Cell Host & Microbe
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2024
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IF 20.6
Lingsha Cheng,Haoqian Wu,Xiaoying Cai,Youying Zhang,Siqi Yu,Yuanlong Hou,Zhe Yin,Qingyuan Yan,Qiong Wang,Taipeng Sun,Guangji Wang,Yonggui Yuan,Xueli Zhang,Haiping Hao,Xiao Zheng
Gene-environment interactions shape behavior and susceptibility to depression. However, little is known about the signaling pathways integrating genetic and environmental inputs to impact neurobehavioral outcomes. We report that gut G-protein-coupled receptor, Gpr35 , engages a microbe-to-brain metabolic pathway to modulate neuronal plasticity and depressive behavior in mice. Psychological stress decreases intestinal epithelial Gpr35 , genetic deletion of which induces depressive-like behavior in a microbiome-dependent manner. Gpr35 −/− mice and individuals with depression have increased Parabacteroides distasonis , and its colonization to wild-type mice induces depression. Gpr35 −/− and Parabacteroides distasonis -colonized mice show reduced indole-3-carboxaldehyde (IAld) and increased indole-3-lactate (ILA), which are produced from opposing branches along the bacterial catabolic pathway of tryptophan. IAld and ILA counteractively modulate neuroplasticity in the nucleus accumbens, a brain region linked to depression. IAld supplementation produces anti-depressant effects in mice with stress or gut epithelial Gpr35 deficiency. Together, these findings elucidate a gut microbe-brain signaling mechanism that underlies susceptibility to depression.
研究领域:
神经科学
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微生物学
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遗传学
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DOI
PubMed
高影响因子
CELLULAR AND MOLECULAR LIFE SCIENCES
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2025
·Vol. 82
·期 1
·1-16
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IF 6.2
Zhao Xueqin,Li Yuanhao,Yang Liu,Chen Xi,Zhang Jialong,Chen Tong,Wang Haoqi,Li Fei,Cheng Chen,Wu Jingjing,Cong Jingjing,Yin Wenwei,Li Jing,Wang Xuefu
Acetaminophen (APAP) overdose induces acute liver injury and represents the most frequent cause of drug-induced liver injury worldwide. Macrophage-mediated inflammation plays detrimental roles during the early stage of liver injury. However, the potential targets regulating inflammation to improve drug-induced liver injury remains undefined. In this study, we reported that G protein-coupled receptor 35 (GPR35) improves drug-induced liver injury by blocking macrophage-mediated inflammation via the Gαs-cyclic AMP-protein kinase A (Gαs-cAMP-PKA) pathway. The ablation of GPR35 exacerbates APAP-induced liver injury, characterized by higher levels of alanine aminotransferase and aspartate aminotransferase in sera, larger damaged areas, and increased levels of pro-inflammatory cytokines. More hepatic macrophages appeared in the inflamed liver of mice with GPR35 deficiency. In contrast, the agonists of GPR35 alleviated APAP-induced liver injury. The depletion of macrophages abolished GPR35-mediated protection. Mechanistically, GPR35 ablation facilitated the activation of pro-inflammatory AKT, MAPK, and NF-κB signaling pathways at the downstream of Toll-like receptors in macrophages. GPR35 agonists activated Gαs-cAMP-PKA signaling to inhibit the activation of these pro-inflammatory signaling pathways and then suppress the inflammatory response in macrophages. Thus, our findings demonstrate that GPR35 prevents drug-induced liver injury by blocking macrophage-mediated inflammation via the Gαs-cAMP-PKA pathway, indicating that GPR35 is a potential target for the development of novel medicines that control drug-induced liver injury.
研究领域:
药理学
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肝脏病学
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免疫学
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DOI
PubMed
高影响因子
FEBS Open Bio
·
2023
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IF 2.6
Di Wang,Wenbao Wang,Xue Bing,Chenguang Xu,Jiahua Qiu,Jiangang Shen,Jinwen Huang,Junda Li,Pi Liu,Biao Xie
Ulcerative colitis (UC) is a recurrent inflammatory disease related to gut microbiota disorder. Metabolites and their sensors play an important role in the communication between gut microbes and their host. Our previous study revealed that G protein-coupled receptor 35 (GPR35) is a key guardian of kynurenic acid (KA) and a core element of the defense responses against gut damage. However, the mechanism remains unknown. In this study, a DSS-induced rat colitis model was established and 16S rRNA sequencing was applied to explore the influence of GPR35-mediated KA sensing on gut microbiota homeostasis. Our results demonstrated that GPR35-mediated KA sensing is a necessary component in maintaining gut barrier integrity against DSS-induced damage. Furthermore, we provide compelling evidence suggesting that GPR35-mediated KA sensing plays a crucial role in maintaining gut microbiota homeostasis, which contributes to alleviation of DSS-induced colitis. In addition, five classes (Actinobacteria, Beta-/Gamma-proteobacteria, Erysipelotrichi, and Coriobacteriia) and six genera ( Corynebacterium , Allobaculum , Parabacteroides , Sutterella , Shigella , and Xenorhabdus ) were identified as the marked bacterial taxa that characterized the progression and outcome of colitis and are regulated by GPR35-mediated KA sensing. Our findings highlight that GPR35-mediated KA sensing is an essential defense mechanism against disorder of gut microbiota in UC. The results provide insights into the key role of specific metabolites and their monitor in maintaining gut homeostasis.
研究领域:
免疫学
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微生物学
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胃肠病学
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分子生物学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Xiaolin Cen,Suiqing Mai,Rongrong Huang,Shiqin Lin,Yishang Chen,Shuqin Zhang,Pei Zhao,Dong Guo,Xinzhi Liang,Yitao Zhao,Huancun Feng,Zhisheng Xiao,Xinya Lu,Haoyu Wan,Hong Wang,Denghui Xie,Jianxin Pang,Qun Zhang
Background GPR35, a member of the G protein-coupled receptor (GPCR) family, promotes osteogenic differentiation and ameliorates inflammation when its expression is enhanced. However, its role in bone homeostasis under hyperuricemia (HUA) conditions remains unexplored, and effective clinical agents for managing osteoporosis comorbid with HUA are scarce. This study aimed to investigate the osteoprotective potential of the GPR35 agonist isobavachin (IBC) against HUA-induced bone loss, focusing on its mechanism involving NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome modulation. Methods Bone tissue markers of bone homeostasis and inflammatory infiltration were evaluated in patients with hyperuricemia. To delineate the relationship of HUA, bone homeostasis, and GPR35, osteoblasts (OB) and osteoclasts (OC) were treated with high concentrations of soluble uric acid, in conjunction with label-free cellular assays. The mechanisms underlying the effects of the GPR35 agonist IBC were investigated using molecular docking, in vitro cell culture with IBC treatment, and siRNA-mediated gene silencing. Furthermore, hyperuricemic model mice were established in C57BL/6J mice to corroborate the bone loss induced by HUA and evaluate the osteoprotective efficacy of IBC. Results Analysis of bone tissue from HUA patients revealed increased activity of both OB and OC, along with inflammatory cell infiltration. Consistently, in vitro experiments demonstrated that exposure to high concentrations of soluble uric acid specifically and significantly impaired OB differentiation and mineralization. This inhibitory effect was closely associated with NLRP3 inflammasome activation. Furthermore, high concentrations of soluble uric acid treatment modulated GPR35 expression levels in cultured cells. Critically, the GPR35 agonist IBC activated GPR35 and promoted osteogenic effects. Mechanistically, GPR35 knockdown experiments confirmed that IBC exerted its bone-promoting actions primarily via the GPR35-NLRP3 signaling axis. Importantly, these findings were corroborated in a chronic hyperuricemia mouse model, where IBC treatment effectively attenuated HUA-induced bone loss compared to the standard antihyperuricemic agent allopurinol. Conclusions Our findings demonstrate that GPR35 activation protects OB from HUA-induced bone loss. The GPR35 agonist IBC enhances osteogenic differentiation by modulating the GPR35-NLRP3 signaling axis, effectively attenuating bone loss in HUA. These results identify IBC as a promising novel therapeutic candidate for managing HUA-associated osteoporosis.
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高影响因子
Acta Pharmaceutica Sinica B
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2020
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IF 7.097
Di Wang,Danting Li,Yuxin Zhang,Jie Chen,Ying Zhang,Chuyao Liao,Siyuan Qin,Yuan Tian,Zunjian Zhang,Fengguo Xu
Intestinal toxicity induced by chemotherapeutics has become an important reason for the interruption of therapy and withdrawal of approved agents. In this study, we demonstrated that chemotherapeutics-induced intestinal damage were commonly characterized by the sharp upregulation of tryptophan (Trp)−kynurenine (KYN)−kynurenic acid (KA) axis metabolism. Mechanistically, chemotherapy-induced intestinal damage triggered the formation of an interleukin-6 (IL-6)−indoleamine 2,3-dioxygenase 1 (IDO1)−aryl hydrocarbon receptor (AHR) positive feedback loop, which accelerated kynurenine pathway metabolism in gut. Besides, AHR and G protein-coupled receptor 35 (GPR35) negative feedback regulates intestinal damage and inflammation to maintain intestinal integrity and homeostasis through gradually sensing kynurenic acid level in gut and macrophage, respectively. Moreover, based on virtual screening and biological verification, vardenafil and linagliptin as GPR35 and AHR agonists respectively were discovered from 2388 approved drugs. Importantly, the results that vardenafil and linagliptin significantly alleviated chemotherapy-induced intestinal toxicity in vivo suggests that chemotherapeutics combined with the two could be a promising therapeutic strategy for cancer patients in clinic. This work highlights GPR35 and AHR as the guardian of kynurenine pathway metabolism and core component of defense responses against intestinal damage.
研究领域:
药理学
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免疫学
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分子生物学
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胃肠病学
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DOI
PubMed
高影响因子
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