL mice. (A) Flow cytometer analysis for CD11b+ (MΦ), CD3+ (T-cells), CD19+ (B-cells), and Ly6C+ (monocytes and MΦ) cells in the PF. FSC-H: Forward Scatter-Height; FSC-A: Forward Scatter-Area; SSC-A: Side Scatter-Area. (B) Quantification of CD11b+, CD3+, CD19+, and Ly6C+ cells in the groups of Sham-SD (n=5), Sham-HFD (n=5), ELL-SD (n=10) and ELL-HFD (n=10). (C) TIM4+ and Ly6C+ MΦ were quantified in the PF. Data were analyzed through One-way ANOVA followed by Tukey’s post hoc test and expressed as the mean ± SEM. Different letters indicated significant differences among the groups (P<0.05). ELL: endometrial-like lesion, SD: standard diets, and HFD: high-fat diets.
Figure 5
Figure 5
Quantification of TNFα, IL1β, IL6, and IL10 in the peritoneal fluid (PF). Peritoneal (A) TNFα, (B) IL1β, (C) IL6, and (D) IL10 were measured with IQELISA and analyzed with ANOVA followed by Tukey’s post hoc test. Values in graphs are expressed as the mean ± SEM (n=5). Different letters indicated significant differences among the groups (P<0.05). ELL: endometrial-like lesion, SD: standard diets, and HFD: high-fat diets.
Figure 6
Figure 6
HFD stimulates pain-related mediators in the DRG of ELL mice. (A) Immunofluorescence results of BDNF, CGRP, SP, TRPV1, and neurofilament (NF, green) in DRG. NF was used as a marker of DRG cell body and was co-stained with BDNF, CGRP, SP, or TRPV1. (B) BDNF, CGRP, SP, or TRPV1 positive DRG per NF positive DRG was counted and quantified (n=5 per group). One-way ANOVA followed by Tukey’s post hoc test was used for statistical analysis. Data were shown as mean ± SEM. Different letters indicated significant differences among the groups (P<0.05). ELL: endometrial-like lesion, SD: standard diets, and HFD: high-fat diets. DRG: dorsal root ganglia.
Figure 7
Figure 7
HFD altered the composition of the gut microbiota. (A) Box plots corresponding to the Chao1 diversity index (alpha diversity). (B) Principal Coordinates Analysis (PCoA) of beta-diversity based on weighted Unifrac dissimilarities in fecal samples. P = 0.001, R=0.422. (n=5 per group). (C) Heatmap representation of relative abundances of the phyla in feces. (D) Heatmap depiction of the relative abundances of the genera in feces (n=5 per group). ELL: endometrial-like lesion, SD: standard diets, and HFD: high-fat diets.
See this image and copyright information in PMC

Update of

Similar articles

See all similar articles

Cited by

References

    1. Zondervan KT, Becker CM, Missmer SA. Endometriosis. New Engl J Med. (2020) 382:1244–56. doi: 10.1056/NEJMra1810764 - DOI - PubMed
    1. Shafrir AL, Farland LV, Shah DK, Harris HR, Kvaskoff M, Zondervan K, et al. . Risk for and consequences of endometriosis: A critical epidemiologic review. Best Pract Res Clin Obstet Gynaecol. (2018) 51:1–15. doi: 10.1016/j.bpobgyn.2018.06.001 - DOI - PubMed
    1. Nnoaham KE, Hummelshoj L, Webster P, d'Hooghe T, de Cicco Nardone F, de Cicco Nardone C, et al. . Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertility sterility. (2011) 96:366–373 e8. doi: 10.1016/j.fertnstert.2011.05.090 - DOI - PMC - PubMed
    1. Zondervan KT, Becker CM, Koga K, Missmer SA, Taylor RN, Vigano P. Endometriosis. Nat Rev Dis Primers. (2018) 4:9. doi: 10.1038/s41572-018-0008-5 - DOI - PubMed
    1. As-Sanie S, Black R, Giudice LC, Gray Valbrun T, Gupta J, Jones B, et al. . Assessing research gaps and unmet needs in endometriosis. Am J Obstet Gynecol. (2019) 221:86–94. doi: 10.1016/j.ajog.2019.02.033 - DOI - PubMed