The gut microbiota plays a significant role in the progression of fatty liver disease; however, the mediators and their mechanisms remain to be elucidated. Comparing metabolite profile differences between germ-free and conventionally raised mice against differences between mice fed a low- and high-fat diet (HFD), we identified tryptamine and indole-3-acetate (I3A) as metabolites that depend on the microbiota and are depleted under a HFD. Both metabolites reduced fatty-acid- and LPS-stimulated production of pro-inflammatory cytokines in macrophages and inhibited the migration of cells toward a chemokine, with I3A exhibiting greater potency. In hepatocytes, I3A attenuated inflammatory responses under lipid loading and reduced the expression of fatty acid synthase and sterol regulatory element-binding protein-1c. These effects were abrogated in the presence of an aryl-hydrocarbon receptor (AhR) antagonist, indicating that the effects are AhR dependent. Our results suggest that gut microbiota could influence inflammatory responses in the liver through metabolites engaging host receptors.

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There is increasing evidence that the intestinal microbiota plays a mechanistic role in the etiology of non-alcoholic fatty liver disease (NAFLD). Animal and human studies have linked small molecule metabolites produced by commensal bacteria in the gut contribute to not only intestinal inflammation, but also to hepatic inflammation. These immunomodulatory metabolites are capable of engaging host cellular receptors, and may mediate the observed association between gut dysbiosis and NAFLD. This review focuses on the effects and potential mechanisms of three specific classes of metabolites that synthesized or modified by gut bacteria: short chain fatty acids, amino acid catabolites, and bile acids. In particular, we discuss their role as ligands for cell surface and nuclear receptors regulating metabolic and inflammatory pathways in the intestine and liver. Studies reveal that the metabolites can both agonize and antagonize their cognate receptors to reduce or exacerbate liver steatosis and inflammation, and that the effects are metabolite-and context-specific. Further studies are warranted to more comprehensively understand bacterial metabolite-mediated gut-liver in NAFLD. This understanding could help identify novel therapeutics and therapeutic targets to intervene in the disease through the gut microbiota.

Ultraviolet (UV)-induced pigmentation is very common in clinical practice, but the current treatments are rarely effective, accompanied by some side effects. Ganoderma lucidum polysaccharide (GLP) is a natural antioxidant with no toxic side effects, which can antagonize UVB-induced fibroblast photo aging. The study aims to explore the role of GLP in inhibiting UVB-induced melanogenesis and its possible mechanism. The expression of melanogenesis genes such as microphthalmia-associated transcription factor (MITF), tyrosine (TYR), tyrosinase related protein 1 (TYRP1), tyrosinase related protein 2 (TYRP2), ras-related protein Rab-27A (Rab27A), and Myosin shows an upward trend after exposure of B16F10 and PIG1 cells to UVB irradiation, but GLP can downregulate the expression of genes related to UVB-induced melanogenesis. GLP can inhibit UVB-activated protein kinase A (PKA) and mitogen-activated protein kinase (MAPK) signaling pathways. Besides, GLP protects mitochondria from UVB damage and inhibits reactive oxygen species (ROS) production. Also, UVB-induced cyclic adenosine monophosphate (cAMP) can be inhibited. It has been found in the experiments of UVB-induced skin pigmentation in zebrafish that GLP is capable of inhibiting UVB-induced skin pigmentation. Meanwhile, it can greatly relieve erythema reaction in guinea pig skin caused by high-dosage UVB irradiation. In conclusion, this study shows that GLP can inhibit UVB-induced melanogenesis by antagonizing cAMP/ PKA and ROS/MAPK signaling pathways and is a potential natural safe whitening sunscreen additive. K E Y W O R D S Ganoderma lucidum polysaccharide (GLP), melanogenesis, mitogen-activated protein kinase signaling pathway (MAPK), protein kinase A (PKA) signaling pathway, ultraviolet B (UVB) J Cell Physiol. 2019;234:7330-7340. wileyonlinelibrary.com/journal/jcp 7330 | Abbreviations: cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-binding protein; GLP, Ganoderma lucidum polysaccharide; IgG, immunoglobulin G; MAPK, mitogenactivated protein kinase; MITF, microphthalmia-associated transcription factor; PKA, protein kinase A; PVDF, polyvinylidene difluoride; Rab27A, ras-related protein Rab-27A; ROS, reactive oxygen species; RT-PCR, reverse transcription polymerase chain reaction; TYR, tyrosine; TYRP1, tyrosinase related protein 1; TYRP2, tyrosinase related protein 2; UVB, ultraviolet B. *Shuanghai Hu and Jinhua Huang have contributed equally to this study.