Pu-erh tea displays cholesterol-lowering properties, but the underlying mechanism has not been elucidated. Theabrownin is one of the most active and abundant pigments in Pu-erh tea. Here, we show that theabrownin alters the gut microbiota in mice and humans, predominantly suppressing microbes associated with bile-salt hydrolase (BSH) activity. Theabrownin increases the levels of ileal conjugated bile acids (BAs) which, in turn, inhibit the intestinal FXR-FGF15 signaling pathway, resulting in increased hepatic production and fecal excretion of BAs, reduced hepatic cholesterol, and decreased lipogenesis. The inhibition of intestinal FXR-FGF15 signaling is accompanied by increased gene expression of enzymes in the alternative BA synthetic pathway, production of hepatic chenodeoxycholic acid, activation of hepatic FXR, and hepatic lipolysis. Our results shed light into the mechanisms behind the cholesterol- and lipid-lowering effects of Pu-erh tea, and suggest that decreased intestinal BSH microbes and/or decreased FXR-FGF15 signaling may be potential anti-hypercholesterolemia and anti-hyperlipidemia therapies.

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There are three major dendritic cell (DC) subsets in both humans and mice, that is, plasmacytoid DCs and two types of conventional DCs (cDCs), cDC1s and cDC2s. cDC2s are important for polarizing CD4 naive T cells into different subsets, including Th1, Th2, Th17, Th22, and regulatory T cells. In mice, cDC2s can be further divided into phenotypically and functionally distinct subgroups. However, subsets of human cDC2s have not been reported. In the present study, we showed that human blood CD1c cDCs (cDC2s) can be further separated into two subpopulations according to their CD5 expression status. Comparative transcriptome analyses showed that the CD5 DCs expressed higher levels of cDC2-specific genes, including IFN regulatory factor 4, which is essential for the cDC2 development and its migration to lymph nodes. In contrast, CD5 DCs preferentially expressed monocyte-related genes, including the lineage-specific transcription factor MAFB. Furthermore, compared with the CD5 subpopulation, the CD5 subpopulation showed stronger migration toward CCL21 and overrepresentation among migratory DCs in lymph nodes. Additionally, the CD5 DCs induced naive T cell proliferation more potently than did the CD5 DCs. Moreover, CD5 DCs induced higher levels of IL-10-, IL-22-, and IL-4-producing T cell formation, whereas CD5 DCs induced higher levels of IFN-γ-producing T cell formation. Thus, we show that human blood CD1c cDC2s encompass two subsets that differ significantly in phenotype, that is, gene expression and functions. We propose that these two subsets of human cDC2s could potentially play contrasting roles in immunity or tolerance.

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Background: The composition of the bile acid (BA) pool is closely associated with obesity and is modified by gut microbiota. Perturbations of gut microbiota shape the BA composition, which, in turn, may alter important BA signaling and affect host metabolism. Methods: We investigated BA composition of high BMI subjects from a human cohort study and a high fat diet (HFD) obesity prone (HF-OP) / HFD obesity resistant (HF-OR) mice model. Gut microbiota was analysed by metagenomics sequencing. GLP-1 secretion and gene regulation studies involved ELISA, qPCR, Western blot, Immunohistochemistry, and Immunofluorescence staining. Findings: We found that the proportion of non-12-OH BAs was significantly decreased in the unhealthy high BMI subjects. The HF-OR mice had an enhanced level of non-12-OH BAs. Non-12-OH BAs including ursodeoxycholate (UDCA), chenodeoxycholate (CDCA), and lithocholate (LCA) were decreased in the HF-OP mice and associated with altered gut microbiota. Clostridium scindens was decreased in HF-OP mice and had a positive correlation with UDCA and LCA. Gavage of Clostridium scindens in mice increased the levels of hepatic non-12-OH BAs, accompanied by elevated serum 7a-hydroxy-4-cholesten-3-one (C4) levels. In HF-OP mice, altered BA composition was associated with significantly downregulated expression of GLP-1 in ileum and PGC1a, UCP1 in brown adipose tissue. In addition, we identified that UDCA attenuated the high fat dietinduced obesity via enhancing levels of non-12-OH BAs. Interpretation: Our study highlights that dysregulated BA signaling mediated by gut microbiota contributes to obesity susceptibility, suggesting modulation of BAs could be a promising strategy for obesity therapy.

Inflammatory cells and mediators form a major part of the tumor microenvironment and play important roles in the regulation of cancer initiation, tumor cell proliferation, and metastasis. MicroRNAs (miRNAs) play important roles in several physiological and pathological processes, including the regulation of the inflammatory microenvironment in cancer. Transforming growth factor-β (TGF-β) is an inflammation-related cytokine that functions in both tumor suppression and promotion; however, its underlying molecular mechanisms remain unclear. Recent evidence indicates an association between miRNAs and TGF-β signaling, providing new insight into the nature of the inflammatory microenvironment in cancer. The present review is an overview of the interaction between miRNAs and inflammatory cytokines, with emphasis on the cross talk between TGF-β signaling and miRNAs and their influence on cancer cell behavior. The emerging roles of miRNAs in cancer-related inflammation and the potential to target miRNA signaling pathways for cancer therapy are also discussed.

Hyocholic acid (HCA) is a major bile acid (BA) species in the BA pool of pigs, a species known for its exceptional resistance to spontaneous development of diabetic phenotypes. HCA and its derivatives are also present in human blood and urine. We investigate whether human HCA profiles can predict the development of metabolic disorders. We find in the first cohort (n = 1107) that both obesity and diabetes are associated with lower serum concentrations of HCA species. A separate cohort study (n = 91) validates this finding and further reveals that individuals with pre-diabetes are associated with lower levels of HCA species in feces. Serum HCA levels increase in the patients after gastric bypass surgery (n = 38) and can predict the remission of diabetes two years after surgery. The results are replicated in two independent, prospective cohorts (n = 132 and n = 207), where serum HCA species are found to be strong predictors for metabolic disorders in 5 and 10 years, respectively. These findings underscore the association of HCA species with diabetes, and demonstrate the feasibility of using HCA profiles to assess the future risk of developing metabolic abnormalities.

Comprehensive and accurate characterization of brain metabolome is fundamental to brain science, but has been hindered by technical limitations. We profiled the brain metabolome in male Wistar rats at different ages (day 1 to week 111) using high-sensitivity and high-resolution mass spectrometry. Totally 380 metabolites were identified and 232 of them were quantitated. Compared with anatomical regions, age had a greater effect on variations in the brain metabolome. Lipids, fatty acids and amino acids accounted for the largest proportions of the brain metabolome, and their concentrations varied across the lifespan. The levels of polyunsaturated fatty acids were higher in infancy (week 1 to week 3) compared with later ages, and the ratio of omega-6 to omega-3 fatty acids increased in the aged brain (week 56 to week 111). Importantly, a panel of 20 bile acids were quantitatively measured, most of which have not previously been documented in the brain metabolome. This study extends the breadth of the mammalian brain metabolome as well as our knowledge of functional brain development, both of which are critically important to move the brain science forward.