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[Preprint]. 2023 Nov 13:2023.11.09.566474.
doi: 10.1101/2023.11.09.566474.

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 , Ramakrishna Kommagani  2 , 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. bioRxiv. .

Update in

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 alter an inflammatory environment in endometriosis and discern their contribution to endometriotic-associated hyperalgesia. Our results showed that HFD-induced obesity enhanced abdominal mechanical allodynia that was induced by endometriotic lesions. Peritoneal inflammatory macrophages and cytokine levels increased by lesion induction were elevated by chronic exposure to HFD. Pain-related mediators in the dorsal root ganglia were further stimulated 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; pain.

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Conflict of interest statement

Conflict of Interest: The authors declare that they have no competing interests.

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). Female mice were fed either SD or HFD starting at the age of 5 weeks (defined as Week 0). (C) Blood glucose levels by cardiac puncture were measured by Contour Next (n=5). (D) Plasma insulin levels were quantified by ELISA (n=5). 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. Statistical differences among the groups were reported with the compact letter display (shown as a vs b; P
Figure 2.
Figure 2.
Diet-induced obesity increases macrophage infiltration in the lesion. (A) Lesion number (n=18). (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. a vs b; P
Figure 3.
Figure 3.
HFD accelerates endometriosis-associated abdominal hyperalgesia. Von Frey tests were performed on mice to the lower abdomen and hind paw at the pre-induction time point after 12 weeks of SD or HFD feeding (A and C, n=10), or 6 weeks post-lesion induction (B and 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 and C), or one-way ANOVA followed by Tukey’s post hoc test (B and D). a vs b; P
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. (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. a vs b vs c; p
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). a vs b vs c; P
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. a vs b vs c; P
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.
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