A cross-omics data analysis strategy for metabolite-microbe pair identification.

Given the pivotal roles of metabolomics and microbiomics, numerous data mining approaches aim to uncover their intricate connections. However, the complex many-to-many associations between metabolome-microbiome profiles yield numerous statistically significant but biologically unvalidated candidates. To address these challenges, we introduce BiOFI, a strategic framework for identifying metabolome-microbiome correlation pairs (Bi-Omics). BiOFI employs a comprehensive scoring system, incorporating intergroup differences, effects on feature correlation networks, and organism abundance. Meanwhile, it establishes a built-in database of metabolite-microbe-KEGG functional pathway linking relationships. Furthermore, BiOFI can rank related feature pairs by combining importance scores and correlation strength. Validation on a dataset of cesarean-section infants confirms the strategy's validity and interpretability. The BiOFI R package is freely accessible at https://github.com/chentianlu/BiOFI.

Gut bacteria-driven homovanillic acid alleviates depression by modulating synaptic integrity.

The gut-brain axis is implicated in depression development, yet its underlying mechanism remains unclear. We observed depleted gut bacterial species, including Bifidobacterium longum and Roseburia intestinalis, and the neurotransmitter homovanillic acid (HVA) in individuals with depression and mouse depression models. Although R. intestinalis does not directly produce HVA, it enhances B. longum abundance, leading to HVA generation. This highlights a synergistic interaction among gut microbiota in regulating intestinal neurotransmitter production. Administering HVA, B. longum, or R. intestinalis to mouse models with chronic unpredictable mild stress (CUMS) and corticosterone (CORT)-induced depression significantly improved depressive symptoms. Mechanistically, HVA inhibited synaptic autophagic death by preventing excessive degradation of microtubule-associated protein 1 light chain 3 (LC3) and SQSTM1/p62 proteins, protecting hippocampal neurons' presynaptic membrane. These findings underscore the role of the gut microbial metabolism in modulating synaptic integrity and provide insights into potential novel treatment strategies for depression.

Serum Bile Acids Improve Prediction of Alzheimer's Progression in a Sex-Dependent Manner.

Sex disparities in serum bile acid (BA) levels and Alzheimer's disease (AD) prevalence have been established. However, the precise link between changes in serum BAs and AD development remains elusive. Here, authors quantitatively determined 33 serum BAs and 58 BA features in 4 219 samples collected from 1 180 participants from the Alzheimer's Disease Neuroimaging Initiative. The findings revealed that these BA features exhibited significant correlations with clinical stages, encompassing cognitively normal (CN), early and late mild cognitive impairment, and AD, as well as cognitive performance. Importantly, these associations are more pronounced in men than women. Among participants with progressive disease stages (n = 660), BAs underwent early changes in men, occurring before AD. By incorporating BA features into diagnostic and predictive models, positive enhancements are achieved for all models. The area under the receiver operating characteristic curve improved from 0.78 to 0.91 for men and from 0.76 to 0.83 for women for the differentiation of CN and AD. Additionally, the key findings are validated in a subset of participants (n = 578) with cerebrospinal fluid amyloid-beta and tau levels. These findings underscore the role of BAs in AD progression, offering potential improvements in the accuracy of AD prediction.

Hyodeoxycholic acid alleviates non-alcoholic fatty liver disease through modulating the gut-liver axis.

Non-alcoholic fatty liver disease (NAFLD) is regarded as a pandemic that affects about a quarter of the global population. Recently, host-gut microbiota metabolic interactions have emerged as distinct mechanistic pathways implicated in the development of NAFLD. Here, we report that a group of gut microbiota-modified bile acids (BAs), hyodeoxycholic acid (HDCA) species, are negatively correlated with the presence and severity of NAFLD. HDCA treatment has been shown to alleviate NAFLD in multiple mouse models by inhibiting intestinal farnesoid X receptor (FXR) and upregulating hepatic CYP7B1. Additionally, HDCA significantly increased abundances of probiotic species such as Parabacteroides distasonis, which enhances lipid catabolism through fatty acid-hepatic peroxisome proliferator-activated receptor alpha (PPARα) signaling, which in turn upregulates hepatic FXR. These findings suggest that HDCA has therapeutic potential for treating NAFLD, with a unique mechanism of simultaneously activating hepatic CYP7B1 and PPARα.

Theabrownin and Poria cocos Polysaccharide Improve Lipid Metabolism via Modulation of Bile Acid and Fatty Acid Metabolism.

Nonalcoholic fatty liver disease (NAFLD) is prevalent worldwide, while no pharmaceutical treatment has been approved. Natural herbs are promising for their amelioration effect on lipid metabolism. Theabrownin (TB) and Poria cocos polysaccharide (PCP) have been reported to have effect on hyperlipidemia and diabetes. Here, we compared the effect of individual TB or PCP and the combination of TB and PCP (TB + PCP) on NAFLD phenotypes and the alteration of metabolism in the mice with high-fat diet. The results showed that TB, PCP, and TB + PCP reduced serum and hepatic lipid levels, among which TB + PCP was the most effective. Serum metabolomic profile and liver mRNA analyses revealed that the treatments altered metabolic pathways involved in fatty acid metabolism, bile acid metabolism, and tricarboxylic acid cycle, which was also most significant in the TB + PCP group. This study demonstrated that TB, PCP, especially the combination of TB and PCP could be potential therapeutic formula for NAFLD that promoted lipid utilization and inhibited lipid synthesis and absorption.

Gut microbiota-bile acid crosstalk contributes to the rebound weight gain after calorie restriction in mice.

Calorie restriction (CR) and fasting are common approaches to weight reduction, but the maintenance is difficult after resuming food consumption. Meanwhile, the gut microbiome associated with energy harvest alters dramatically in response to nutrient deprivation. Here, we reported that CR and high-fat diet (HFD) both remodeled the gut microbiota with similar microbial composition, Parabacteroides distasonis was most significantly decreased after CR or HFD. CR altered microbiota and reprogramed metabolism, resulting in a distinct serum bile acid profile characterized by depleting the proportion of non-12α-hydroxylated bile acids, ursodeoxycholic acid and lithocholic acid. Downregulation of UCP1 expression in brown adipose tissue and decreased serum GLP-1 were observed in the weight-rebound mice. Moreover, treatment with Parabacteroides distasonis or non-12α-hydroxylated bile acids ameliorated weight regain via increased thermogenesis. Our results highlighted the gut microbiota-bile acid crosstalk in rebound weight gain and Parabacteroides distasonis as a potential probiotic to prevent rapid post-CR weight gain.

Bile Acid-Microbiome Interaction Promotes Gastric Carcinogenesis.

Bile reflux gastritis (BRG) is associated with the development of gastric cancer (GC), but the specific mechanism remains elusive. Here, a comprehensive study is conducted to explore the roles of refluxed bile acids (BAs) and microbiome in gastric carcinogenesis. The results show that conjugated BAs, interleukin 6 (IL-6), lipopolysaccharide (LPS), and the relative abundance of LPS-producing bacteria are increased significantly in the gastric juice of both BRG and GC patients. A secondary BA, taurodeoxycholic acid (TDCA), is significantly and positively correlated with the LPS-producing bacteria in the gastric juice of these patients. TDCA promotes the proliferation of normal gastric epithelial cells (GES-1) through activation of the IL-6/JAK1/STAT3 pathway. These results are further verified in two mouse models, one by gavage of TDCA, LPS, and LPS-producing bacteria (Prevotella melaninogenica), respectively, and the other by bile reflux (BR) surgery, mimicking clinical bile refluxing. Moreover, the bile reflux induced gastric precancerous lesions observed in the post BR surgery mice can be prevented by treatment with cryptotanshinone, a plant-derived STAT3 inhibitor. These results reveal an important underlying mechanism by which bile reflux promotes gastric carcinogenesis and provide an alternative strategy for the prevention of GC associated with BRG.

Hyocholic acid species as novel biomarkers for metabolic disorders.

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.

Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism.

Hyocholic acid (HCA) and its derivatives are found in trace amounts in human blood but constitute approximately 76% of the bile acid (BA) pool in pigs, a species known for its exceptional resistance to type 2 diabetes. Here, we show that BA depletion in pigs suppressed secretion of glucagon-like peptide-1 (GLP-1) and increased blood glucose levels. HCA administration in diabetic mouse models improved serum fasting GLP-1 secretion and glucose homeostasis to a greater extent than tauroursodeoxycholic acid. HCA upregulated GLP-1 production and secretion in enteroendocrine cells via simultaneously activating G-protein-coupled BA receptor, TGR5, and inhibiting farnesoid X receptor (FXR), a unique mechanism that is not found in other BA species. We verified the findings in TGR5 knockout, intestinal FXR activation, and GLP-1 receptor inhibition mouse models. Finally, we confirmed in a clinical cohort, that lower serum concentrations of HCA species were associated with diabetes and closely related to glycemic markers.

Anti-Adipogenic Effect of Theabrownin Is Mediated by Bile Acid Alternative Synthesis via Gut Microbiota Remodeling.

Theabrownin is one of the most bioactive compounds in Pu-erh tea. Our previous study revealed that the hypocholesterolemic effect of theabrownin was mediated by the modulation of bile salt hydrolase (BSH)-enriched gut microbiota and bile acid metabolism. In this study, we demonstrated that theabrownin ameliorated high-fat-diet (HFD)-induced obesity by modifying gut microbiota, especially those with 7α-dehydroxylation on the species level, and these changed microbes were positively correlated with secondary bile acid (BA) metabolism. Thus, altered intestinal BAs resulted in shifting bile acid biosynthesis from the classic to the alternative pathway. This shift changed the BA pool by increasing non-12α-hydroxylated-BAs (non-12OH-BAs) and decreasing 12α-hydroxylated BAs (12OH-BAs), which improved energy metabolism in white and brown adipose tissue. This study showed that theabrownin was a potential therapeutic modality for obesity and other metabolic disorders via gut microbiota-driven bile acid alternative synthesis.

Theabrownin from Pu-erh tea attenuates hypercholesterolemia via modulation of gut microbiota and bile acid metabolism.

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.