Publications by authors named "Pengcheng Tu"

35 Publications

An Introduction to Next Generation Sequencing Bioinformatic Analysis in Gut Microbiome Studies.

Biomolecules 2021 Apr 2;11(4). Epub 2021 Apr 2.

Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.

The gut microbiome is a microbial ecosystem which expresses 100 times more genes than the human host and plays an essential role in human health and disease pathogenesis. Since most intestinal microbial species are difficult to culture, next generation sequencing technologies have been widely applied to study the gut microbiome, including 16S rRNA, 18S rRNA, internal transcribed spacer (ITS) sequencing, shotgun metagenomic sequencing, metatranscriptomic sequencing and viromic sequencing. Various software tools were developed to analyze different sequencing data. In this review, we summarize commonly used computational tools for gut microbiome data analysis, which extended our understanding of the gut microbiome in health and diseases.
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http://dx.doi.org/10.3390/biom11040530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066849PMC
April 2021

Icariin promotes the repair of PC12 cells by inhibiting endoplasmic reticulum stress.

BMC Complement Med Ther 2021 Feb 19;21(1):69. Epub 2021 Feb 19.

Department of Traumatology and Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, People's Republic of China.

Background: Endoplasmic reticulum stress (ERS) is one of the main mechanisms of spinal cord injury (SCI) pathology and can affect the physiological state of neurons. Icariin (ICA), the main pharmacological component of Epimedium, can relieve the symptoms of patients with SCI and has obvious protective effects on neurons through ERS.

Methods: PC12 cells were induced to differentiate into neurons by nerve growth factor and identified by flow cytometry. Cell proliferation was detected by CCK8 method, cell viability was detected by SRB assay, apoptosis was detected by flow cytometry and microstructure of ER was observed by transmission electron microscope. Western blot was used to detect the protein expression of CHOP and Grp78, and qPCR was used to detect the mRNA expression of CHOP and Grp78.

Results: The results of CCK8, SRB and flow cytometry showed that ICA could relieve ERS and reduce apoptosis of PC12 cells. The results of transmission microscope showed that ICA could reduce apoptosis of PC12 cells caused by ERS. The results of Western blot and q-PCR showed that ICA could inhibit ERS by down-regulating the expression of CHOP and Grp78.

Conclusions: ICA can inhibit ERS and promote the repair of PC12 cells by down-regulating the expression of CHOP and Grp78. ICA has the potential to promote the recovery of spinal cord injury.
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http://dx.doi.org/10.1186/s12906-021-03233-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896365PMC
February 2021

Canidin-3-glucoside prevents nano-plastics induced toxicity via activating autophagy and promoting discharge.

Environ Pollut 2021 Apr 21;274:116524. Epub 2021 Jan 21.

Department of Food Science and Nutrition, Zhejiang University, Hangzhou, 310058, People's Republic of China; Zhejiang Key Laboratory for Agro-food Processing, Zhejiang University, Hangzhou, 310058, People's Republic of China; Fuli Institute of Food Science, Zhejiang University, Hangzhou, 310058, People's Republic of China; National Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang University, Hangzhou, 310058, People's Republic of China. Electronic address:

Increasing attention has been brought to microplastics pollution recently, while emerging evidences indicate that nano-plastics degraded from microplastics are more of research significance owing to stronger toxicity. However, there is little study focused on the prevention of nano-plastics induced toxicity until now. Canidin-3-glucoside (C3G), a natural anthocyanin proved to possess multiple functions like antioxidant and intestinal tissue protection. Thus, we proposed whether C3G could act as a molecular weapon against nano-plastics induced toxicity. In Caco2 cell and Caenorhabditis elegans (C. elegans) models, we found that polystyrene (PS) nano-plastics exposure resulted in physiological toxicity and oxidative damage, which could be restored by C3G. More significantly in Caco2 cells, we observed that autophagy was activated via Sirt1-Foxo1 signaling pathway to attenuate PS induced toxicity after C3G intervention and further verified by adding autophagy inhibitor 3-Methyladenine (3-MA). Meanwhile, PS co-localization with lysosomes was observed, indicating the encapsulation and degradation of PS. In C. elegans, by detecting LGG-1/LC3 expression in GFP-targeted LGG-1 report gene (LGG-1:GFP) labeled transgenic DA2123 strain, the co-localization of LGG-1:GFP with PS was found as well, means that autophagy is involved in C3G's beneficial effects. Furthermore, we were surprised to find that C3G could promote the discharge of PS from N2 nematodes, which reduces PS toxicity more directly.
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http://dx.doi.org/10.1016/j.envpol.2021.116524DOI Listing
April 2021

[Research progress of different mechanical stimulation regulating chondrocytes metabolism].

Sheng Wu Yi Xue Gong Cheng Xue Za Zhi 2020 Dec;37(6):1101-1108

Department of Traumatology & Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, P.R.China;Laboratory of New Techniques of Restoration & Reconstruction of Orthopedics and Traumatology, Nanjing University of Chinese Medicine, Nanjing 210023, P.R.China;School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, P.R.China.

As a kind of mechanical effector cells, chondrocytes can produce a variety of physical and chemical signals under the stimulation of multiaxial load , which affect their own growth, development and apoptosis. Therefore, simulating the mechanical environment has become a research hotspot in the culture of chondrocytes . Although a large number of reports have fully proved that different mechanical stimulation can regulate the metabolism of chondrocytes, the loading scheme has not been agreed. Starting from different mechanical forms, this review will explore the differences in the regulation of chondrocyte metabolism by different mechanical stimuli, so as to find an advantage scheme to promote the growth and proliferation of chondrocytes and to develop a more stable, effective and reliable experimental strategy.
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http://dx.doi.org/10.7507/1001-5515.202001044DOI Listing
December 2020

Jisuikang Promotes the Repair of Spinal Cord Injury in Rats by Regulating NgR/RhoA/ROCK Signal Pathway.

Evid Based Complement Alternat Med 2020 28;2020:9542359. Epub 2020 Nov 28.

Department of Traumatology and Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.

Jisuikang (JSK) is an herbal formula composed of many kinds of traditional Chinese medicine, which has been proved to be effective in promoting the rehabilitation of patients with spinal cord injury (SCI) after more than ten years of clinical application. However, the mechanisms of JSK promoting nerve regeneration are yet to be clarified. The aim of this study was to investigate the effects of JSK protecting neurons, specifically the regulation of NgR/RhoA/ROCK signal pathway. The motor function of rats was evaluated by the BBB score and inclined plate test, Golgi staining and transmission electron microscope were used to observe the microstructure of nerve tissue, and fluorescence double-labeling method was used to detect neuronal apoptosis. In this study, we found that JSK could improve the motor function of rats with SCI, protect the microstructure (mitochondria, endoplasmic reticulum, and dendritic spine) of neurons, and reduce the apoptosis rate of neurons in rats with SCI. In addition, JSK could inhibit the expression of Nogo receptor (NgR) in neurons and the NgR/RhoA/ROCK signal pathway in rats with SCI. These results indicated JSK could improve the motor function of rats with SCI by inhibiting the NgR/RhoA/ROCK signal pathway, which suggests the potential applicability of JSK as a nerve regeneration agent.
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http://dx.doi.org/10.1155/2020/9542359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735860PMC
November 2020

Prior surgical uterine evacuation of pregnancy and infertility: protocol for systematic review and meta-analysis.

BMJ Open 2020 07 2;10(7):e034837. Epub 2020 Jul 2.

National Research Institute for Family Planning, Beijing, China

Introduction: Prior surgical uterine evacuation is associated with an increased risk of infertility. However, findings are inconsistent, highlighting the need for a clear consensus on the effect of prior surgical uterine evacuation on the risk of infertility. Therefore, the aim of this systematic review and meta-analysis is to summarise the available evidence examining the association between prior surgical uterine evacuation and the risk of infertility.

Methods And Analysis: A systematic search of electronic databases (ie, PubMed, Scopus, ClinicalTrials.gov, EMBASE and ScienceDirect) will be conducted since their inception until October 2019 with no limit for language using a detailed prespecified search strategy. Both the authors will independently screen titles and abstracts and select full-text articles, perform data extraction and appraise the quality of included studies using a bias classification tool. Meta-analyses will be performed to calculate the overall pooled estimates using the generic inverse variance method. This systematic review and meta-analysis will follow the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines.

Ethics And Dissemination: Given that this is a protocol based on published data, there is no requirement for ethics approval. It is anticipated that the dissemination of results will be reported according to the PRISMA statement. The results will be published in peer-reviewed journals and presented at scientific conferences.

Prospero Registration Number: CRD42019117266.
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http://dx.doi.org/10.1136/bmjopen-2019-034837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333799PMC
July 2020

Gut Microbiome Toxicity: Connecting the Environment and Gut Microbiome-Associated Diseases.

Toxics 2020 Mar 12;8(1). Epub 2020 Mar 12.

Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

The human gut microbiome can be easily disturbed upon exposure to a range of toxic environmental agents. Environmentally induced perturbation in the gut microbiome is strongly associated with human disease risk. Functional gut microbiome alterations that may adversely influence human health is an increasingly appreciated mechanism by which environmental chemicals exert their toxic effects. In this review, we define the functional damage driven by environmental exposure in the gut microbiome as gut microbiome toxicity. The establishment of gut microbiome toxicity links the toxic effects of various environmental agents and microbiota-associated diseases, calling for more comprehensive toxicity evaluation with extended consideration of gut microbiome toxicity.
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http://dx.doi.org/10.3390/toxics8010019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151736PMC
March 2020

Osthole-loaded N-octyl-O-sulfonyl chitosan micelles (NSC-OST) inhibits RANKL-induced osteoclastogenesis and prevents ovariectomy-induced bone loss in rats.

J Cell Mol Med 2020 04 3;24(7):4105-4117. Epub 2020 Mar 3.

Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine, Nanjing, China.

Osthole (OST), a derivative of Fructus Cnidii, has been proved to have potential anti-osteoporosis effects in our recent studies. However, its pharmacological effects are limited in the human body because of poor solubility and bioavailability. Under the guidance of the classical theory of Chinese medicine, Osthole-loaded N-octyl-O-sulfonyl chitosan micelles (NSC-OST), which has not previously been reported in the literature, was synthesized in order to overcome the defects and obtain better efficacy. In this study, we found that NSC-OST inhibited on the formation and resorption activity of osteoclasts through using a bone marrow macrophage (BMM)-derived osteoclast culture system in vitro, rather than affecting the viability of cells. We also found that NSC-OST inhibited osteoclast formation, hydroxyapatite resorption and RANKL-induced osteoclast marker protein expression. In terms of mechanism, NSC-OST suppressed the NFATc1 transcriptional activity and the activation of NF-κB signalling pathway. In vivo, ovariectomized (OVX) rat models were established for further research. We found that NSC-OST can attenuate bone loss in OVX rats through inhibiting osteoclastogenesis. Consistent with our hypothesis, NSC-OST is more effective than OST in parts of the results. Taken together, our findings suggest that NSC-OST can suppress RANKL-induced osteoclastogenesis and prevents ovariectomy-induced bone loss in rats and could be considered a safe and more effective anti-osteoporosis drug than OST.
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http://dx.doi.org/10.1111/jcmm.15064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171421PMC
April 2020

Metabolite Profiling of the Gut Microbiome in Mice with Dietary Administration of Black Raspberries.

ACS Omega 2020 Jan 17;5(3):1318-1325. Epub 2020 Jan 17.

Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.

Mounting evidence has linked gut microbiome to health benefits of various functional foods. We previously reported that administration of a diet rich in black raspberry (BRB) changed the composition and diverse functional pathways in the mouse gut microbiome. To further characterize the functional profile in the gut microbiome of mice on BRB diet, in this follow-up study, we examined the metabolome differences in the gut microbiome driven by BRB consumption via targeted and untargeted metabolomic approaches. A distinct metabolite profile was observed in the gut microbiome of the mice on BRB diet, likely resulting from a combination of microbiome functional changes and unique precursors in BRBs. A number of functional metabolites, such as tetrahydrobiopterin and butyrate that were significantly increased in the gut microbiome may be linked to the beneficial health effects of BRB consumption. These findings suggest the important role of the gut microbiome in the health effects of BRBs and provide a connection among the health benefits of functional foods and the gut microbiome.
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http://dx.doi.org/10.1021/acsomega.9b00237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990444PMC
January 2020

Lipid and Cholesterol Homeostasis after Arsenic Exposure and Antibiotic Treatment in Mice: Potential Role of the Microbiota.

Environ Health Perspect 2019 09 18;127(9):97002. Epub 2019 Sep 18.

Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, North Carolina, USA.

Background: Arsenic-induced liver X receptor/retinoid X receptor (LXR/RXR) signaling inhibition is a potential mechanism underlying the cardiovascular effects caused by arsenic. The gut microbiota can influence arsenic toxic effects.

Objective: We aimed to explore whether gut microbiota play a role in arsenic-induced LXR/RXR signaling inhibition and the subsequent lipid and cholesterol dysbiosis.

Methods: Conventional and antibiotic-treated mice (AB-treated mice) were exposed to and arsenic for 2 wk. Hepatic mRNAs were extracted and sequenced. The expression levels of genes associated with LXR/RXR signaling were quantified by quantitative real-time polymerase chain reaction (qPCR), and serum and hepatic cholesterol levels were measured. Liquid chromatography-mass spectrometry (LC-MS)-based lipidomics were used to examine serum and hepatic lipids.

Results: Pathway analysis indicated that arsenic exposure differentially influenced the hepatic signaling pathways in conventional and AB-treated mice. The expression of sterol regulatory element-binding protein 1 (), 3-hydroxy-3-methylglutaryl-CoA reductase (), and cytochrome P450 family 7 subfamily A member 1 (), as well as cholesterol efflux genes, including ATP binding cassette subfamily G member 5/8 () and cluster of differentiation 36 (), was lower in arsenic-exposed conventional mice but not in AB-treated mice. Similarly, under arsenic exposure, the hepatic expression of scavenger receptor class B member 1 (), which is involved in reverse cholesterol transport (RCT), was lower in conventional mice, but was higher in AB-treated animals compared with controls. Correspondingly, arsenic exposure exerted opposite effects on the serum cholesterol levels in conventional and AB-treated mice, i.e., higher serum cholesterol levels in conventional mice but lower levels in AB-treated mice than in respective controls. Serum lipid levels, especially triglyceride (TG) levels, were higher in conventional mice exposed to arsenic, while arsenic exposure did not significantly affect the serum lipids in AB-treated mice. Liver lipid patterns were also differentially perturbed in a microbiota-dependent manner.

Conclusions: Our results suggest that in mice, the gut microbiota may be a critical factor regulating arsenic-induced LXR/RXR signaling perturbation, suggesting that modulation of the gut microbiota might be an intervention strategy to reduce the toxic effects of arsenic on lipid and cholesterol homeostasis. https://doi.org/10.1289/EHP4415.
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http://dx.doi.org/10.1289/EHP4415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792374PMC
September 2019

Dietary administration of black raspberries modulates arsenic biotransformation and reduces urinary 8-oxo-2'-deoxyguanosine in mice.

Toxicol Appl Pharmacol 2019 08 20;377:114633. Epub 2019 Jun 20.

Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States of America. Electronic address:

Arsenic in drinking water is a worldwide public health problem due to its pathogenic induction of oxidative stress in various organ systems. Phytochemicals present in polyphenolic-rich fruits such as black raspberries (BRBs) have diverse health benefits, including antioxidation and modulation of enzymes in xenobiotic metabolism. We used a mouse model combined with a standardized BRB-rich diet to investigate the impact of BRB consumption on arsenic biotransformation. We observed a significant reduction of urinary 8-oxo-2'-deoxyguanosine (8-oxodG) together with elevated levels of methylation and urinary excretion of arsenic in mice concurrently fed BRBs upon arsenic exposure. Moreover, enzyme expression and liver metabolites involved in arsenic metabolism were found to be different between mice on BRB and control diets with arsenic exposure. These data indicate that BRB consumption affected arsenic biotransformation in vivo likely via alterations in related metabolic enzymes and cofactors, providing evidence on reduction of arsenic toxicity by consumption of BRBs.
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http://dx.doi.org/10.1016/j.taap.2019.114633DOI Listing
August 2019

Osthole inhibits osteoclasts formation and bone resorption by regulating NF-κB signaling and NFATc1 activations stimulated by RANKL.

J Cell Biochem 2019 09 13;120(9):16052-16061. Epub 2019 May 13.

Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.

Chinese herbal medicine Fructus Cnidii has an outstanding effect on chronic lumbar pain and impotence, also has been used against osteoporosis with high frequency. Yet, the mechanisms of osthole, a derivative of Fructus Cnidii, on osteoclasts remains barely known. In this study, it was found out that osthole (10 mol/L, 10 mol/L) had the influence of inhibiting osteoclast formation and bone resorptive activities induced by receptor activator of nuclear factor κB ligand (RANKL), rather than affecting the viability of osteoclast-like cells. Furthermore, osthole could also inhibit the messenger RNA expressions of c-Src, tartrate-resistant acid phosphatase, β3-Integrin, matrix metallopeptidase 9, and cathepsin K. The results of the mechanistic study indicated that osthole regulated the nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) and nuclear factor-κB (NF-κB) activations following the RANKL stimulation. These findings suggested that the inhibitory effects of osthole were associated with restraining the activations of NFATc1 and NF-κB induced by RANKL. Thus osthole can be used as a potential treatment for abnormal bone-resorption related diseases.
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http://dx.doi.org/10.1002/jcb.28886DOI Listing
September 2019

Chronic Arsenic Exposure Induces Oxidative Stress and Perturbs Serum Lysolipids and Fecal Unsaturated Fatty Acid Metabolism.

Chem Res Toxicol 2019 06 8;32(6):1204-1211. Epub 2019 May 8.

Department of Environmental Sciences and Engineering , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina 27599 , United States.

Chronic arsenic exposure from drinking water is a global public health issue, which is associated with numerous human diseases and influences millions of people worldwide. The effects of arsenic exposure to the metabolic networks remain elusive. Here, we exposed female C57BL/6J mice to 1 ppm inorganic arsenic in drinking water for 3 months to investigate how arsenic exposure perturbs serum and fecal metabolic profiles. We found decreased levels of serum compounds with antioxidative activities in arsenic-treated mice, in accordance with elevated oxidative stress indicated by higher urinary 8-oxo-2'-deoxyguanosine (8-oxo-dG) levels. Moreover, the levels of multiple lysophosphatidylcholines (lysoPCs) were significantly increased in the sera of arsenic-exposed mice, including lysoPC (O-18:0), lysoPC (20:3), lysoPC (18:1), and lysoPC (22:6). Arsenic exposure perturbed the levels of several key polyunsaturated fatty acids (PUFAs) in the fecal samples in concert with alterations in related microbial pathways. Additionally, changes in the abundances of many functional metabolites, together with decreased levels of amino acids, were found in the fecal samples of arsenic-treated mice. By delineating the impact of arsenic exposure on the metabolic profiles, the findings may provide new biomarkers and mechanistic insights into arsenic-associated diseases.
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http://dx.doi.org/10.1021/acs.chemrestox.9b00039DOI Listing
June 2019

[Research progress on signaling molecules involved in articular cartilage repair].

Sheng Wu Yi Xue Gong Cheng Xue Za Zhi 2019 Apr;36(2):343-348

Nanjing University of Chinese Medicine, Nanjing 210023, P.R.China;Department of Traumatology & Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, P.R.China.

After the articular cartilage injury, the metabolic level is increased during the progressive degeneration, the chondrocytes secrete a variety of inflammatory factors, and the original cell phenotype is gradually changed. For a long time, a large number of researchers have done a lot of researches to promote anabolism of chondrocytes and to maintain the stability of chondrocyte phenotype. There are many molecular signaling pathways involved in the process of promoting cartilage repair. This review focuses on the key signaling molecules in articular cartilage repair, such as transforming growth factor-beta and bone morphogenetic protein, and reveals their roles in the process of cartilage injury and repair, so that researchers in related fields can understand the molecular mechanism of cartilage injury and repair widely and deeply. Based on this, they may find promising targets and biological methods for the treatment of cartilage injury.
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http://dx.doi.org/10.7507/1001-5515.201806021DOI Listing
April 2019

Subchronic low-dose 2,4-D exposure changed plasma acylcarnitine levels and induced gut microbiome perturbations in mice.

Sci Rep 2019 03 13;9(1):4363. Epub 2019 Mar 13.

Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.

The gut microbiota critically confers various health benefits, whereas environmental chemicals can affect its constitution and functionality thereby increasing disease risk. In the present study, we aim to evaluate the toxic effects of a wildly-used herbicide 2,4-D (2,4-dichlorophenoxyacetic acid) on the gut microbiome and host using an occupationally relevant dose. A mouse model was used combined with metagenomic sequencing and metabolomic profiling to examine the alterations induced by subchronic low-dose 2,4-D exposure in fecal and plasma samples. The metagenomics results revealed a distinct gut microbial community with profound changes in diverse microbial pathways including urea degradation, amino acid and carbohydrate metabolism in 2,4-D-treated mice. Moreover, the metabolomics results revealed that the metabolic profiles in treatment group were differentiated from control group in both fecal and plasma samples. Toxic effects on the host of 2,4-D at an occupationally relevant dose were observed indicated by decreased acylcarnitine levels in plasma. These findings indicated that 2,4-D can cause toxicity and substantially impact the gut microbiome in mice at occupationally relevant doses, inferring that the relationship between environmental contaminants and microbiota is largely underestimated calling for more comprehensive consideration of the toxicity of occupational exposures.
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http://dx.doi.org/10.1038/s41598-019-40776-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416245PMC
March 2019

Serum Metabolomics Identifies Altered Bioenergetics, Signaling Cascades in Parallel with Exposome Markers in Crohn's Disease.

Molecules 2019 Jan 27;24(3). Epub 2019 Jan 27.

Department of Population Health and Pathobiology, North Carolina State University, Raleigh, NC 27695, USA.

Inflammatory bowel disease (IBD) has stimulated much interest due to its surging incidences and health impacts in the U.S. and worldwide. However, the exact cause of IBD remains incompletely understood, and biomarker is lacking towards early diagnostics and effective therapy assessment. To tackle these, the emerging high-resolution mass spectrometry (HRMS)-based metabolomics shows promise. Here, we conducted a pilot untargeted LC/MS metabolomic profiling in Crohn's disease, for which serum samples of both active and inactive cases were collected, extracted, and profiled by a state-of-the-art compound identification workflow. Results show a distinct metabolic profile of Crohn's from control, with most metabolites downregulated. The identified compounds are structurally diverse, pointing to important pathway perturbations ranging from energy metabolism (e.g., β-oxidation of fatty acids) to signaling cascades of lipids (e.g., DHA) and amino acid (e.g., L-tryptophan). Importantly, an integral role of gut microbiota in the pathogenesis of Crohn's disease is highlighted. Xenobiotics and their biotransformants were widely detected, calling for massive exposomic profiling for future cohort studies as such. This study endorses the analytical capacity of untargeted metabolomics for biomarker development, cohort stratification, and mechanistic interpretation; the findings might be valuable for advancing biomarker research and etiologic inquiry in IBD.
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http://dx.doi.org/10.3390/molecules24030449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6385106PMC
January 2019

Quantitative proteomics reveals systematic dysregulations of liver protein metabolism in sucralose-treated mice.

J Proteomics 2019 03 17;196:1-10. Epub 2019 Jan 17.

Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States. Electronic address:

Sucralose, one kind of "sugar-free" artificial sweeteners, is widely used as food and drinks additives. It is generally considered that sucralose is safe because majority of ingested sucralose is not metabolized and absorbed by human body. However, increasing evidence shows the negative effects of artificial sweeteners in perturbations of gut microbiota which plays an important role in a variety of processes related to host health such as immune system development. Specifically, sucralose uptake can alter the homeostasis of mouse gut microbiota, resulting in the significant changes of gut bacterial genera diversity, metabolic patterns, and fecal metabolite profiles as well as inducing host liver inflammation. Therefore, there is a need to study liver proteome changes which may be potentially affected by sucralose-induced dysbiosis. In this study, isobaric labeling-based quantitative proteomics was performed to reveal the liver functional proteome changes in male C57BL/6J mice with sucralose administration in drinking water for six-month period. The labeled tryptic peptides were off-line fractionated before LC-MS/MS analysis to improve proteome coverage detected. SIGNIFICANCE: We demonstrated the first quantitative proteomics for mice liver proteome to evaluate the effect of sucralose consumption. In total, >5700 protein groups were identified from 18 mouse liver tissues (9 from control group; 9 from sucralose-treated group), and 4327 protein groups were quantified in all samples without any missing values. Among them, 113 protein groups were identified with statistical significance (q value <0.05) as differentially expressed proteins. Bioinformatics analysis revealed the systematic dysregulations of protein metabolism after sucralose treatment. Importantly, our findings proposed that enhanced inflammation may be triggered by ribosomal inactivation in sucralose treated mice liver.
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http://dx.doi.org/10.1016/j.jprot.2019.01.011DOI Listing
March 2019

Serum Metabolomics Reveals That Gut Microbiome Perturbation Mediates Metabolic Disruption Induced by Arsenic Exposure in Mice.

J Proteome Res 2019 03 25;18(3):1006-1018. Epub 2019 Jan 25.

Department of Environmental Sciences and Engineering , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina 27599 , United States.

Arsenic contamination in drinking water has been a worldwide health concern for decades. In addition to being a well-recognized carcinogen, arsenic exposure has also been linked to diabetes, neurological effects, and cardiovascular diseases. Recently, increasing evidence has indicated that gut microbiome is an important risk factor in modulating the development of diseases. We aim to investigate the role of gut microbiome perturbation in arsenic-induced diseases by coupling a mass-spectrometry-based metabolomics approach and an animal model with altered gut microbiome induced by bacterial infection. Serum metabolic profiling has revealed that gut microbiome perturbation and arsenic exposure induced the dramatic changes of numerous metabolite pathways, including fatty acid metabolism, phospholipids, sphingolipids, cholesterols, and tryptophan metabolism, which were not or were less disrupted when the gut microbiome stayed normal. In summary, this study suggests that gut microbiome perturbation can exacerbate or cause metabolic disorders induced by arsenic exposure.
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http://dx.doi.org/10.1021/acs.jproteome.8b00697DOI Listing
March 2019

Isobaric Labeling Quantitative Metaproteomics for the Study of Gut Microbiome Response to Arsenic.

J Proteome Res 2019 03 16;18(3):970-981. Epub 2019 Jan 16.

Department of Environmental Sciences and Engineering , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina 27599 , United States.

Quantitative metaproteomics is a relatively new research field that applies proteomics techniques to study microbial proteins of the microbiome and holds great potential in truly quantifying the functional proteins actually expressed by microbes in the biological environment, such as the gastrointestinal tract. The significant association between arsenic exposure and gut microbiome perturbations has been reported; however, metaproteomics has not yet been applied to study arsenic-induced proteome changes of the microbiome. Most importantly, to our knowledge, isobaric-labeling-based large-scale metaproteomics has not been reported using the advanced database-search approaches such as MetaPro-IQ and matched metagenome database-search strategies to provide high quantification accuracy and fewer missing quantification values. In the present study, a new experimental workflow coupled to isobaric labeling and MetaPro-IQ was demonstrated for the metaproteomics study of arsenic-induced gut microbiome perturbations. The advantages of this workflow were also discussed. For all 18 fecal samples analyzed, 7611 protein groups were quantified without any missing values. The consistent results of expression profiles were observed between 16S rRNA gene sequencing and metaproteomics. This isobaric-labeling-based workflow demonstrated the significant improvement of quantitative metaproteomics for gut microbiome study.
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http://dx.doi.org/10.1021/acs.jproteome.8b00666DOI Listing
March 2019

The Carbamate Aldicarb Altered the Gut Microbiome, Metabolome, and Lipidome of C57BL/6J Mice.

Chem Res Toxicol 2019 01 8;32(1):67-79. Epub 2019 Jan 8.

Department of Environmental Sciences and Engineering , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina 27599 , United States.

The gut microbiome is highly involved in numerous aspects of host physiology, from energy harvest to stress response, and can confer many benefits to the host. The gut microbiome development could be affected by genetic and environmental factors, including pesticides. The carbamate insecticide aldicarb has been extensively used in agriculture, which raises serious public health concerns. However, the impact of aldicarb on the gut microbiome, host metabolome, and lipidome has not been well studied yet. Herein, we use multiomics approaches, including16S rRNA sequencing, shotgun metagenomics sequencing, metabolomics, and lipidomics, to elucidate aldicarb-induced toxicity in the gut microbiome and the host metabolic homeostasis. We demonstrated that aldicarb perturbed the gut microbiome development trajectory, enhanced gut bacterial pathogenicity, altered complex lipid profile, and induced oxidative stress, protein degradation, and DNA damage. The brain metabolism was also disturbed by the aldicarb exposure. These findings may provide a novel understanding of the toxicity of carbamate insecticides.
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http://dx.doi.org/10.1021/acs.chemrestox.8b00179DOI Listing
January 2019

Gut microbiome disruption altered the biotransformation and liver toxicity of arsenic in mice.

Arch Toxicol 2019 01 24;93(1):25-35. Epub 2018 Oct 24.

Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.

The mammalian gut microbiome (GM) plays a critical role in xenobiotic biotransformation and can profoundly affect the toxic effects of xenobiotics. Previous in vitro studies have demonstrated that gut bacteria have the capability to metabolize arsenic (As); however, the specific roles of the gut microbiota in As metabolism in vivo and the toxic effects of As are largely unknown. Here, we administered sodium arsenite to conventionally raised mice (with normal microbiomes) and GM-disrupted mice with antibiotics to investigate the role of the gut microbiota in As biotransformation and its toxicity. We found that the urinary total As levels of GM-disrupted mice were much higher, but the fecal total As levels were lower, than the levels in the conventionally raised mice. In vitro experiments, in which the GM was incubated with As, also demonstrated that the gut bacteria could adsorb or take up As and thus reduce the free As levels in the culture medium. With the disruption of the gut microbiota, arsenic biotransformation was significantly perturbed. Of note, the urinary monomethylarsonic acid/dimethylarsinic acid ratio, a biomarker of arsenic metabolism and toxicity, was markedly increased. Meanwhile, the expression of genes of one-carbon metabolism, including folr2, bhmt, and mthfr, was downregulated, and the liver S-adenosylmethionine (SAM) levels were significantly decreased in the As-treated GM-disrupted mice only. Moreover, As exposure altered the expression of genes of the p53 signaling pathway, and the expression of multiple genes associated with hepatocellular carcinoma (HCC) was also changed in the As-treated GM-disrupted mice only. Collectively, disruption of the GM enhances the effect of As on one-carbon metabolism, which could in turn affect As biotransformation. GM disruption also increases the toxic effects of As and may increase the risk of As-induced HCC in mice.
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http://dx.doi.org/10.1007/s00204-018-2332-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727877PMC
January 2019

Characterization of the Functional Changes in Mouse Gut Microbiome Associated with Increased Population Modulated by Dietary Black Raspberries.

ACS Omega 2018 Sep 10;3(9):10927-10937. Epub 2018 Sep 10.

Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27519, United States.

Gut microbiome plays an essential role in host health through host-gut microbiota metabolic interactions. Desirable modulation of beneficial gut bacteria, such as , can confer health benefits by altering microbiome-related metabolic profiles. The purpose of this study is to examine the effects of a black raspberry-rich diet to reshape the gut microbiome by selectively boosting population in C57BL/6J mice. Remarkable changes of the mouse gut microbiome were revealed at both compositional and functional levels with an expected increase of in concert with a profound impact on multiple gut microbiome-related functions, including vitamin biosynthesis, aromatic amino acid metabolism, carbohydrate metabolism, and oxidative stress. These functional alterations in the gut microbiome by an easily accessed freeze-dried black raspberry-supplemented diet may provide novel insights on the improvement of human health via gut microbiome modulation.
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http://dx.doi.org/10.1021/acsomega.8b00064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166222PMC
September 2018

Individual susceptibility to arsenic-induced diseases: the role of host genetics, nutritional status, and the gut microbiome.

Mamm Genome 2018 02 10;29(1-2):63-79. Epub 2018 Feb 10.

Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.

Arsenic (As) contamination in water or food is a global issue affecting hundreds of millions of people. Although As is classified as a group 1 carcinogen and is associated with multiple diseases, the individual susceptibility to As-related diseases is highly variable, such that a proportion of people exposed to As have higher risks of developing related disorders. Many factors have been found to be associated with As susceptibility. One of the main sources of the variability found in As susceptibility is the variation in the host genome, namely, polymorphisms of many genes involved in As transportation, biotransformation, oxidative stress response, and DNA repair affect the susceptibility of an individual to As toxicity and then influence the disease outcomes. In addition, lifestyles and many nutritional factors, such as folate, vitamin C, and fruit, have been found to be associated with individual susceptibility to As-related diseases. Recently, the interactions between As exposure and the gut microbiome have been of particular concern. As exposure has been shown to perturb gut microbiome composition, and the gut microbiota has been shown to also influence As metabolism, which raises the question of whether the highly diverse gut microbiota contributes to As susceptibility. Here, we review the literature and summarize the factors, such as host genetics and nutritional status, that influence As susceptibility, and we also present potential mechanisms of how the gut microbiome may influence As metabolism and its toxic effects on the host to induce variations in As susceptibility. Challenges and future directions are also discussed to emphasize the importance of characterizing the specific role of these factors in interindividual susceptibility to As-related diseases.
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http://dx.doi.org/10.1007/s00335-018-9736-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191311PMC
February 2018

Effects of the Artificial Sweetener Neotame on the Gut Microbiome and Fecal Metabolites in Mice.

Molecules 2018 Feb 9;23(2). Epub 2018 Feb 9.

Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Although artificial sweeteners are widely used in food industry, their effects on human health remain a controversy. It is known that the gut microbiota plays a key role in human metabolism and recent studies indicated that some artificial sweeteners such as saccharin could perturb gut microbiome and further affect host health, such as inducing glucose intolerance. Neotame is a relatively new low-caloric and high-intensity artificial sweetener, approved by FDA in 2002. However, the specific effects of neotame on gut bacteria are still unknown. In this study, we combined high-throughput sequencing and gas chromatography-mass spectrometry (GC-MS) metabolomics to investigate the effects of neotame on the gut microbiome and fecal metabolite profiles of CD-1 mice. We found that a four-week neotame consumption reduced the alpha-diversity and altered the beta-diversity of the gut microbiome. Firmicutes was largely decreased while Bacteroidetes was significantly increased. The Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis also indicated that the control mice and neotame-treated mice have different metabolic patterns and some key genes such as butyrate synthetic genes were decreased. Moreover, neotame consumption also changed the fecal metabolite profiles. Dramatically, the concentrations of multiple fatty acids, lipids as well as cholesterol in the feces of neotame-treated mice were consistently higher than controls. Other metabolites, such as malic acid and glyceric acid, however, were largely decreased. In conclusion, our study first explored the specific effects of neotame on mouse gut microbiota and the results may improve our understanding of the interaction between gut microbiome and neotame and how this interaction could influence the normal metabolism of host bodies.
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http://dx.doi.org/10.3390/molecules23020367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017827PMC
February 2018

The organophosphate malathion disturbs gut microbiome development and the quorum-Sensing system.

Toxicol Lett 2018 Feb 31;283:52-57. Epub 2017 Oct 31.

Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States. Electronic address:

The gut microbiome has tremendous potential to impact health and disease. Various environmental toxicants, including insecticides, have been shown to alter gut microbiome community structures. However, the mechanism that compositionally and functionally regulates gut microbiota remains unclear. Quorum sensing is known to modulate intra- and interspecies gene expression and coordinate population responses. It is unknown whether quorum sensing is disrupted when environmental toxicants cause perturbations in the gut microbiome community structure. To reveal the response of the quorum-sensing system to environmental exposure, we use a combination of Illumina-based 16S rRNA gene amplicon and shotgun metagenome sequencing to examine the impacts of a widely used organophosphate insecticide, malathion, on the gut microbiome trajectory, quorum sensing system and behaviors related to quorum sensing, such as motility and pathogenicity. Our results demonstrated that malathion perturbed the gut microbiome development, quorum sensing and quorum sensing related behaviors. These findings may provide a novel mechanistic understanding of the role of quorum-sensing in the gut microbiome toxicity of malathion.
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http://dx.doi.org/10.1016/j.toxlet.2017.10.023DOI Listing
February 2018

Nicotine Alters the Gut Microbiome and Metabolites of Gut-Brain Interactions in a Sex-Specific Manner.

Chem Res Toxicol 2017 12 16;30(12):2110-2119. Epub 2017 Nov 16.

Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.

As the primary active substance in tobacco, nicotine affects the activity of the central nervous system, and its effects are sex-dependent. There are complex interactions between the gut and brain, and the gut microbiome can influence neuronal activity and host behavior, with diverse chemical signaling being involved. However, it is unclear whether nicotine can affect the normal gut microbiome and associated chemical signaling of the gut-brain axis. Sex is an important factor that shapes the gut microbiome, but the role of sex in the interaction among nicotine, gut bacteria, and related metabolites remains unknown. In this study, we applied high-throughput sequencing and gas chromatography-mass spectrometry (GC-MS) to explore how nicotine exposure affects the gut microbiome and its metabolism in female and male C57BL/6J mice, with a focus on the chemical signaling involved in gut-brain interactions. 16S sequencing results indicated that the community composition of the gut microbiome was differentially perturbed by nicotine in females and males. Differential alterations of bacterial carbohydrate metabolic pathways are consistent with lower body weight gain in nicotine-treated males. Oxidative stress response and DNA repair genes were also specifically enriched in the nicotine-treated male gut microbiome. The fecal metabolome indicated that multiple neurotransmitters, such as glutamate, gamma-aminobutyric acid (GABA), and glycine, were differentially altered in female and male mice. Some neuroactive metabolites, including leucine and uric acid, were also changed. This study demonstrates a sex-dependent effect of nicotine on gut microbiome community composition, functional bacterial genes, and the fecal metabolome.
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http://dx.doi.org/10.1021/acs.chemrestox.7b00162DOI Listing
December 2017

The Effects of an Environmentally Relevant Level of Arsenic on the Gut Microbiome and Its Functional Metagenome.

Toxicol Sci 2017 Dec;160(2):193-204

Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27519.

Multiple environmental factors induce dysbiosis in the gut microbiome and cause a variety of human diseases. Previously, we have first demonstrated that arsenic alters the composition of the gut microbiome. However, the functional impact of arsenic on the gut microbiome has not been adequately assessed, particularly at environmentally relevant concentrations. In this study, we used 16S rRNA sequencing and metagenomics sequencing to investigate how exposure to 100 ppb arsenic for 13 weeks alters the composition and functional capacity of the gut microbiome in mice. Arsenic exposure altered the alpha and beta diversities as well as the composition profile of the gut microbiota. Metagenomics data revealed that the abundances of genes involved in carbohydrate metabolism, especially pyruvate fermentation, short-chain fatty acid synthesis, and starch utilization, and were significantly changed. Moreover, lipopolysaccharide biosynthesis genes, multiple stress response genes, and DNA repair genes were significantly increased in the gut microbiome of arsenic-exposed mice. The genes involved in the production or processing of multiple vitamins, including folic acid and vitamins B6, B12, and K2, were also enriched in arsenic-treated mice. In, addition, genes involved in multidrug resistance and conjugative transposon proteins were highly increased after treatment with arsenic. In conclusion, we demonstrate that arsenic exposure, at an environmentally relevant dose, not only perturbed the communal composition of the gut microbiome but also profoundly altered a variety of important bacterial functional pathways.
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http://dx.doi.org/10.1093/toxsci/kfx174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837326PMC
December 2017

Gut Microbiome Response to Sucralose and Its Potential Role in Inducing Liver Inflammation in Mice.

Front Physiol 2017 24;8:487. Epub 2017 Jul 24.

Department of Environmental Sciences and Engineering, University of North Carolina at Chapel HillChapel Hill, NC, United States.

Sucralose is the most widely used artificial sweetener, and its health effects have been highly debated over the years. In particular, previous studies have shown that sucralose consumption can alter the gut microbiota. The gut microbiome plays a key role in processes related to host health, such as food digestion and fermentation, immune cell development, and enteric nervous system regulation. Inflammation is one of the most common effects associated with gut microbiome dysbiosis, which has been linked to a series of human diseases, such as diabetes and obesity. The aim of this study was to investigate the structural and functional effects of sucralose on the gut microbiota and associated inflammation in the host. In this study, C57BL/6 male mice received sucralose in their drinking water for 6 months. The difference in gut microbiota composition and metabolites between control and sucralose-treated mice was determined using 16S rRNA gene sequencing, functional gene enrichment analysis and metabolomics. Inflammatory gene expression in tissues was analyzed by RT-PCR. Alterations in bacterial genera showed that sucralose affects the gut microbiota and its developmental dynamics. Enrichment of bacterial pro-inflammatory genes and disruption in fecal metabolites suggest that 6-month sucralose consumption at the human acceptable daily intake (ADI) may increase the risk of developing tissue inflammation by disrupting the gut microbiota, which is supported by elevated pro-inflammatory gene expression in the liver of sucralose-treated mice. Our results highlight the role of sucralose-gut microbiome interaction in regulating host health-related processes, particularly chronic inflammation.
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http://dx.doi.org/10.3389/fphys.2017.00487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522834PMC
July 2017

Manganese-induced sex-specific gut microbiome perturbations in C57BL/6 mice.

Toxicol Appl Pharmacol 2017 09 10;331:142-153. Epub 2017 Jun 10.

Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, 27599, United States. Electronic address:

Overexposure to manganese (Mn) leads to toxic effects, such as promoting the development of Parkinson's-like neurological disorders. The gut microbiome is deeply involved in immune development, host metabolism, and xenobiotics biotransformation, and significantly influences central nervous system (CNS) via the gut-brain axis, i.e. the biochemical signaling between the gastrointestinal tract and the CNS. However, it remains unclear whether Mn can affect the gut microbiome and its metabolic functions, particularly those linked to neurotoxicity. In addition, sex-specific effects of Mn have been reported, with no mechanism being identified yet. Recently, we have shown that the gut microbiome is largely different between males and females, raising the possibility that differential gut microbiome responses may contribute to sex-selective toxicity of Mn. Here, we applied high-throughput sequencing and gas chromatography-mass spectrometry (GC-MS) metabolomics to explore how Mn exposure affects the gut microbiome and its metabolism in C57BL/6 mice. Mn exposure perturbed the gut bacterial compositions, functional genes and fecal metabolomes in a highly sex-specific manner. In particular, bacterial genes and/or key metabolites of neurotransmitter synthesis and pro-inflammatory mediators are significantly altered by Mn exposure, which can potentially affect chemical signaling of gut-brain interactions. Likewise, functional genes involved in iron homeostasis, flagellar motility, quorum sensing, and Mn transportation/oxidation are also widely changed by Mn exposure. Taken together, this study has demonstrated that Mn exposure perturbs the gut microbiome and its metabolic functions, which highlights the potential role of the gut microbiome in Mn toxicity, particularly its sex-specific toxic effects.
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http://dx.doi.org/10.1016/j.taap.2017.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5653225PMC
September 2017

Profound perturbation induced by triclosan exposure in mouse gut microbiome: a less resilient microbial community with elevated antibiotic and metal resistomes.

BMC Pharmacol Toxicol 2017 06 12;18(1):46. Epub 2017 Jun 12.

Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.

Background: Environmental chemical-induced perturbations of gut microbiome are associated with a series of adverse health outcomes. The effects of triclosan on human health have been controversial in recent years. The purpose of this study is to investigate the functional impact of triclosan on the mouse gut microbiome and the link between triclosan exposure and resistomes in gut bacteria.

Methods: We combined 16S rRNA gene sequencing and shotgun metagenomics sequencing to examine the compositional and functional impact of triclosan exposure on the gut microbiota of C57BL/6 mice.

Results: 16S rRNA sequencing results revealed that 13-week triclosan exposure in drinking water induced significant perturbations in mouse gut bacterial assemblages with distinct trajectories compared to controls. Metagenomics sequencing results indicated a remarkable enrichment of gut bacterial genes related to triclosan resistance, stress response, antibiotic resistance and heavy metal resistance.

Conclusions: Triclosan exposure has a profound impact on the mouse gut microbiome by inducing perturbations at both compositional and functional levels. To our best knowledge, this is the first evidence regarding the functional alterations of gut microbiome induced by triclosan exposure, which may provide novel mechanistic insights into triclosan exposure and associated diseases.
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http://dx.doi.org/10.1186/s40360-017-0150-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469155PMC
June 2017