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The Gut Microbiota-Produced Indole-3-Propionic Acid Confers the Antihyperlipidemic Effect of Mulberry-Derived 1-Deoxynojirimycin.

ABSTRACT: Hyperlipidemia is a worldwide epidemic with an obvious gender disparity in incidence. Modulations on gut microbiota by traditional Chinese medicines (TCM) are emerging as a potential rationale governing the profitable effects of drugs on hyperlipidemia. However, it is unclear how gut microbes regulate the progression of hyperlipidemia. Here, we found that mulberry leaf extract (MLE) and its active component 1-deoxynojirimycin (DNJ) diminished hyperglycemia and hypertriglyceridemia with similar efficacy in male and female mice but preferentially alleviated hypercholesterolemia in female mice. Further investigations showed that DNJ sex-specifically downregulated the expression of lipogenic genes, especially cholesterol-biosynthetic genes. Oral administration of DNJ imposed more profound modulation on gut microbiota in female mice than in male ones, as estimated by 16S rRNA metatranscriptomic analysis. DNJ markedly enriched Akkermansia and Clostridium group XIVa and promoted the production of indole-3-propionic acid (IPA) in a sexually dimorphic way. Importantly, IPA tightly associates with the antihyperlipidemic effect of DNJ and exhibited a potent lipid-lowering effect both in vitro and in vivo Together, our results have established a regulatory mechanism by which DNJ sex-specifically improves hyperlipidemia, offering an in-depth theoretical basis for therapeutic exploitation of DNJ as a sex-specific intervention against hyperlipidemia.IMPORTANCE Hyperlipidemia has been intensively focused on by researchers around the world owing to its major contribution to cardiovascular diseases. Various evidence reveals that women are more susceptible than male counterparts to dyslipidemia, making sex-dependent therapeutic strategies and drugs urgently needed. In the present work, we demonstrate that DNJ, the main active component of mulberry leaves, exerts an obvious female-preferential antihyperlipidemic effect through specifically enriching Akkermansia and Clostridium XIVa and elevating an active microbial metabolite, indole-3-propionic acid (IPA), in female mice. Moreover, we have corroborated the potent lipid-lowering efficacy of IPA both in vitro and in vivo These findings not only indicate a potential mechanism by which gut microbes and their metabolites confer the beneficial role of DNJ in ameliorating hyperlipidemia but also provide an in-depth theoretical basis for therapeutic exploitation of DNJ as a female-specific intervention against hyperlipidemia.

SUBMITTER: Li Y

PROVIDER: S-EPMC7542557 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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The Gut Microbiota-Produced Indole-3-Propionic Acid Confers the Antihyperlipidemic Effect of Mulberry-Derived 1-Deoxynojirimycin.

Li Yougui Y Xu Wenyi W Zhang Fang F Zhong Shi S Sun Yuqing Y Huo Jinxi J Zhu Jianxun J Wu Chongming C

mSystems 20201006 5

Hyperlipidemia is a worldwide epidemic with an obvious gender disparity in incidence. Modulations on gut microbiota by traditional Chinese medicines (TCM) are emerging as a potential rationale governing the profitable effects of drugs on hyperlipidemia. However, it is unclear how gut microbes regulate the progression of hyperlipidemia. Here, we found that mulberry leaf extract (MLE) and its active component 1-deoxynojirimycin (DNJ) diminished hyperglycemia and hypertriglyceridemia with similar e ...[more]

PMID: 33024047

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Project description:This study was aimed to investigate whether 1-deoxynojirimycin (DNJ) affects the digestion system of young geese and assess whether mulberry leaf, which contains this substance, has disadvantages that compromise its value as poultry feed. One hundred and twenty-eight 12-day-old male Wanxi white geese were randomly assigned into 4 treatment groups. The control group was fed an ordinary diet without DNJ. The other groups namely L-DNJ, M-DNJ, and H-DNJ had their basic diets supplemented with 0.05 mg/g, 0.1 mg/g, and 0.15 mg/g DNJ, respectively. The geese were fed for 6 wk, and the apparent digestibility test was conducted in the last week. Intestinal parameters, digestive organs, and enzymes were determined. 16S rRNA gene sequencing was conducted for cecal flora composition. The results revealed that DNJ decreased body and liver weight and increased feed conversion ratio in comparison with the control (P < 0.05); however, it did not influence the weight and length of the intestine or the pancreas weight. The utilization of organic matter, metabolizable energy, ether extract, acid detergent fiber, and calcium in feed were reduced in the M-DNJ and L-DNJ groups compared with those in the control (P < 0.05); however, the utilization of crude protein was increased in all DNJ-treated groups (P < 0.01). In the H-DNJ group, the usage of soluble phosphorus was also increased (P < 0.05). High-dose DNJ increased the activity of trypsin in the pancreas but reduced those of amylase (P < 0.05) and lipase (P > 0.05) in the pancreas and duodenum. The intestinal villi were short, even impaired, in DNJ-treated groups. High-throughput sequencing data revealed that DNJ supplement reduced the α-diversity indices of the cecal microbiota. The principal component analysis further suggested a difference in community structure between the DNJ treatment groups and control. High-dose DNJ increased the relative abundance of Bacteroides, Escherichia-Shigella, and Butyricicoccus but reduced that of unclassified Ruminococcaceae compared with the control (P < 0.05). In conclusion, changes in the digestive system caused by DNJ seriously affected the metabolism of nutrients in geese and reduced their growth performance. Attention should be paid to the adverse effects of DNJ when using mulberry leaves as poultry feed.

Project description:Background: The gut microbiome has been linked to the onset of cardiometabolic diseases, in part facilitated through gut microbiota-dependent metabolites such as trimethylamine-N-oxide. However, molecular pathways associated to heart failure mediated by microbial metabolites remain largely elusive. Mitochondria play a pivotal role in cellular energy metabolism and mitochondrial dysfunction has been associated to heart failure pathogenesis. Aim of the current study was to evaluate the impact of gut-derived metabolites on mitochondrial function in cardiomyocytes via an in vitro screening approach. Methods: Based on a systematic Medline research, 25 microbial metabolites were identified and screened for their metabolic impact with a focus on mitochondrial respiration in HL-1 cardiomyocytes. Oxygen consumption rate in response to different modulators of the respiratory chain were measured by a live-cell metabolic assay platform. For one of the identified metabolites, indole-3-propionic acid, studies on specific mitochondrial complexes, cytochrome c, fatty acid oxidation, mitochondrial membrane potential, and reactive oxygen species production were performed. Mitochondrial function in response to this metabolite was further tested in human hepatic and endothelial cells. Additionally, the effect of indole-3-propionic acid on cardiac function was studied in isolated perfused hearts of C57BL/6J mice. Results: Among the metabolites examined, microbial tryptophan derivative indole-3-propionic acid could be identified as a modulator of mitochondrial function in cardiomyocytes. While acute treatment induced enhancement of maximal mitochondrial respiration (+21.5 ± 7.8%, p < 0.05), chronic exposure led to mitochondrial dysfunction (-18.9 ± 9.1%; p < 0.001) in cardiomyocytes. The latter effect of indole-3-propionic acids could also be observed in human hepatic and endothelial cells. In isolated perfused mouse hearts, indole-3-propionic acid was dose-dependently able to improve cardiac contractility from +26.8 ± 11.6% (p < 0.05) at 1 μM up to +93.6 ± 14.4% (p < 0.001) at 100 μM. Our mechanistic studies on indole-3-propionic acids suggest potential involvement of fatty acid oxidation in HL-1 cardiomyocytes. Conclusion: Our data indicate a direct impact of microbial metabolites on cardiac physiology. Gut-derived metabolite indole-3-propionic acid was identified as mitochondrial modulator in cardiomyocytes and altered cardiac function in an ex vivo mouse model.

Dataset Information

The Gut Microbiota-Produced Indole-3-Propionic Acid Confers the Antihyperlipidemic Effect of Mulberry-Derived 1-Deoxynojirimycin.

Publications

The Gut Microbiota-Produced Indole-3-Propionic Acid Confers the Antihyperlipidemic Effect of Mulberry-Derived 1-Deoxynojirimycin.

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