Gut microbiota‐derived endotoxin enhanced the incidence of cardia bifida during cardiogenesis

Zhang, Jing; Wang, Guang; Liu, Jia; Gao, Lin; Li, Meng; Wang, Chao‐jie; Chuai, Manli; Bao, Yongping; Li, Ge; Li, Rui-Man; Yang, Xuesong

doi:10.1002/jcp.26175

Cited by 11 publications

(10 citation statements)

References 46 publications

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“…Humans are constantly exposed to low levels of LPS through infection. However, intestinal dysbacteriosis could remarkably increase the LPS level and cause shedding of LPS from gastrointestinal tract into the blood system (Aleshukina, ; J. Zhang et al, ). LPS could pass through the placenta reaching the fetus (Kohmura, Kirikae, Kirikae, Nakano, & Sato, ; Xu et al, ), and has been proved to be associated with adverse developmental outcome, including embryonic resorption, fetal death, intrauterine growth restriction, preterm labor, and delivery in animals (Aisemberg et al, ; Xu et al, ).…”

Section: Discussionmentioning

confidence: 99%

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Microbiota‐derived lipopolysaccharide retards chondrocyte hypertrophy in the growth plate through elevating Sox9 expression

Cheng

Wang

et al. 2018

Journal Cellular Physiology

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Accumulating data show that the cytotoxicity of bacterial lipopolysaccharides (LPS) from microbiota or infection is associated with many disorders observed in the clinics. However, it is still obscure whether or not embryonic osteogenesis is affected by the LPS exposure during gestation. Using the early chicken embryo model, we could demonstrate that LPS exposure inhibits chondrogenesis of the 8‐day chicken embryos by Alcian Blue‐staining and osteogenesis of 17‐day by Alcian Blue and Alizarin Red staining. Further analysis of the growth plates showed that the length of the proliferating zone (PZ) increases whereas that of the hypertrophic zone (HZ) decreased following LPS exposure. However there is no significant change on cell proliferation in the growth plates. Immunofluorescent staining, western blot analysis, and quantitive polymerase chain reaction revealed that Sox9 and Col2a1 are highly expressed at the messenger RNA level and their protein products are also abundant. LPS exposure causes a downregulation of Runx2 and Col10a1 expression in 8‐day hindlimbs, and a suppression of Runx2, Col10a1, and Vegfa expression in 17‐day phalanges. Knocking down Sox9 in ATDC5 cells by small interfering RNA transfection lead to the expression reduction of Col2a1, Runx2, and Col10a1, implying the vital role of Sox9 in the process of LPS‐induced delay in the transition from proliferating chondrocytes to hypertrophic chondrocytes in the growth plate. In the presence of LPS, the antioxidant defense regulator nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) is highly expressed, and the activities of superoxide dismutase 1 (SOD1), SOD2, and glutaredoxin rise in 17‐day phalanges and ADTC5 cells. Simultaneously, an increase of intracellular ROS is observed. When Nrf2 expression was knocked down in ATDC5 cells, the expressions of Sox9, Col2a1, Runx2, Col10a1, and Vegfa were also going down as well. Taken together, our current data suggest that LPS exposure during gestation could restrict the chondrocytes conversion from proliferating to hypertrophic in the growth plate, in which LPS‐induced Sox9 plays a crucial role to trigger the cascade of downstream genes by excessive ROS production and Nrf2 elevation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Microbiota‐derived lipopolysaccharide retards chondrocyte hypertrophy in the growth plate through elevating Sox9 expression

Cheng

Wang

et al. 2018

Journal Cellular Physiology

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“…To assess the extent of oxidative stress caused by high salt, samples from HH7 and HH10 chick embryos or primary cardiomyocytes were homogenized and analyzed for SOD (superoxide dismutase), GSH‐Px (glutathione peroxidase), and MDA (malondialdehyde) (Kalaz et al, ). The protein content of the chick embryos or primary cardiomyocytes was performed as previously reported (Zhang et al, ).…”

Section: Methodsmentioning

confidence: 99%

“…Annexin V‐FITC (BD Biosciences, San Jose, CA) and Propidium Iodide (PI) double staining were used to identify and quantify apoptotic chick myocardial cells (Zhang et al, ).…”

Section: Methodsmentioning

confidence: 99%

High salt‐induced excess reactive oxygen species production resulted in heart tube malformation during gastrulation

Gao¹,

Wang²,

Zhang³

et al. 2018

Journal Cellular Physiology

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An association has been proved between high salt consumption and cardiovascular mortality. In vertebrates, the heart is the first functional organ to be formed. However, it is not clear whether high-salt exposure has an adverse impact on cardiogenesis. Here we report high-salt exposure inhibited basement membrane breakdown by affecting RhoA, thus disturbing the expression of Slug/E-cadherin/N-cadherin/Laminin and interfering with mesoderm formation during the epithelial-mesenchymal transition(EMT). Furthermore, the DiI cell migration trajectory in vivo and scratch wound assays in vitro indicated that high-salt exposure restricted cell migration of cardiac progenitors, which was caused by the weaker cytoskeleton structure and unaltered corresponding adhesion junctions at HH7. Besides, down-regulation of GATA4/5/6, Nkx2.5, TBX5, and Mef2c and up-regulation of Wnt3a/β-catenin caused aberrant cardiomyocyte differentiation at HH7 and HH10. High-salt exposure also inhibited cell proliferation and promoted apoptosis. Most importantly, our study revealed that excessive reactive oxygen species(ROS)generated by high salt disturbed the expression of cardiac-related genes, detrimentally affecting the above process including EMT, cell migration, differentiation, cell proliferation and apoptosis, which is the major cause of malformation of heart tubes.

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“…In pregnant women, intestinal microbiota dysbiosis could cause metabolic endotoxemia and elevate blood LPS levels, which can pass through the placental barrier, negatively influencing the developing fetus [13,21,32]. LPS-induced developmental toxicity at early gestational stages has been previously characterized as well [33]. We have also reported that LPS exposure during gestation could restrict the conversion of chondrocytes from proliferating to hypertrophic in the growth plate [34]; however, it is still obscure whether embryonic osteogenesis is affected by the LPS exposure during gestation.…”

Section: Discussionmentioning

confidence: 99%

Dysbacteriosis-Derived Lipopolysaccharide Causes Embryonic Osteopenia through Retinoic-Acid-Regulated DLX5 Expression

You

Zhu

et al. 2020

IJMS

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Growing evidence suggests an adverse impact of gut microbiota dysbiosis on human health. However, it remains unclear whether embryonic osteogenesis is affected by maternal gut dysbacteriosis. In this study, we observed that elevated lipopolysaccharide (LPS) levels led to skeletal developmental retardation in an established mouse model of gut microbiota dysbiosis. Using chick embryos exposed to dysbacteriosis-derived LPS, we found restriction in the development of long bones as demonstrated by Alcian blue and alizarin red staining. Micro-CT and histological analysis exhibited decreased trabecular volume, bone mineral density, and collagen production, as well as suppressed osteoblastic gene expression (Ocn, Runx2, Osx, and Dlx5) in chick embryonic phalanges following LPS treatment. Atomic force microscopy manifested decreased roughness of MC3T3-E1 cells and poorly developed matrix vesicles (MVs) in presence of LPS. The expression of the aforementioned osteoblastic genes was suppressed in MC3T3-E1 cells as well. High-throughput RNA sequencing indicated that retinoic acid (RA) may play an important role in LPS-induced osteopenia. The addition of RA suppressed Dlx5 expression in MC3T3-E1 cells, as was also seen when exposed to LPS. Quantitative PCR, Western blot, and immunofluorescent staining showed that retinoic acid receptor α (RARα) was upregulated by LPS or RA treatment, while the expression of DLX5 was downregulated. CYP1B1 expression was increased by LPS treatment in MC3T3-E1 cells, which might be attributed to the increased inflammatory factors and subsequently activated NF-κB signaling. Eventually, blocking RA signals with AGN193109 successfully restored LPS-inhibited osteoblastic gene expression. Taken together, our data reveals that maternal gut microbiota dysbiosis can interfere with bone ossification, in which Dlx5 expression regulated by RA signaling plays an important role.

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Gut microbiota‐derived endotoxin enhanced the incidence of cardia bifida during cardiogenesis

Cited by 11 publications

References 46 publications

Microbiota‐derived lipopolysaccharide retards chondrocyte hypertrophy in the growth plate through elevating Sox9 expression

Microbiota‐derived lipopolysaccharide retards chondrocyte hypertrophy in the growth plate through elevating Sox9 expression

High salt‐induced excess reactive oxygen species production resulted in heart tube malformation during gastrulation

Dysbacteriosis-Derived Lipopolysaccharide Causes Embryonic Osteopenia through Retinoic-Acid-Regulated DLX5 Expression

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