Metformin reprograms tryptophan metabolism via gut Microbiome-Derived bile acid metabolites to ameliorate Depression-Like behaviors in mice.

As an adjunct therapy, metformin enhances the efficacy of conventional antidepressant medications. However, its mode of action remains unclear. Here, metformin was found to ameliorate depression-like behaviors in mice exposed to chronic restraint stress (CRS) by normalizing the dysbiotic gut microbiome. Fecal transplants from metformin-treated mice ameliorated depressive behaviors in stressed mice. Microbiome profiling revealed that Akkermansia muciniphila (A. muciniphila), in particular, was markedly increased in the gut by metformin and that oral administration of this species alone was sufficient to reverse CRS-induced depressive behaviors and normalize aberrant stress-induced 5-hydroxytryptamine (5-HT) metabolism in the brain and gut. Untargeted metabolomic profiling further identified the bile acid metabolites taurocholate and deoxycholic acid as direct A. muciniphila-derived molecules that are, individually, sufficient to rescue the CRS-induced impaired 5-HT metabolism and depression-like behaviors. Thus, we report metformin reprograms 5-HT metabolism via microbiome-brain interactions to mitigate depressive syndromes, providing novel insights into gut microbiota-derived bile acids as potential therapeutic candidates for depressive mood disorders from bench to bedside.

Metformin Attenuates the Metabolic Disturbance and Depression-like Behaviors Induced by Corticosterone and Mediates the Glucose Metabolism Pathway.

BACKGROUND: Metabolism disturbances are common in patients with depression. The drug metformin has been reported to exhibit antidepressant activity. The purpose of this study was to investigate metabolism disturbances induced by corticosterone (CORT) and determine if metformin can reverse these effects and their accompanying depression-like behaviors. METHODS: Rats were exposed to corticosterone with or without metformin administration. Depression-like behaviors were tested. Gene expression was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis. In addition, the metabolites were quantified by LC-MS/MS analysis. RESULTS: Metformin attenuated the depression-like behaviors induced by CORT. Furthermore, metformin reversed disturbances in body weight, serum glucose, and triglyceride levels, as well as hepatic TG levels induced by CORT. Metformin normalized the alterations in the expression of glucose metabolism-related genes (PGC-1α, G6pc, Pepck, Gck, PYGL, Gys2, PKLR, GLUT4) and insulin resistance-related genes (AdipoR1, AdipoR2) in the muscles and livers of rats induced by CORT. Metabolomic analysis showed that metformin reversed the effects of CORT on 11 metabolites involved in the pathways of the tricarboxylic acid cycle, glycolysis, and gluconeogenesis (3-phospho-D-glycerate, ß-D-fructose 6-phosphate, D-glucose 6-phosphate, and pyruvate). CONCLUSION: Our findings suggest that metformin can attenuate metabolism disturbances and depression-like behaviors induced by CORT mediating the glucose metabolism pathway.

Exposure to dibutyl phthalate impairs lipid metabolism and causes inflammation via disturbing microbiota-related gut-liver axis.

Dibutyl phthalate (DBP), a kind of typical environmental pollutant, is widely used as plasticizers, and its neurotoxicity and developmental toxicity have been found in recent years. However, whether oral DBP exposure will affect the homeostasis of gut microbiota and its adverse response in liver of mammalians remain unclear. In the present study, 10-week experimental cycles of vehicle or DBP (0.1 and 1 mg/kg) were given to 6-week-old C57BL/6J mice by oral gavage. Our results revealed that the body weight of mice was increased after exposure to both low and high doses of DBP. The serum levels of hepatic triglyceride and total cholesterol were significantly increased in response to both doses of DBP. In addition, some pivotal genes related to lipogenesis were also increased in liver at the mRNA level. Evaluation of gut microbiota by 16S rRNA sequencing technology showed that 0.1 mg/kg DBP exposure significantly affected gut microbiota at the phylum and genus levels. Moreover, DBP exposure decreased mucus secretion and caused inflammation in the gut, leading to the impairment of intestinal barrier function. Exposure to DBP inhibited the expression of peroxisome proliferator-activated receptor-γ and activated the expression of nuclear factor kappa B. In addition, DBP exposure increased the level of lipopolysaccharide in serum, and increased the expression of toll-like receptor 4 and the levels of inflammatory cytokines, such as interleukin (IL)-1ß, IL-6, and tumor necrosis factor alpha, in the liver. These results indicated that exposure to DBP disturbed the homeostasis of gut microbiota, induced hepatic lipid metabolism disorder, and caused liver inflammation in mice via the related gut-liver axis signaling pathways.

Exposure to jet lag aggravates depression-like behaviors and age-related phenotypes in rats subject to chronic corticosterone.

Our previous finding demonstrated that chronic corticosterone (CORT) may be involved in mediating the pathophysiology of premature aging in rats. Frequent jet lag increases the risk for many diseases, including obesity and type 2 diabetes, and is associated with the aging processes. However, the effect of jet lag on CORT-induced depression and its association with aging phenotypes remain unclear. In this study, the rats were exposed to both CORT and jet lag treatment, and the differences were analyzed and compared to rats with single CORT treatment. Our results showed that jet lag treatment aggravated CORT-induced depression-like behavior evidenced by sucrose intake test, forced swimming test, and open field test. Additionally, this treatment aggravated the shortening of telomeres, which possibly resulted in decreased telomerase activity, and downregulated the expression of telomere-binding factor 2 (TRF2) and telomerase reverse transcriptase compared to that in CORT rats, as revealed by quantitative real-time-polymerase chain reaction and western blot analysis, respectively. The shortening of telomeres may have been caused by increased oxidative stress, which was associated with the inhibition of sirtuin 3. Exposure to jet lag also aggravated the degeneration of mitochondrial functions, as shown by the decreases in the mRNA expression of COX1, ND1, and Tfam. Our findings provide physiological evidence that jet lag exposure may worsen stress-induced depression and age-related abnormalities.

ß-Cypermethrin and its metabolite 3-phenoxybenzoic acid induce cytotoxicity and block granulocytic cell differentiation in HL-60 cells.

The most widely used type II pyrethroid is ß-cypermethrin (ß-CYP), and 3-phenoxybenzoic acid (3-PBA) is one of its primary metabolites. Although CYP has been shown to pose toxic effects in some immune cells, as of now the immunotoxicity of CYP on immune progenitor cells has not been well studied. In this study, we evaluated the immunotoxicity of ß-CYP and 3-PBA on the human promyelocytic leukemia cell line, HL-60. Both ß-CYP and 3-PBA reduced cell viability. In addition, both ß-CYP and 3-PBA stimulated the intrinsic apoptotic pathway in a dose- and time-dependent manner, while only ß-CYP induced cell cycle arrest in G1 stage. Moreover, exposure to ß-CYP and 3-PBA at 100 µM inhibited all-trans retinoic acid (ATRA)-induced mRNA expressions of the granulocytic differentiation-related genes, CD11b and CSF-3R. Furthermore, exposure to ß-CYP and 3-PBA resulted in a downregulation of the granulocytic differentiation promoting transcriptional factors, PU.1 and C/EBPε. Furthermore, we found that ß-CYP and 3-PBA exposure led to elevated levels of cellular reactive oxygen species (ROS), and that pretreatment with N-acetylcysteine (NAC) blocked the toxic effects caused by ß-CYP and 3-PBA. The results obtained in the present study provide evidence showing the immunotoxic effects of ß-CYP and 3-PBA on promyelocytic cells as well as its possible underlying mechanism.

Effect of chronic corticosterone-induced depression on circadian rhythms and age-related phenotypes in mice.

Disrupted circadian rhythms are a recognized effect of depression, and our previous article demonstrated an association between depression and premature aging, but the underlying mechanisms are not well understood. In the present study, we used a mouse model of chronic corticosterone (CORT)-treated depression to elucidate a mechanism by which depression may be associated with the circadian clock and mediate age-related phenotypes. Mice received a daily injection of 20 mg/kg CORT for 21 consecutive days, and the depression-like behaviors of mice were identified by the sucrose intake test, tail suspension test and open field test. Our findings indicated that CORT injection may be correlated with the circadian clock by impairing circadian rhythms or shifting the phase values of clock genes. We also showed that CORT-treated mice exhibited a significant gradual reduction in body weight gain with increased oxidative stress, including reduced activity of antioxidant-related enzymes, reduced glutathione:glutathione disulfide ratio and cytochrome (Cyt)-C level, and elevated reactive oxygen species content. Moreover, chronic CORT injection affected inflammatory responses, the production of mitochondrial ATP and telomere shortening, which may be associated with the Sirtuin 3 (SIRT3) signaling pathway. Additionally, chronic CORT injection disrupted the circadian rhythms of some indexes of aging phenotypes and altered the phase values of these indexes. Our findings suggest that psychologically stressful conditions such as depression are linked to changes in circadian rhythms and age-related phenotypes.

Exposure to hexafluoropropylene oxide trimer acid (HFPO-TA) impairs 5-HT metabolism by impacting the brain-gut axis in mice.

Hexafluoropropylene oxide trimer acid (HFPO-TA) has been found to cause hepatotoxicity, lipotoxicity, and cytotoxicity. However, the effects of HFPO-TA exposure on nervous system toxicity are still unclear. Here, six-week-old male C57BL/6J mice were treated with 2, 20, and 200 µg/L HFPO-TA for six weeks. The untargeted transcriptome analysis was employed to identify differentially expressed mRNAs in the tissue of mouse hippocampi. Then, the levels of neurotransmitters were detected by ELISA analysis in hippocampal and colonic tissues. Real-time quantitative PCR and western blotting analysis were performed to detect the expression of genes associated with modulation of serotonin (5-HT) metabolism and blood-brain barrier. HFPO-TA exposure reduced the mRNA and protein expression of several tight junction protein-coded genes, including Occludin, Claudin-1, and ZO-1, in mice hippocampi, indicating that the blood-brain barrier was disrupted. Moreover, HFPO-TA exposure elevated the expression of neuroinflammatory factors, including TNF-α, IL-6, IL-1ß, TGF-α, and TGF-ß. Analysis of hippocampal transcriptomics suggested that HFPO-TA exposure would impair 5-HT generation and metabolic pathways. In keeping with this prediction, our findings confirmed that the levels of several neurotransmitters, including tryptophan (TRP), 5-HT, 5-HTP, and 5-HIAA, were all impaired by HFPO-TA exposure in the serum, colon, and hippocampus, as was the colonic and hippocampal expression of TRP and 5-HT metabolism-related genes such as SERT, MAO-A, and IDO. These results suggest that HFPO-TA nervous system toxicity in mice may be partly modulated by the brain-gut axis and that HFPO-TA exposure may negatively impact human mental health.

Mammalian AKT, the Emerging Roles on Mitochondrial Function in Diseases.

Mitochondrial dysfunction may play a crucial role in various diseases due to its roles in the regulation of energy production and cellular metabolism. Serine/threonine kinase (AKT) is a highly recognized antioxidant, immunomodulatory, anti-proliferation, and endocrine modulatory molecule. Interestingly, increasing studies have revealed that AKT can modulate mitochondria-mediated apoptosis, redox states, dynamic balance, autophagy, and metabolism. AKT thus plays multifaceted roles in mitochondrial function and is involved in the modulation of mitochondria-related diseases. This paper reviews the protective effects of AKT and its potential mechanisms of action in relation to mitochondrial function in various diseases.

Impact of a hexafluoropropylene oxide trimer acid (HFPO-TA) exposure on impairing the gut microbiota in mice.

Hexafluoropropylene oxide trimer acid (HFPO-TA) has been used as an alternative of perfluorooctanoic acid (PFOA) in the fluoropolymer industry for several years. HFPO-TA is reported to have high capability of bioaccumulation, widespread environmental distribution, and multiple toxicities. However, its potential toxicity on the intestines and gut microbiota remains unknown. In the present study, male mice were orally exposed to 200 µg/L HFPO-TA for 6 weeks, and after total genomic DNA extraction, 16S rRNA amplicon pyrosequencing was performed. Our results demonstrated that HFPO-TA exposure resulted in the imbalance of cecal microbiota and alterations of cecal microbiota diversity. At the phylum level, the relative abundances of Proteobacteria, Deferribacteres, and Tenericutes increased in mice after exposure to HFPO-TA, while the relative abundances of Verrucomicrobia, Cyanobacteria, and TM7 decreased. At the genus level, the relative abundances of Ver Akkermansia, Pre Prevotella, Lac Coprococcus, Por_Parabacteroides, and Lac Dorea decreased in HFPO-TA exposed mice. Meanwhile, the increased relative abundances of Def_Mucispirillum, Des_Desulfovibrio and Odo Odoribacter were observed in HFPO-TA exposed mice. Additionally, KEGG metabolic pathway analysis revealed that HFPO-TA exposure changed the unsaturated fatty acid synthesis, fatty acid metabolism, glyoxylic acid and dicarboxylic acid metabolism, galactose metabolism pathway and other metabolic pathways. Collectively, all these findings indicate the potential gut toxicity of HFPO-TA and is perceived as a risk of health on gut microbiota. Future investigations should be warranted.

Crocin-I Protects Against High-Fat Diet-Induced Obesity via Modulation of Gut Microbiota and Intestinal Inflammation in Mice.

Crocin-I can regulate physiological changes in the human body by altering inflammation and microbial composition. Gut microbiota are also involved in modulating the pathophysiology of obesity. However, crocin-I's effect on obesity and the mechanism underlying its effects on gut microbiota and inflammation remain poorly understood. Here, high-fat diet (HFD) -induced obese mice were administrated crocin-I (20 mg/kg/day) for 10 weeks using an oral gavage (HFD-C20 group). HFD-C20, HFD, and Normal chow (NC) groups were compared. The fat content, colon tissue inflammatory cytokine levels, gut microbiota, and short-chain fatty acids (SCFAs) levels were measured. We show that crocin-I reduced body weight and liver weight and improved glucose resistance in HFD-induced mice, and reduced the lipid accumulation in the liver. Strikingly, crocin-I alleviated intestinal microbial disorders and decreased the F/B ratio and the abundance of Proteobacteria in HFD-induced obese mice. Crocin-I also rescued the decrease in the levels of SCFAs and repaired altered intestinal barrier functioning and intestinal inflammation in HFD-induced obese mice. These findings indicate that crocin-I may inhibit obesity by modulating the composition of gut microbiota and intestinal inflammation.

Oral exposure to a hexafluoropropylene oxide trimer acid (HFPO-TA) disrupts mitochondrial function and biogenesis in mice.

Hexafluoropropylene oxide trimer acid (HFPO-TA) is reported to have hepatotoxicity, lipotoxicity, and cytotoxicity. In this study, the toxicological effects of HFPO-TA on mitochondrial function and biogenesis were studied. Mice were exposed to drinking water which contained either 2, 20, or 200 µg/L HFPO-TA. Results showed exposure to HFPO-TA induced disadvantageous physiological changes in mice, including increases in liver weight, altered cell morphology, and inflammatory responses. Specifically, exposure to 200 µg/L HFPO-TA increased mitochondria number, relative mitochondrial DNA (mtDNA) content, and mRNA levels of mitochondrial genes encoded by mtDNA. Significant increases in TFAM mRNA and protein levels were also observed. Liver metabolome analysis also showed exposure to 200 µg/L HFPO-TA further enhanced increases in metabolites and altered metabolic pathways that correlated with mitochondrial function, especially the production of ATP. HFPO-TA exposure increased protein expression of mitochondrial complex I-V, and the activities of key enzymes involved in TCA cycle (α-ketoglutarate dehydrogenase, citrate synthase, and succinate dehydrogenase). Furthermore, exposure to 200 µg/L HFPO-TA significantly up-regulating mRNA and protein levels of Opa1, Mfn1, Mfn2, Fis1, and Mff, but did not change Drp1. These findings suggest HFPO-TA could have detrimental effects on health of animals, particularly it was associated with disrupted mitochondrial energy metabolism.

Exposure to hexafluoropropylene oxide dimer acid (HFPO-DA) disturbs the gut barrier function and gut microbiota in mice.

Hexafluoropropylene oxide dimer acid (HFPO-DA) is the substitute for perfluoro octanoic acid (PFOA), and recently it has been detected in environmental water samples worldwide and has multiple toxicities. However, whether it will affect the intestines and gut microbiota remains unclear. In this study, in order to evaluate the gut toxicity of HFPO-DA in mammals, male mice were orally exposed to 0, 2, 20, 200 µg/L HFPO-DA, respectively, for 6 weeks. Our results showed that HFPO-DA exposure caused colonic inflammation which was coupled with increased TNF-α levels in serum and increased mRNA expression levels of TNF-α, p65, TLR4, MCP-1 of the colon in mice after exposure to 200 µg/L HFPO-DA. We also found that HFPO-DA exposure induced the decreased mRNA expression levels and protein levels of MUC2 and ZO-1, which means the dysfunction of gut barrier in the colon. In the ileum, we found that HFPO-DA exposure induced the increased mRNA expression levels of various inflammatory factors, but no obvious changes was found to barrier function. Additionally, HFPO-DA exposure caused the imbalance of cecal gut microbiota and changes of cecal microbiota diversity. Taken together, all these results indicate the potential gut toxicity of HFPO-DA and is perceived as a major problem of health risk that affects the inflammation, gut barrier dysfunction, and gut microbiota disturbance in mammals.

Comorbid major depression in first-episode drug-naïve patients with schizophrenia: Analysis of the Depression in Schizophrenia in China (DISC) study.

BACKGROUND: Depression is very common in patients with schizophrenia, but few studies have investigated the diagnosed major depressive episode (MDE) in first episode and drug naive (FEDN) schizophrenia. To our best knowledge, this is the first large sample study to examine the prevalence, clinical correlates and associated factors of diagnosed MDE in FEDN schizophrenia, as well as the relationship between depressive symptoms and psychopathological symptoms in these schizophrenia patients. METHODS: A total of 996 FEDN schizophrenia patients were recruited. The 17-item Hamilton Depression Rating Scale (HAMD17) and Positive and Negative Syndrome Scale (PANSS) were used to assess the severity of depression and psychopathology, respectively. RESULTS: Our results demonstrated that MDE coexisted in nearly half (49.30%) of FEDN schizophrenia patients. Male gender, smoking, PANSS general psychopathology and early age of onset were associated with MDE in patients with FEDN schizophrenia (all p<0.05). In schizophrenia patients with MDE, oridinal logistic regression showed that men (OR=6.65, 95%CI: 4.12-10.45, p<0.001) and smoking (OR=1.94, 95%CI: 1.25-3.01, p=0.003) were positively associated with severity category of depression (all p<0.05), while multivariate regression showed that HAMD17 total score was significantly associated with the PANSS general psychopathology (B=0.06, t=2.72, p=0.007) and total scores (B=0.04, t=2.57, p=0.01). CONCLUSION: Our study shows that the prevalence of comorbid MDE is high in FEDN schizophrenia patients. Some demographic and clinical variables are associated with the severity of depression in these schizophrenia patients.

Nicotinamide mononucleotide ameliorates the depression-like behaviors and is associated with attenuating the disruption of mitochondrial bioenergetics in depressed mice.

BACKGROUND: Nicotinamide mononucleotide (NMN) has been shown to stimulate oxidative phosphorylation in mitochondria and to improve various pathologies in patients and mouse disease models. However, whether NMN mediates mitochondrial energy production and its mechanism of action in depressed animals remain unclear. METHODS: Mice were subcutaneously injected with corticosterone (CORT; 20 mg/kg) each day for 6 weeks, while another group was given an additional dose of NMN (300 mg/kg) by oral gavage in the last 2 weeks. Then, transcriptome analyses, metabolome analyses and transient gene knockdown in primary mouse cells were performed. RESULTS: NMN administration alleviated depression-like behavior and the liver weight to body weight ratio in a mouse model of CORT-induced depression. Transcriptome and metabolome analyses revealed that in depressed mice, NMN reduced the mRNA expression of genes involved in fatty acid synthesis, stimulation of ß-oxidation and glycolysis, and increased production of acetyl-coenzyme A for the tricarboxylic acid cycle. Importantly, NMN supplementation increased NAD+ levels to enhance sirtuin (SIRT)3 activity, thereby improving mitochondrial energy metabolism in the hippocampus and liver of CORT-treated mice. Sirt3knockdown in primary mouse astrocytes reversed the effect of NMN by inhibiting energy production, although it did not affect NAD+ synthesis LIMITATIONS: Group sample sizes were small, and only one type of primary mouse cell was used CONCLUSION: These results provide evidence for the beneficial role of NMN in energy production and suggest that therapeutic strategies that increase the level of NMN can be an effective treatment for depression.

Depression-like behaviors are accompanied by disrupted mitochondrial energy metabolism in chronic corticosterone-induced mice.

Stress exerts its negative effects by interference with mitochondrial energy production in rodents, and is able to impair mitochondrial bioenergetics. However, the underlying mechanism that stress hormone impacts depression-like behaviors and mitochondrial energy metabolism is still not well understood. Here, we investigated the changes of depression-like behaviors and mitochondrial energy metabolism induced by chronic corticosterone (CORT). The results showed that after treatment with CORT for 6 weeks, mice displayed depression-like behaviors, which were identified by tail suspension test, forced swimming test and open field test. Then, the livers were isolated and tested by RNA sequencing and metabolome analysis. RNA sequencing showed 354 up-regulated genes and 284 down-regulated genes, and metabolome analysis revealed 280 metabolites with increased abundances and 193 metabolites with reduced abundances in the liver of mice after CORT, which were closely associated with lipid metabolism and oxidative phosphorylation in mitochondria. Based on these findings, the changes of mitochondrial energy metabolism were investigated, and we revealed that CORT condition inhibited glycolysis and fatty acid degradation pathway, and activated synthesis of triacylglycerol, leading to the reduced levels of acetyl-CoA and attenuated TCA cycle. Also, the pathways of NAD+ synthesis were inhibited, resulting in the reduced activity of sirtuin 3 (SIRT3). Thus, all of these observations disrupted the function of mitochondria, and led to the decrease of ATP production. Our findings uncover a novel mechanism of stress on depression-like behaviors and mitochondrial energy metabolism in rodents.

Crocin-I alleviates the depression-like behaviors probably via modulating "microbiota-gut-brain" axis in mice exposed to chronic restraint stress.

BACKGROUND: Depressive disorder is rapidly advancing in the worldwide, and therapeutic strategy through "gut-brain" axis has been proved to be effective. Crocin, has been found to have antidepressant activity. However, there is no thorough research for the effects of crocin-I (a major active component of crocin) on depression and its underlying mechanism. METHODS: We investigated the antidepressant effect of six-week oral administration of crocin-I in a mice model of depression induced by four-week CRS. Based on the "microbiota-gut-brain" axis, we determined the effects of crocin-I administration on gut microbiota, intestinal barrier function, short chain fatty acids and neurochemical indicators. RESULTS: Administration of crocin-I at a dose of 40 mg/kg for six weeks mitigated depression-like behaviors of depressed mice as evidenced by behaviors tests. In addition, crocin-I reduced the levels of lipopolysaccharide (LPS), Interleukin-6and tumor necrosis factor-α (TNF-α) in serum and TNF-α expression in the hippocampus, and increased the hippocampal brain-derived neurotrophic factor. Besides, 16 s rRNA sequencing revealed that crocin-I mitigated the gut microbiota dysbiosis in depressed mice as represented by the decreased abundance of Proteobacteria and Bacteroidetes, Sutterella spp. and Ruminococcus spp. and increased abundances of Firmicutes, Lactobacillus spp. and Bacteroides spp. Moreover, gas chromatography-mass spectrometry revealed that crocin-I reversed the decreased levels of short-chain fatty acids (SCFAs) in feces of depressed mice. Furthermore, crocin-I improved the impaired intestinal barrier by increasing expression of Occludin and Claudin-1, which contributed to the decreased LPS leakage. LIMITATIONS: Only the male mice were used; the dose-effect relationship should be observed. CONCLUSION: These results suggested that crocin-I effectively alleviated depression-like behavior, likely depended on the gut microbiota and its modulation of intestinal barrier and SCFAs.

Exposure to low concentration of trifluoromethanesulfonic acid induces the disorders of liver lipid metabolism and gut microbiota in mice.

Trifluoromethanesulfonic acid (TFMS) is the shortest chain perfluorinated compound. Recently, it has been identified as a persistent and mobile organic chemical with a maximum concentration of 1 µg/L in the environment. However, its toxicological mechanism remains unclear. In this study, to evaluate the liver and intestinal toxicity of TFMS in mammals, male mice were orally exposed to 0, 1, 10 and 100 µg/kg for 12 weeks. Our results showed that TFMS exposure reduced the epididymal fat weight in mice, caused the decrease of serum and liver triglyceride (TG) level and the increase of serum low density lipoprotein (LDL) level. Also, we observed the inflammatory cell infiltration in the liver of mice exposed to 10 µg/kg and 100 µg/kg TFMS, which was coupled with the increased mRNA expression levels of inflammatory factors such as COX2, TNF-α, IL-1ß in the liver. In addition, the mRNA expression levels of lipid metabolism-related genes (PPAR-α, ACOX, SCD1, PPAR-γ, etc.) were significantly decreased in the liver of mice after exposure to both doses of TFMS. We also found TFMS exposure caused the imbalance of cecal gut microbiota and change of cecal microbiota diversity. KEGG pathway predictions showed that the exposure of 100 µg/kg TFMS changed the synthesis and degradation of ketone bodies, benzoate degradation and several other metabolic pathways. Our findings indicated that TFMS exposure disturbed the liver lipid metabolism possibly via altering the gut microbiota.

Crocin-I ameliorates the disruption of lipid metabolism and dysbiosis of the gut microbiota induced by chronic corticosterone in mice.

Glucocorticoids (GCs) are widely used as anti-inflammatory and immunosuppressive drugs. However, chronic treatment with GCs in clinical settings has a series of side effects, such as metabolic disorders, gut microbiota dysbiosis and neurological impairment. Therefore, searching for a functional substance that can alleviate these side effects is greatly meaningful to clinical patients. Crocin is the main active ingredient of saffron, which has been reported to have numerous pharmacological activities. However, the action of crocin-I, one major member of the crocin family, on the physiological mediation in the individuals receiving GC treatment remains unclear. In this study, we aimed to evaluate the efficacy of crocin-I on lipid metabolism and the gut microbiota in a mouse model of chronic corticosterone (CORT) treatment. Our findings showed that crocin-I reduced the levels of triglycerides and total cholesterol and the ratio of low density lipoprotein to high density lipoprotein in the serum of CORT-treated mice. In addition, transcriptome analysis revealed that crocin-I was effective in mediating the amelioration of lipid metabolism, mainly in fatty acid metabolism and steroid biosynthesis in CORT-treated mice. Moreover, metabolome analysis demonstrated that crocin-I could restore the disturbed metabolites in the liver of CORT-treated mice, most of which are long-chain fatty acids. Furthermore, high-throughput sequencing of 16s rRNA revealed that crocin-I could mitigate the dysbiosis of the gut microbiota caused by CORT at a dose of 40 mg kg-1, by resulting in a significant increase in the alpha diversity of the microbes in the cecal contents and a significant reduction in the abundance of Firmicutes, whereas by increasing the abundance of Bacteroidetes. These results indicated that oral administration of crocin-I could modify the composition of the gut microbiota and alleviate hepatic lipid disorder in mice treated with a high dose of GCs.