Currently approved therapeutical strategies for inflammatory bowel diseases(IBD)suffer from variable efficacy and association with risk of serious side effects.Therefore,efforts have been made in searching for alterna...Currently approved therapeutical strategies for inflammatory bowel diseases(IBD)suffer from variable efficacy and association with risk of serious side effects.Therefore,efforts have been made in searching for alternative therapeutics strategies utilizing gut microbiota manipulation.In this study,we show that the probiotic strain Ligilactobacillus salivarius Li01(Li01)and the phytochemical prebiotic resveratrol(RSV)have synergistic effect in ameliorating colitis in mice.Oral coadministration of Li01(109 CFU/d)and RSV(1.5 g/kg/d)promoted restoration of various inflammatory injuries and gut microbiota composition,exhibiting a favorable anti-inflammatory effect in DSS-induced colitis mice.The combination treatment was associated with reductions in the levels of proinflammatory cytokines IL-1βand IL-6 and increases in the levels of the anti-inflammatory cytokine IL-17A in mouse serum.Moreover,the combination treatment was found to alter the composition and metabolism of the gut microbiota,especially influencing the production of short chain fatty acids and anti-inflammatory related molecules.The mechanism underlying the improved anti-inflammatory effect from the RSV and Li01 combination treatment was found to be associated with the environmental sensor mammalian aryl hydrocarbon receptor(AHR)and tryptophan metabolism pathway.Administration of RSV in combination with Li01 in different mouse model led to enhanced conversion of RSV into metabolites,including dihydroresveratrol(DHR),resveratrol-sulfate,and resveratrol-glucuronide.DHR was found to be the dominant metabolite of RSV in conventional and colitis mice.An increased DHR/RSV ratio was confirmed to activate AHR and contribute to an enhanced anti-inflammatory effect.DHR is considered as a potential AHR ligand.The DHR/RSV ratio also affected the serotonin pathway by controlling the expression of Tph1,SERT,and 5-HT7R leading to amelioration of colitis in mice.Our data suggest that treatment with a combination of Li01 and RSV has potential as a therapeutic strategy for IBD;further investigation of this combination in clinical settings is warranted.展开更多
Emerging evidences have indicated the role of ferroptosis in the progression of metabolicassociated fatty liver disease(MAFLD);thus,inhibiting ferroptosis is a promising strategy for the development of MAFLD therapeut...Emerging evidences have indicated the role of ferroptosis in the progression of metabolicassociated fatty liver disease(MAFLD);thus,inhibiting ferroptosis is a promising strategy for the development of MAFLD therapeutics.Recent studies have demonstrated the antioxidative effect of the gut commensal bacterium Akkermansia muciniphila(A.muc);however,whether it can alleviate ferroptosis remains unclear.The current study indicates A.muc intervention efficiently reversed highfat high-fructose diet(HFHFD)-induced lipid peroxidation and ferroptosis in the liver.These beneficial effects were mediated by activation of the hepatic AMPK/SIRT1/PGC-1a axis,as evidenced by the finding that AMPK deficiency abrogated the amelioration of lipid peroxidation in vitro and in vivo.Furthermore,the short-chain fatty acids(SCFAs)were enriched upon A.muc treatment,and acetate was identified as a key activator of hepatic AMPK signalling.Mechanistically,microbiota-derived acetate was transported to the liver and metabolized to adenosine monophosphate(AMP),which triggered AMPK activation.Furthermore,a colonization assay in germ-free mice confirmed that A.muc mediated antiferroptotic effects in the absence of other microbes.These data indicated that A.muc exerts antiferroptotic effects against MAFLD,at least partially by producing acetate,which activates the hepatic AMPK/SIRT1/PGC-1a axis to alleviate ferroptosis via the inhibition of polyunsaturated fatty acid(PUFA)synthesis.展开更多
Consuming a high-fat diet(HFD)is widely recognized to cause obesity and result in chronic brain inflammation that impairs cognitive function.Repetitive transcranial magnetic stimulation(rTMS)has shown effectiveness in...Consuming a high-fat diet(HFD)is widely recognized to cause obesity and result in chronic brain inflammation that impairs cognitive function.Repetitive transcranial magnetic stimulation(rTMS)has shown effectiveness in both weight loss and cognitive improvement,although the exact mechanism is still unknown.Our study examined the effects of rTMS on the brain and intestinal microecological dysfunction.rTMS successfully reduced cognitive decline caused by an HFD in behavioral assessments involving the Y maze and novel object recognition.This was accompanied by an increase in the number of new neurons and the transcription level of genes related to synaptic plasticity(spindlin 1,synaptophysin,and postsynaptic protein-95)in the hippocampus.It was reached that rTMS decreased the release of high mobility group box 1,activation of microglia,and inflammation in the brains of HFD rats.rTMS also reduced hypothalamic hypocretin levels and improved peripheral blood lipid metabolism.In addition,rTMS recovered the HFD-induced gut microbiome imbalances,metabolic disorders,and,in particular,reduced levels of the microvirus.Our research emphasized that rTMS enhanced cognitive abilities,resulting in positive impacts on brain inflammation,neurodegeneration,and the microbiota in the gut,indicating the potential connection between the brain and gut,proposing that rTMS could be a new approach to addressing cognitive deficits linked to obesity.展开更多
Micro/nanoplastics(MNPs)are detected in human liver,and pose significant risks to human health.Oral exposure to MNPs derived from non-biodegradable plastics can induce toxicity in mouse liver.Similarly,nasal exposure ...Micro/nanoplastics(MNPs)are detected in human liver,and pose significant risks to human health.Oral exposure to MNPs derived from non-biodegradable plastics can induce toxicity in mouse liver.Similarly,nasal exposure to non-biodegradable plastics can cause airway dysbiosis in mice.However,the hepatotoxicity induced by foodborne and airborne biodegradable MNPs remains poorly understood.Here we show the hepatotoxic effects of biodegradable polylactic acid(PLA)MNPs through multi-omics analysis of various biological samples from mice,including gut,fecal,nasal,lung,liver,and blood samples.Our results show that both foodborne and airborne PLA MNPs compromise liver function,disrupt serum antioxidant activity,and cause liver pathology.Specifically,foodborne MNPs lead to gut microbial dysbiosis,metabolic alterations in the gut and serum,and liver transcriptomic changes.Airborne MNPs affect nasal and lung microbiota,alter lung and serum metabolites,and disrupt liver transcriptomics.The gut Lachnospiraceae_NK4A136_group is a potential biomarker for foodborne PLA MNP exposure,while nasal unclassified_Muribaculaceae and lung Klebsiella are potential biomarkers for airborne PLA MNP exposure.The relevant results suggest that foodborne PLA MNPs could affect the“gut microbiota-gutliver”axis and induce hepatoxicity,while airborne PLA MNPs could disrupt the“airway microbiota-lungliver”axis and cause hepatoxicity.These findings have implications for diagnosing PLA MNPs-induced hepatotoxicity and managing biodegradable materials in the environment.Our current study could be a starting point for biodegradable MNPs-induced hepatotoxicity.More research is needed to verify and inhibit the pathways that are crucial to MNPs-induced hepatotoxicity.展开更多
基金The animal experiments in this study were approved by the Tab of Animal Experimental Ethical Inspection of the First Affliated Hospital,College of Medicine,Zhejiang University(no.20211433).
文摘Currently approved therapeutical strategies for inflammatory bowel diseases(IBD)suffer from variable efficacy and association with risk of serious side effects.Therefore,efforts have been made in searching for alternative therapeutics strategies utilizing gut microbiota manipulation.In this study,we show that the probiotic strain Ligilactobacillus salivarius Li01(Li01)and the phytochemical prebiotic resveratrol(RSV)have synergistic effect in ameliorating colitis in mice.Oral coadministration of Li01(109 CFU/d)and RSV(1.5 g/kg/d)promoted restoration of various inflammatory injuries and gut microbiota composition,exhibiting a favorable anti-inflammatory effect in DSS-induced colitis mice.The combination treatment was associated with reductions in the levels of proinflammatory cytokines IL-1βand IL-6 and increases in the levels of the anti-inflammatory cytokine IL-17A in mouse serum.Moreover,the combination treatment was found to alter the composition and metabolism of the gut microbiota,especially influencing the production of short chain fatty acids and anti-inflammatory related molecules.The mechanism underlying the improved anti-inflammatory effect from the RSV and Li01 combination treatment was found to be associated with the environmental sensor mammalian aryl hydrocarbon receptor(AHR)and tryptophan metabolism pathway.Administration of RSV in combination with Li01 in different mouse model led to enhanced conversion of RSV into metabolites,including dihydroresveratrol(DHR),resveratrol-sulfate,and resveratrol-glucuronide.DHR was found to be the dominant metabolite of RSV in conventional and colitis mice.An increased DHR/RSV ratio was confirmed to activate AHR and contribute to an enhanced anti-inflammatory effect.DHR is considered as a potential AHR ligand.The DHR/RSV ratio also affected the serotonin pathway by controlling the expression of Tph1,SERT,and 5-HT7R leading to amelioration of colitis in mice.Our data suggest that treatment with a combination of Li01 and RSV has potential as a therapeutic strategy for IBD;further investigation of this combination in clinical settings is warranted.
基金supported by the National Natural Science Foundation of China(81790631,81874142,and 82073041)the National Key Research and Development Program of China(2018YFC2000500,2021YFA1301104,and 2021YFC2301804)+2 种基金the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-045,China)the Research Project of Jinan Microecological Biomedicine Shandong Laboratory(JNL-2022001A,China)the China Postdoctoral Science Foundation(2023M743125).
文摘Emerging evidences have indicated the role of ferroptosis in the progression of metabolicassociated fatty liver disease(MAFLD);thus,inhibiting ferroptosis is a promising strategy for the development of MAFLD therapeutics.Recent studies have demonstrated the antioxidative effect of the gut commensal bacterium Akkermansia muciniphila(A.muc);however,whether it can alleviate ferroptosis remains unclear.The current study indicates A.muc intervention efficiently reversed highfat high-fructose diet(HFHFD)-induced lipid peroxidation and ferroptosis in the liver.These beneficial effects were mediated by activation of the hepatic AMPK/SIRT1/PGC-1a axis,as evidenced by the finding that AMPK deficiency abrogated the amelioration of lipid peroxidation in vitro and in vivo.Furthermore,the short-chain fatty acids(SCFAs)were enriched upon A.muc treatment,and acetate was identified as a key activator of hepatic AMPK signalling.Mechanistically,microbiota-derived acetate was transported to the liver and metabolized to adenosine monophosphate(AMP),which triggered AMPK activation.Furthermore,a colonization assay in germ-free mice confirmed that A.muc mediated antiferroptotic effects in the absence of other microbes.These data indicated that A.muc exerts antiferroptotic effects against MAFLD,at least partially by producing acetate,which activates the hepatic AMPK/SIRT1/PGC-1a axis to alleviate ferroptosis via the inhibition of polyunsaturated fatty acid(PUFA)synthesis.
基金support of funds from the National Natural Science Foundation(82271561)the Medical Science and Technology Project of Zhejiang Province(2022RC024).
文摘Consuming a high-fat diet(HFD)is widely recognized to cause obesity and result in chronic brain inflammation that impairs cognitive function.Repetitive transcranial magnetic stimulation(rTMS)has shown effectiveness in both weight loss and cognitive improvement,although the exact mechanism is still unknown.Our study examined the effects of rTMS on the brain and intestinal microecological dysfunction.rTMS successfully reduced cognitive decline caused by an HFD in behavioral assessments involving the Y maze and novel object recognition.This was accompanied by an increase in the number of new neurons and the transcription level of genes related to synaptic plasticity(spindlin 1,synaptophysin,and postsynaptic protein-95)in the hippocampus.It was reached that rTMS decreased the release of high mobility group box 1,activation of microglia,and inflammation in the brains of HFD rats.rTMS also reduced hypothalamic hypocretin levels and improved peripheral blood lipid metabolism.In addition,rTMS recovered the HFD-induced gut microbiome imbalances,metabolic disorders,and,in particular,reduced levels of the microvirus.Our research emphasized that rTMS enhanced cognitive abilities,resulting in positive impacts on brain inflammation,neurodegeneration,and the microbiota in the gut,indicating the potential connection between the brain and gut,proposing that rTMS could be a new approach to addressing cognitive deficits linked to obesity.
基金supported by the National Natural Science Foundation of China(82003441).
文摘Micro/nanoplastics(MNPs)are detected in human liver,and pose significant risks to human health.Oral exposure to MNPs derived from non-biodegradable plastics can induce toxicity in mouse liver.Similarly,nasal exposure to non-biodegradable plastics can cause airway dysbiosis in mice.However,the hepatotoxicity induced by foodborne and airborne biodegradable MNPs remains poorly understood.Here we show the hepatotoxic effects of biodegradable polylactic acid(PLA)MNPs through multi-omics analysis of various biological samples from mice,including gut,fecal,nasal,lung,liver,and blood samples.Our results show that both foodborne and airborne PLA MNPs compromise liver function,disrupt serum antioxidant activity,and cause liver pathology.Specifically,foodborne MNPs lead to gut microbial dysbiosis,metabolic alterations in the gut and serum,and liver transcriptomic changes.Airborne MNPs affect nasal and lung microbiota,alter lung and serum metabolites,and disrupt liver transcriptomics.The gut Lachnospiraceae_NK4A136_group is a potential biomarker for foodborne PLA MNP exposure,while nasal unclassified_Muribaculaceae and lung Klebsiella are potential biomarkers for airborne PLA MNP exposure.The relevant results suggest that foodborne PLA MNPs could affect the“gut microbiota-gutliver”axis and induce hepatoxicity,while airborne PLA MNPs could disrupt the“airway microbiota-lungliver”axis and cause hepatoxicity.These findings have implications for diagnosing PLA MNPs-induced hepatotoxicity and managing biodegradable materials in the environment.Our current study could be a starting point for biodegradable MNPs-induced hepatotoxicity.More research is needed to verify and inhibit the pathways that are crucial to MNPs-induced hepatotoxicity.
