Gut microbial bile acid metabolite skews macrophage polarization and contributes to high-fat diet-induced colonic inflammation

Wang, Lingyu; Gong, Zizhen; Zhang, Xiuyuan; Zhu, Fangxinxing; Liu, Yuchen; Jin, Chaozhi; Du, Xixi; Xu, Congfeng; Chen, Yingwei; Cai, Wei; Tian, Chunyan; Wu, Jin Shang

doi:10.1080/19490976.2020.1819155

Cited by 104 publications

(72 citation statements)

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“…As shown in Figures 4A-E, this finding supported the occurrence of damage of the ileal mucosal barrier in diabetic KKAy mice (DM group) and repaired ileal inflammatory damage after treatment with both doses of SZ-A. LPS production is also responsible for inducing monocyte-and macrophage-mediated inflammation in the intestine (Wang et al, 2020). Gut macrophages, which reside in the connective tissue underlying the gut epithelium, the lamina propria, are considered key players for the maintenance of intestinal homeostasis and inflammation (Yang et al, 2020).…”

Section: Discussionsupporting

confidence: 78%

Ramulus Mori (Sangzhi) Alkaloids (SZ-A) Ameliorate Glucose Metabolism Accompanied by the Modulation of Gut Microbiota and Ileal Inflammatory Damage in Type 2 Diabetic KKAy Mice

Liu

Cao

et al. 2021

Front. Pharmacol.

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The novel Traditional Chinese Medicine Ramulus Mori (Sangzhi) alkaloid tablets (SZ-A) are approved by The China National Medical Products Administration for the treatment of type 2 diabetes mellitus (T2DM). However, the extensive pharmacological characteristics and the underlying mechanism are unknown. This study investigated the mechanisms by which SZ-A ameliorates glucose metabolism in KKAy mice, an animal model of T2DM. Diabetic KKAy mice were treated intragastrically with SZ-A once daily for 8 weeks, after which glucose levels, lipid metabolism, gut microbiome, systemic inflammatory factors, luminal concentrations of short-chain fatty acids (fecal samples), and ileal proteomic changes were evaluated. The ileum tissues were collected, and the effects of SZ-A on pathological inflammatory damage were evaluated by hematoxylin and eosin staining, immunofluorescence, and immunohistochemistry. The mRNA and protein expression levels of various inflammatory markers, including monocyte chemoattractant protein-1 and phosphorylated nuclear factor kappa B p65, were detected in the ileum tissues. SZ-A improved glucose metabolism with enhanced insulin response and elevated glucagon-like peptide 1 (GLP-1) nearly 2.7-fold during the glucose tolerance test in diabetic KKAy mice. Gut microbiota analysis demonstrated that SZ-A administration elevated the abundance of Bacteroidaceae and Verrucomicrobia, reduced the levels of Rikenellaceae and Desulfovibrionaceae; and increased the concentrations of fecal acetic and propionic acids compared to the diabetic model group. Additionally, SZ-A markedly improved ileal inflammatory injury and pro-inflammatory macrophage infiltration and improved intestinal mucosal barrier function in diabetic KKAy mice. SZ-A also attenuated the levels of circulating endotoxin, pro-inflammatory cytokines, and chemokines in the mice sera. Collectively, SZ-A ameliorated the overall metabolic profile including glucose and lipid metabolism in KKAy mice, which may be associated with an improvement in GLP-1 and insulin secretion, at least in part by modulating the gut microbiome and relieving the degree of ileal and systemic inflammation.

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Section: Discussionsupporting

confidence: 78%

Ramulus Mori (Sangzhi) Alkaloids (SZ-A) Ameliorate Glucose Metabolism Accompanied by the Modulation of Gut Microbiota and Ileal Inflammatory Damage in Type 2 Diabetic KKAy Mice

Liu

Cao

et al. 2021

Front. Pharmacol.

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“…4A to 4E, this nding supported the occurrence of damage of the ileal mucosal barrier in diabetic KKAy mice (DM group) and repaired ileal in ammatory damage after treatment with both doses of SZ-A. LPS production is also responsible for inducing monocyte-and macrophage-mediated in ammation in the intestine [25]. Gut macrophages, which reside in the connective tissue underlying the gut epithelium, the lamina propria, are considered key players for the maintenance of intestinal homeostasis and in ammation [26].…”

Section: Discussionsupporting

confidence: 65%

A Novel Traditional Chinese Medicine, Ramulus Mori (Sangzhi) Alkaloids Ameliorate Glucose Metabolism Accompanied by the Modulation of Gut Microbiota and Ileal Inflammatory Damage in Type 2 Diabetic KKAy Mice

Liu

Cao

et al. 2020

Preprint

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Background: The novel Traditional Chinese Medicine Ramulus Mori (Sangzhi) alkaloid tablets (SZ-A) are approved by The China National Medical Products Administration for the treatment of type 2 diabetes mellitus (T2DM). However, the extensive pharmacological characteristics and the underlying mechanism are unknown. This study investigated the mechanisms by which SZ-A ameliorates glucose metabolism in KKAy mice, an animal model of T2DM.Methods: Diabetic KKAy mice were treated intragastrically with SZ-A once daily for 8 weeks, after which glucose levels, lipid metabolism, gut microbiome, systemic inflammatory factors, luminal concentrations of short-chain fatty acids (fecal samples), and ileal proteomic changes were evaluated. The ileum tissues were collected, and the effects of SZ-A on pathological inflammatory damage were evaluated by hematoxylin and eosin staining, immunofluorescence, and immunohistochemistry. The mRNA and protein expression levels of various inflammatory markers, including monocyte chemoattractant protein-1 and phosphorylated nuclear factor kappa B p65, were detected in the ileum tissues. Results: SZ-A improved glucose metabolism with enhanced insulin response and elevated glucagon-like peptide 1 (GLP-1) during the glucose tolerance test in diabetic KKAy mice. Gut microbiota analysis demonstrated that SZ-A administration elevated the abundance of Bacteroidaceae and Verrucomicrobia, reduced the levels of Rikenellaceae and Desulfovibrionaceae; and increased the concentrations of fecal acetic and propionic acids compared to the diabetic model group. Additionally, SZ-A markedly improved ileal inflammatory injury and pro-inflammatory macrophage infiltration and improved intestinal mucosal barrier function in diabetic KKAy mice. SZ-A also attenuated the levels of circulating endotoxin, pro-inflammatory cytokines, and chemokines in the mice sera.Conclusions: SZ-A ameliorated the overall metabolic profile including glucose and lipid metabolism in KKAy mice, which may be associated with an improvement in GLP-1 and insulin secretion, at least in part by modulating the gut microbiome and relieving the degree of ileal and systemic inflammation.

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“…Among them, SCFAs were the most abundant and extensively investigated metabolites [ 58 ]. In HFD mice and DSS mice, BA was evaluated as an effective metabolic factor correlated with the gut microbiota which affects the health of the host relative to SCFAs [ 19 – 21 ]. Our results also showed that microbial change induced by LPS stimulation is deleterious to BA enterohepatic circulation.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, microbiota-derived metabolites, including the endotoxin LPS, bile acids (BAs), trimethylamine N-oxide (TMAO), indolepropionic acid (IPA), and short-chain fatty acids (SCFAs), have attracted wider scientific attentions [11,[14][15][16], though SCFAs are the most common and abundant metabolites [17]. However, BAs, important endogenous molecules, have gradually been paid more attention in the field of liver diseases and intestinal inflammation [18][19][20]. Compared with SCFAs, BAs have been identified to be more relevant with gut microbiota in mice feeding on a high-fat diet (HFD) [21].…”

Section: Introductionmentioning

confidence: 99%

Gut Immunity and Microbiota Dysbiosis Are Associated with Altered Bile Acid Metabolism in LPS‐Challenged Piglets

Xiao

Cheng

et al. 2021

Oxidative Medicine and Cellular Longevity

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Bacterial infections are among the major factors that cause stress and intestinal diseases in piglets. Lipopolysaccharide (LPS), a major component of the Gram-negative bacteria outer membrane, is commonly employed for inducing an immune response in normal organisms for convenience. The association between LPS stimulation and gut immunity has been reported. However, the effects of gut immunity on microbial homeostasis and metabolism of host, especially bile acid and lipid metabolism in piglets, remain unclear. Hence, in the current study, we elucidated the effect of gut immunity on microbial balance and host metabolism. Twenty-one-day-old healthy piglets (male) were randomly assigned into the CON and LPS groups. After 4 hours of treatment, related tissues and cecal contents were obtained for further analysis. The obtained results showed that stimulated LPS considerably damaged the morphology of intestinal villi and enhanced the relative expression of proinflammatory cytokines. Besides, LPS partially changed the microbial structure as indicated by β-diversity and increased operational taxonomic units (OTUs) related to Oxalobacter and Ileibacterium. Furthermore, bile acid, a large class of gut microbiota metabolites, was also assessed by many proteins related to the enterohepatic circulation of bile acids. It was also revealed that LPS markedly inhibited the mRNA and protein expression of TGR5 and FXR (bile acid receptors) in the ileum, which expressed negative feedback on bile acid de novo synthesis. Additionally, results indicated upregulated mRNA of genes associated with the production of bile acid in the liver tissues. Moreover, LPS reduced the expression of bile acid transporters in the ileum and liver tissues and further disturbed the normal enterohepatic circulation. Taken together, gut immunity and microbial dysbiosis are associated with altered bile acid metabolism in LPS-challenged piglets, which provided theoretical basis for revealing the potential mechanism of intestinal inflammation in swine and seeking nutrients to resist intestinal damage.

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Gut microbial bile acid metabolite skews macrophage polarization and contributes to high-fat diet-induced colonic inflammation

Abstract: Gut microbial bile acid metabolite skews macrophage polarization and contributes to high-fat dietinduced colonic inflammation,

Cited by 104 publications

References 50 publications

Ramulus Mori (Sangzhi) Alkaloids (SZ-A) Ameliorate Glucose Metabolism Accompanied by the Modulation of Gut Microbiota and Ileal Inflammatory Damage in Type 2 Diabetic KKAy Mice

Ramulus Mori (Sangzhi) Alkaloids (SZ-A) Ameliorate Glucose Metabolism Accompanied by the Modulation of Gut Microbiota and Ileal Inflammatory Damage in Type 2 Diabetic KKAy Mice

A Novel Traditional Chinese Medicine, Ramulus Mori (Sangzhi) Alkaloids Ameliorate Glucose Metabolism Accompanied by the Modulation of Gut Microbiota and Ileal Inflammatory Damage in Type 2 Diabetic KKAy Mice

Gut Immunity and Microbiota Dysbiosis Are Associated with Altered Bile Acid Metabolism in LPS‐Challenged Piglets

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