Gut microbial metabolite hyodeoxycholic acid targets the TLR4/MD2 complex to attenuate inflammation and protect against sepsis

Li, Jiaxin; Chen, Yuqi; Li, Rui; Zhang, Xianglong; Chen, Tao; Mei, Fengyi; Liu, Ruofan; Chen, Mei‐Ling; Ge, Yunshan; Hu, Hongbin; Wei, Rongjuan; Chen, Zhen-Feng; Fan, Hongying; Zeng, Zhenhua; Deng, Yongqiang; Luo, Haihua; Hu, Shuiwang; Cai, Shumin; Wu, Feng; Shi, Nengxian; Wang, Zhang; Zeng, Yunong; Xie, Mingxing; Jiang, Yong; Chen, Zhongqing; Jia, Wei; Chen, Peng

doi:10.1016/j.ymthe.2023.01.018

Cited by 27 publications

(8 citation statements)

References 62 publications

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“…Several other bacterial species, including Eubacterium desmolans ATCC 43058, also showed high similarity in their 16s rRNA gene sequences to HDCA‐1. Conversely, a recent study by Li et al reported that inoculation with an isolated strain of Eubacterium linosum ATCC8486 increased fecal HDCA levels [20]. We also observed a significant increase in the abundance of the genus Eubacterium g23 following GRS administration (Figure 3), and a positive correlation between its abundance and fecal HDCA levels in mice (Table 2).…”

Section: Discussionsupporting

confidence: 41%

“…Recent studies have highlighted the beneficial effects of 6α-hydroxylated bile acids, including HDCA, in improving glucose metabolism dysregulation associated with diabetes through TGR5 stimulation [7,8]. Additionally, HDCA exerts anti-inflammatory effects by antagonizing TLR4-mediated innate immune responses, thereby inhibiting endotoxin-induced inflammation [20] and attenuating the development of nonalcoholic steatohepatitis (NASH) in mice [26,27]. Our previous studies demonstrated that HDCA prevents colitic symptoms in dextran sulfate sodium (DSS)treated mice [28] and hepatic lipid accumulation in mice fed a high-fat diet [29].…”

Section: Discussionmentioning

confidence: 99%

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Goreisan‐induced modulation of fecal bile acid composition and gut microbiota in mice

Watanabe,

Takahashi,

Awale

et al. 2024

Traditional & Kampo Medicine

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AimBile acids are suggested to be involved in the antidiarrhetic effect of Goreisan (GRS). This study aimed to investigate the effect of GRS on fecal bile acid levels and composition of the gut microbiota in mice. Correlation analysis was employed to identify the potential gut microbiota associated with the alterations in fecal bile acid levels induced by GRS.MethodsMale C57BL/6 mice were fed a diet supplemented with GRS water extract for 4 weeks. Feces and cecal contents were collected from the mice to determine bile acid levels and analyze bacterial composition.ResultsGRS administration significantly increased the levels of fecal secondary bile acids, including ω‐muricholic acid (MCA), hyodeoxycholic acid (HDCA), and lithocholic acid (LCA). In contrast, the levels of primary bile acids, such as β‐MCA, cholic acid (CA), and chenodeoxycholic acid (CDCA) showed a marked decrease. Further analysis revealed a positive correlation between the relative abundance of Alloprevotella, Dehalobacterium PAC001221, and Eubacterium g23 and fecal levels of ωMCA, HDCA, and LCA.ConclusionsGRS was suggested to promote the formation of fecal secondary bile acids in mice, possibly through the enhancement of bacterial 7β‐dehydroxylation and 6β‐epimerization activities. These changes may be involved in the antidiarrhetic action of GRS. Concurrent evaluation of fecal bile acids and gut microbiota presents a promising approach for elucidating the novel mechanisms underlying the effects of kampo formulations, particularly in modulating the microbial metabolism of intestinal bile acids.

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Section: Discussionsupporting

confidence: 41%

Section: Discussionmentioning

confidence: 99%

Goreisan‐induced modulation of fecal bile acid composition and gut microbiota in mice

Watanabe,

Takahashi,

Awale

et al. 2024

Traditional & Kampo Medicine

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“…DCA, LCA, GCA), we found that hyocholic acid and its derivatives also showed significant differences in IBD. Considering their reported roles in other disease states, such as diabetes 46 and sepsis, 47 we suggest that the therapeutic or diagnostic potential of these uncommon bile acids in the context of IBD warrants further investigation.…”

Section: Discussionmentioning

confidence: 95%

Bile acid profiling as an effective biomarker for staging in pediatric inflammatory bowel disease

Chen,

Wang,

Deng

et al. 2024

Gut Microbes

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Rapid and accurate clinical staging of pediatric patients with inflammatory bowel disease (IBD) is crucial to determine the appropriate therapeutic approach. This study aimed to identify effective, convenient biomarkers for staging IBD in pediatric patients. We recruited cohorts of pediatric patients with varying severities of IBD to compare the features of the intestinal microbiota and metabolites between the active and remitting disease stages. Metabolites with potential for staging were targeted for further assessment in both patients and colitis model mice. The performance of these markers was determined using machine learning and was validated in a separate patient cohort. Pediatric patients with IBD exhibited distinct gut microbiota structures at different stages of disease activity. The enterotypes of patients with remitting and active disease were Bacteroides-dominant and Escherichia-Shigella-dominant , respectively. The bile secretion pathway showed the most significant differences between the two stages. Fecal and serum bile acid (BA) levels were strongly related to disease activity in both children and mice. The ratio of primary BAs to secondary BAs in serum was developed as a novel comprehensive index, showing excellent diagnostic performance in stratifying IBD activity (0.84 area under the receiver operating characteristic curve in the primary cohort; 77% accuracy in the validation cohort). In conclusion, we report profound insights into the interactions between the gut microbiota and metabolites in pediatric IBD. Serum BAs have potential as biomarkers for classifying disease activity, and may facilitate the personalization of treatment for IBD.

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“…155,156 HDCA (TLR4 antagonist), which controls systemic inflammation, lessens organ damage, and increases survival in septic mice, inhibits the formation of the LPS/TLR4/MD2 ternary complex and prevents the activation of the TLR4 downstream signaling pathway in macrophages. 157 Chlorthalidomide mitigates sepsisinduced oxidative stress, mitochondrial structural damage and dysfunction, and cardiomyocyte apoptosis by controlling macrophage polarization via TLR4/NF-κB/MAPK signaling. 158 RKH binds to TLR4 directly and inhibits TLR4 activation in immune cells, preventing organ damage and death brought on by sepsis.…”

Section: Sepsismentioning

confidence: 99%

Toll‐like receptors in health and disease

Wang,

Huang,

Zhan

et al. 2024

MedComm

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Toll‐like receptors (TLRs) are inflammatory triggers and belong to a family of pattern recognition receptors (PRRs) that are central to the regulation of host protective adaptive immune responses. Activation of TLRs in innate immune myeloid cells directs lymphocytes to produce the most appropriate effector responses to eliminate infection and maintain homeostasis of the body's internal environment. Inappropriate TLR stimulation can lead to the development of general autoimmune diseases as well as chronic and acute inflammation, and even cancer. Therefore, TLRs are expected to be targets for therapeutic treatment of inflammation‐related diseases, autoimmune diseases, microbial infections, and human cancers. This review summarizes the recent discoveries in the molecular and structural biology of TLRs. The role of different TLR signaling pathways in inflammatory diseases, autoimmune diseases such as diabetes, cardiovascular diseases, respiratory diseases, digestive diseases, and even cancers (oral, gastric, breast, colorectal) is highlighted and summarizes new drugs and related clinical treatments in clinical trials, providing an overview of the potential and prospects of TLRs for the treatment of TLR‐related diseases.

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Gut microbial metabolite hyodeoxycholic acid targets the TLR4/MD2 complex to attenuate inflammation and protect against sepsis

Cited by 27 publications

References 62 publications

Goreisan‐induced modulation of fecal bile acid composition and gut microbiota in mice

Goreisan‐induced modulation of fecal bile acid composition and gut microbiota in mice

Bile acid profiling as an effective biomarker for staging in pediatric inflammatory bowel disease

Toll‐like receptors in health and disease

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