Microbially produced vitamin B12 contributes to the lipid-lowering effect of silymarin

Abstract

Silymarin has been used for improving hepatic damage and lipid disorders, but its action mechanism remains to be clarified. Here, we investigate the contributions of the gut microbiota to the improvement of liver lipid metabolism by silymarin. We find i) strong and significant microbial shifts upon silymarin but not silibinin treatment; ii) over 60% variations of liver fat are explained by silymarin-induced bacterial B12 production in male rats but not in male germ-free mice; iii) fecal microbiota transplantation confirms their protective roles against liver fat accumulation; iv) upregulation of one-carbon metabolism and fatty acid degradation pathways are observed based on the liver transcriptome analyses; and v) in humans the delta changes of serum B12 associate negatively with the fluctuations of serum triglycerides. Overall, we reveal a mechanism of action underpinning the lipid-lowering effect of silymarin via the gut microbiota and its vitamin B12 producing capabilities.

Silybin A fromSilybum marianumreprograms lipid metabolism to induce a cell fate-dependent class switch from triglycerides to phospholipids

“…The important role of silymarin/silybin in modulating lipid metabolism has been recognized before, and effects on ACC 67,89,165 , FASN 67,89,156,160,165-167 , SCD-1 15,85,160,168 , GPATs 85 , PNPLA3 85,164,166 , FABP5 85,160,168 , CPT1a 67,85,89,160,167,169 , MTTP 85 , ACOX 85 , PPARα/PPARγ 67,85,160,164,166,169,170 and SREBP-1c 67,85,164-166,169,170 have been reported independently, either under disease 67,75,76,85,141,158,159,164,165 or non-disease conditions 72,156,166,167 , largely without considering their interplay. By converging transcriptomics, metabololipidomics, and functional studies, we put these individual findings into context.…”

“…Recently, silymarin (but not silybin) has been proposed to decrease lipid accumulation during a high-fat diet by altering the vitamin B12-producing capacity of the gut microbiota 75 . On the other hand, silymarin/silybin has been suggested to induce phospholipid turnover by upregulating choline phosphate cytidylyltransferase 76 .…”

“…Several studies have found that administration of silymarin/silybin reduces levels of low-density lipoprotein (LDL), VLDL, cholesterol, and/or TGs, while other studies have not observed substantial changes in the serum lipid profile 62-74 , which is not readily understood but may be related to the dose. Recently, silymarin (but not silybin) has been proposed to decrease lipid accumulation during a high-fat diet by altering the vitamin B12-producing capacity of the gut microbiota 75 . On the other hand, silymarin/silybin has been suggested to induce phospholipid turnover by upregulating choline phosphate cytidylyltransferase 76 .…”

Recent advances in gut microbiota-associated natural products: structures, bioactivities, and mechanisms

“…On the basis of metabolomics, our group and other teams have uncovered significant gut microbiota-derived mediators, including secondary bile acids, 33 short-chain fatty acids, 73 vitamins (such as folic acid 70 and vitamin B12 ref. 82), and choline derivatives (such as TMA), 74 as well as amino acid derivatives, and the underlying enzymes contributing to gut microbiome-based mechanisms. However, our knowledge and data about the metabolisms of the gut microbiome are limited, which hinders accurate identification of the key gut metabolites and proteins.…”