Role of TLR4 in Intestinal Motility Dysfunction
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Role of TLR4 in Intestinal Motility Dysfunction

17/07/2025 Compuscript Ltd
Maternal health and other events occurring during pregnancy determine the health outcomes in offspring. Pre-natal infections are a major risk factor contributing to compromised intestinal barrier integrity and intestinal inflammatory diseases in the offspring. Although previous research has indicated that maternal exposure to LPS during pregnancy causes intestinal barrier damage in the offspring persisting into adulthood, research on its effects on intestinal motility is limited.

In a recent study published in the Genes & Diseases journal, researchers at Children’s Hospital of Chongqing Medical University provide mechanistic insights into how pre-natal LPS exposure affects intestinal motility in offspring.

As a first step, the authors generated intestinal epithelial Tlr4 conditional knockout (Tlr4ΔIEC) mice, by crossing Villin-Cre mice with Tlr4fl/fl mice. The Tlr4ΔIEC mice and Tlr4fl/fl mice were then mated and the females were randomly injected with LPS or PBS during gestation. The male offspring were divided into four groups, Tlr4fl/fl-PBS, Tlr4fl/fl-LPS, Tlr4△IEC-PBS, and Tlr4△IEC-LPS, to investigate the intestinal dynamics following pre-natal LPS exposure.

Prenatal LPS treatment impaired intestinal structure, increased fecal water content and gastrointestinal motility, and induced intestinal TLR4 signaling activation in Tlr4fl/fl offspring mice but not in Tlr4ΔIEC mice, suggesting that TLR4 plays a role in LPS-induced maternal immune activation.

Previous studies have shown that 5-HT, a neurotransmitter, promotes intestinal motility by binding to its corresponding receptors expressed in the intestine. This study revealed that prenatal LPS exposure activates the 5-HT pathways in Tlr4fl/fl offspring mice, evident from the increased expression of tryptophan hydroxylase (TPH1)—a rate-limiting enzyme of 5-HT synthesis—decreased expression of SLC6A4—a transporter protein—increased expression of different 5-HT receptors, and high intestinal levels of 5-HT.

Enterochromaffin (EC) cells are known to produce 5-HT to enhance signal transmission between the gut and brain. LPS stimulation increases TLR4 and 5-HT levels in the BON-1 enterochromaffin cell line, which was reversed upon the addition of TAK242, a TLR4 inhibitor. Furthermore, LPS stimulation upregulates TLR4 and PIEZO1, facilitating their interaction, which subsequently triggers cellular calcium influx and results in increased 5-HT secretion. Similarly, LPS exposure during gestation increased the expression of PIEZO1 in the colonic mucosa of Tlr4fl/fl offspring mice but not in Tlr4ΔIEC mice.

In conclusion, this study offers insights into how the TLR4-PIEZO1 interaction enhances 5-HT secretion, promoting intestinal motility dysfunction, and suggests that targeting TLR4 may help alleviate intestinal motility abnormalities in prenatally infected offspring.

Reference

Title of the original paper: TLR4 interaction with PIEZO1 facilitates the 5-HT-mediated intestinal motility dysfunction in offspring mice induced by LPS exposure during pregnancy

Journal: Genes & Diseases

Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101707

Funding Information:
  • National Natural Science Foundation of China (No. 82372559, 31971089)
  • General Project of Chongqing Natural Science Foundation (China) (No. CSTB2022NSCQ-MSX0107)
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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

Scopus CiteScore: 8.4 | Impact Factor: 9.4

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Attached files
  • (A) The hematoxylin and eosin staining of colon samples from the offspring of Tlr4fl/fl and Tlr4ΔIEC mice treated with phosphate buffer saline (PBS) or lipopolysaccharide (LPS) provided an overview of the colon in both groups. Scale bar = 250 μm (n = 3 per group). (B) Histogram of colonic tissue mucosal layer thickness quantification in offspring mice of the four groups. (C) The colonic transit time in the offspring of Tlr4fl/fl and Tlr4ΔIEC mice after treatment with LPS or PBS (n = 10 per group; two-way ANOVA). (D) Fecal water content in the Tlr4fl/fl and Tlr4ΔIEC offspring with or without LPS exposure (n = 10 per group; two-way ANOVA). (E) The gastrointestinal transit time of the offspring mice in the Tlr4fl/fl and Tlr4ΔIEC groups with or without LPS treatments (n = 10 per group; two-way ANOVA). In the combined Tlr4fl/fl and Tlr4ΔIEC groups, as well as in the combined PBS and LPS groups (n = 20 per group), Tlr4 knockout or LPS treatment independently affected gastrointestinal transit time. Data were presented as mean ± standard error of the mean. The term “Interaction” denotes the effect of LPS on the Tlr4ΔIEC mice compared with Tlr4fl/fl mice. ns, not significant; ∗P < 0.05, ∗∗P < 0.01, ∗∗∗∗P < 0.0001, and ∗∗∗∗P < 0.0001.
  • (A) The mRNA expression levels of TLR4, PIEZO1, and TRPA1 in BON-1 cells treated with different concentrations of LPS were determined by quantitative PCR analysis (n = 5 per group; one-way ANOVA). (B) Calcium images showing calcium influx changes in the BON-1 cells treated with PBS or LPS combined with or without the TLR4 inhibitor TAK-242. Scale bar = 50 μm (n = 3 per group). (C) The co-localization observation of TLR4 (green) and PIEZO1 (red) in the four different treatment groups of BON-1 cell by confocal microscopy. Scale bar = 100 μm (n = 10 per group). (D) TLR4 bound to PIEZO1 in the BON-1 cell treated with or without LPS as determined by co-immunoprecipitation using TLR4 or PIEZO1 antibodies. (E)The concentration of 5-HT in the supernatant of BON-1 cells treated with LPS or PBS, with or without treatment with TAK-242 (n = 10), was determined by ELISA. Data were expressed as mean ± standard error of the mean; ns, not significant; ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001, and ∗∗∗∗P < 0.0001. TLR4, toll-like receptor 4; PIEZO1, Piezo-type mechanosensitive ion channel component 1; TRPA1, transient receptor potential cation channel subfamily A member 1; LPS, lipopolysaccharide; PBS, phosphate buffer saline; 5-HT, 5-hydroxytryptamine.
  • Tlr4fl/fl mice were crossbred with Tlr4ΔIEC mice, and the female mice were intraperitoneally injected with 50 μg/kg of lipopolysaccharide (LPS) or an equivalent volume of phosphate buffer saline (PBS) at gestational day 14.5. After genotyping, the offspring mice were divided into four groups: Tlr4fl/fl-PBS, Tlr4fl/fl-LPS, Tlr4ΔIEC-PBS, and Tlr4ΔIEC-LPS. Intestinal motility and fecal water content were measured at 6 weeks of age. Colon tissue was collected at 8 weeks of age.
17/07/2025 Compuscript Ltd
Regions: Europe, Ireland, Asia, China
Keywords: Science, Life Sciences

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