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Razzaq Meo S, Van de Wiele T, Defoirdt T. Indole signaling in Escherichia coli: a target for antivirulence therapy? Gut Microbes 2025; 17:2499573. [PMID: 40329925 PMCID: PMC12064070 DOI: 10.1080/19490976.2025.2499573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 04/14/2025] [Accepted: 04/24/2025] [Indexed: 05/08/2025] Open
Abstract
Pathogenic Escherichia coli are a major cause of infections in both humans and animals, leading to conditions such as severe diarrheal diseases, urinary tract infections, enteritis, and septicemia. To combat bacterial infections, antibiotics are widely utilized. However, the extensive and inappropriate use of antibiotics has fueled the development and spread of antibiotic resistance, posing a significant challenge to the effective treatment of E. coli. There is consequently an urgent need to explore alternative therapies to control such infections. This review provides an overview of the recent findings concerning indole signaling in E. coli. E. coli uses indole as a quorum sensing molecule, and indole signaling has been reported to decrease various virulence factors in pathogenic E. coli, including motility, biofilm formation, adherence to host cells, expression of the LEE pathogenicity island, and formation of attaching and effacing lesions. This makes indole signaling an interesting target for the development of new therapeutics in the framework of antivirulence therapy. Both natural and synthetic indole analogues have been explored as potential virulence inhibitors. This alternative approach could be advantageous, as it will exert less selective pressure for resistance development than conventional antibiotics.
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Affiliation(s)
- Sofia Razzaq Meo
- Center for Microbial Ecology and Technology (CMET), Department of Biotechnology, Ghent University, Gent, Belgium
| | - Tom Van de Wiele
- Center for Microbial Ecology and Technology (CMET), Department of Biotechnology, Ghent University, Gent, Belgium
| | - Tom Defoirdt
- Center for Microbial Ecology and Technology (CMET), Department of Biotechnology, Ghent University, Gent, Belgium
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2
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Schwieters A, Ahmer BMM. Role of the LuxR solo, SdiA, in eavesdropping on foreign bacteria. FEMS Microbiol Rev 2025; 49:fuaf015. [PMID: 40240290 PMCID: PMC12086679 DOI: 10.1093/femsre/fuaf015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 03/30/2025] [Accepted: 04/15/2025] [Indexed: 04/18/2025] Open
Abstract
Bacteria can cooperate by coordinating their gene expression through the production, release, and detection of small molecules, a phenomenon known as quorum sensing (QS). One type of QS commonly found in Gram-negative bacteria utilizes a LuxI-type enzyme to produce a signaling molecule of the N-acyl-homoserine lactone (AHL) family, and a transcription factor of the LuxR family to detect and respond to the AHL. In a subset of Enterobacteriaceae, including Escherichia coli and Salmonella, no LuxI family member is present and no AHLs are synthesized. However, they encode a LuxR family member, SdiA, that is used to detect the QS molecules of other bacterial species, a behavior known as eavesdropping. Despite significant research on the topic, the overall role of SdiA-mediated eavesdropping in these bacteria remains unclear. In this review, we discuss the phenotypes and regulons of SdiA in the Enterobacteriaceae.
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Affiliation(s)
- Andrew Schwieters
- Department of Microbiology, The Ohio State University, Columbus, OH 43210, United States
| | - Brian M M Ahmer
- Department of Microbiology, The Ohio State University, Columbus, OH 43210, United States
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, United States
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3
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Tian L, Wei Y, Shi Y, Zhao Y, Chen J, Liu X, Lin B. Accuracy of breath tests for colorectal neoplasms diagnosis: a meta-analysis. Eur J Cancer Prev 2024:00008469-990000000-00193. [PMID: 39718217 DOI: 10.1097/cej.0000000000000943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2024]
Abstract
Early noninvasive and rapid screening for colorectal cancer critically influences treatment outcomes. Breath testing, as an emerging screening technology, allows for noninvasive and convenient screening for different biomarkers and is a reliable screening method for various diseases. In this study, a meta-analysis of the accuracy and current status of volatile organic compounds present in exhaled breath for colorectal cancer detection was performed. PubMed, Cochrane Library, and CNKI were searched for relevant studies. The quality of the studies was assessed using the QUADAS-2 criteria, and meta-analysis was performed using RevMan 5.3 and Stata 16. The pooled sensitivity is 90% [95% confidence interval (CI), 85-94%], the pooled specificity is 86% (95% CI, 72-93%), the pooled positive likelihood ratio is 6.3 (95% CI, 3.1-12.6), the negative likelihood ratio is 0.11 (95% CI, 0.07-0.17), and the diagnostic odds ratio is 56 (95% CI, 23-133). Summary receiver operating characteristic analysis revealed an area under the curve of 0.94 (95% CI, 0.91-0.95). The alteration of specific components of exhaled breath is associated with colorectal cancer development, and the selection of biomarkers and detection instruments influence the diagnostic value. What this paper adds to the literature: this meta-analysis provides a comprehensive evaluation of the diagnostic accuracy of volatile organic compounds in breath tests for colorectal cancer, highlighting the influence of biomarker selection and detection methods on screening efficacy.
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Affiliation(s)
- Lei Tian
- Military Medical Sciences Academy, Academy of Military Sciences, Tianjin
| | - Yizhe Wei
- Military Medical Sciences Academy, Academy of Military Sciences, Tianjin
- School of Public Health, Binzhou Medical University, Yantai, China
| | - Yue Shi
- Military Medical Sciences Academy, Academy of Military Sciences, Tianjin
| | - Yiming Zhao
- Military Medical Sciences Academy, Academy of Military Sciences, Tianjin
| | - Jiang Chen
- Military Medical Sciences Academy, Academy of Military Sciences, Tianjin
| | - Xuan Liu
- Military Medical Sciences Academy, Academy of Military Sciences, Tianjin
| | - Bencheng Lin
- Military Medical Sciences Academy, Academy of Military Sciences, Tianjin
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4
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Ishii K, Naito K, Tanaka D, Koto Y, Kurata K, Shimizu H. Molecular Mechanisms of Skatole-Induced Inflammatory Responses in Intestinal Epithelial Caco-2 Cells: Implications for Colorectal Cancer and Inflammatory Bowel Disease. Cells 2024; 13:1730. [PMID: 39451248 PMCID: PMC11505633 DOI: 10.3390/cells13201730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 10/06/2024] [Accepted: 10/16/2024] [Indexed: 10/26/2024] Open
Abstract
Inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), in intestinal epithelial cells significantly contribute to inflammatory bowel disease (IBD) and colorectal cancer (CRC). Given our previous findings that TNF-α is upregulated in intestinal epithelial Caco-2 cells induced by skatole, a tryptophan-derived gut microbiota metabolite, the present study aimed to explore the relationship between skatole and IL-6, alongside TNF-α. Skatole elevated the promoter activity of IL-6 as well as TNF-α, and increased IL-6 mRNA expression and protein secretion. In addition to activating NF-κB, the NF-κB inhibitor BAY 11-7082 reduced skatole-induced cell survival and the mRNA expression of IL-6 and TNF-α. NF-κB activation was attenuated by the extracellular signal-regulated kinase (ERK) pathway inhibitor U0126 and the p38 inhibitor SB203580, but not by the c-Jun N-terminal kinase (JNK) inhibitor SP600125. U126 and SB203580 also decreased the skatole-induced increase in IL-6 expression. When skatole-induced AhR activation was inhibited by CH223191, in addition to promoting NF-κB activation, IL-6 expression was enhanced in a manner similar to that previously reported for TNF-α. Taken together, these results suggest that skatole-elicited NF-κB activation induces IL-6 and TNF-α expression, although AhR activation partially suppresses this process. The ability of skatole to increase the expression of IL-6 and TNF-α may significantly affect the development and progression of these diseases. Moreover, the balance between NF-κB and AhR activation appears to govern the skatole-induced increases in IL-6 and TNF-α expression. Therefore, the present findings provide new insights into the mechanisms linking tryptophan-derived gut microbiota metabolites with colorectal disease.
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Affiliation(s)
- Katsunori Ishii
- Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Kazuma Naito
- Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Dai Tanaka
- Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Yoshihito Koto
- Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Koichi Kurata
- Graduate School of Life and Environmental Science, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Hidehisa Shimizu
- Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
- Graduate School of Life and Environmental Science, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
- Department of Life Science and Biotechnology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
- The United Graduate School of Agricultural Sciences, Tottori University, 4-101 Koyama-Minami, Tottori 680-8553, Tottori, Japan
- Estuary Research Center, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
- Interdisciplinary Center for Science Research, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
- Institute of Agricultural and Life Sciences, Academic Assembly, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
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5
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Gupta SK, Vyavahare S, Duchesne Blanes IL, Berger F, Isales C, Fulzele S. Microbiota-derived tryptophan metabolism: Impacts on health, aging, and disease. Exp Gerontol 2023; 183:112319. [PMID: 37898179 DOI: 10.1016/j.exger.2023.112319] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 10/05/2023] [Accepted: 10/25/2023] [Indexed: 10/30/2023]
Abstract
The intricate interplay between gut microbiota and the host is pivotal in maintaining homeostasis and health. Dietary tryptophan (TRP) metabolism initiates a cascade of essential endogenous metabolites, including kynurenine, kynurenic acid, serotonin, and melatonin, as well as microbiota-derived Trp metabolites like tryptamine, indole propionic acid (IPA), and other indole derivatives. Notably, tryptamine and IPA, among the indole metabolites, exert crucial roles in modulating immune, metabolic, and neuronal responses at both local and distant sites. Additionally, these metabolites demonstrate potent antioxidant and anti-inflammatory activities. The levels of microbiota-derived TRP metabolites are intricately linked to the gut microbiota's health, which, in turn, can be influenced by age-related changes. This review aims to comprehensively summarize the cellular and molecular impacts of tryptamine and IPA on health and aging-related complications. Furthermore, we explore the levels of tryptamine and IPA and their corresponding bacteria in select diseased conditions, shedding light on their potential significance as biomarkers and therapeutic targets.
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Affiliation(s)
- Sonu Kumar Gupta
- Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Sagar Vyavahare
- Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Ian L Duchesne Blanes
- Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Ford Berger
- Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Carlos Isales
- Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA; Centre for Healthy Aging, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Sadanand Fulzele
- Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA; Centre for Healthy Aging, Medical College of Georgia, Augusta University, Augusta, GA, USA; Department of Cell Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA; Department of Orthopedic Surgery, Medical College of Georgia, Augusta University, Augusta, GA, USA.
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6
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Masse KE, Lu VB. Short-chain fatty acids, secondary bile acids and indoles: gut microbial metabolites with effects on enteroendocrine cell function and their potential as therapies for metabolic disease. Front Endocrinol (Lausanne) 2023; 14:1169624. [PMID: 37560311 PMCID: PMC10407565 DOI: 10.3389/fendo.2023.1169624] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 07/05/2023] [Indexed: 08/11/2023] Open
Abstract
The gastrointestinal tract hosts the largest ecosystem of microorganisms in the body. The metabolism of ingested nutrients by gut bacteria produces novel chemical mediators that can influence chemosensory cells lining the gastrointestinal tract. Specifically, hormone-releasing enteroendocrine cells which express a host of receptors activated by these bacterial metabolites. This review will focus on the activation mechanisms of glucagon-like peptide-1 releasing enteroendocrine cells by the three main bacterial metabolites produced in the gut: short-chain fatty acids, secondary bile acids and indoles. Given the importance of enteroendocrine cells in regulating glucose homeostasis and food intake, we will also discuss therapies based on these bacterial metabolites used in the treatment of metabolic diseases such as diabetes and obesity. Elucidating the mechanisms gut bacteria can influence cellular function in the host will advance our understanding of this fundamental symbiotic relationship and unlock the potential of harnessing these pathways to improve human health.
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Affiliation(s)
| | - Van B. Lu
- Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada
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7
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Natural Product Skatole Ameliorates Lipotoxicity-Induced Multiple Hepatic Damage under Hyperlipidemic Conditions in Hepatocytes. Nutrients 2023; 15:nu15061490. [PMID: 36986221 PMCID: PMC10052055 DOI: 10.3390/nu15061490] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 03/14/2023] [Accepted: 03/19/2023] [Indexed: 03/22/2023] Open
Abstract
Skatole (3-methylindole, 3MI) is a natural-origin compound derived from plants, insects, and microbial metabolites in human intestines. Skatole has an anti-lipid peroxidation effect and is a biomarker for several diseases. However, its effect on hepatocyte lipid metabolism and lipotoxicity has not been elucidated. Hepatic lipotoxicity is induced by excess saturated free fatty acids in hyperlipidemia, which directly damages the hepatocytes. Lipotoxicity is involved in several metabolic diseases and hepatocytes, particularly affecting nonalcoholic fatty liver disease (NAFLD) progression. NAFLD is caused by the accumulation of fat by excessive free fatty acids (FFAs) in the blood and is accompanied by hepatic damage, such as endoplasmic reticulum (ER) stress, abnormal glucose and insulin metabolism, oxidative stress, and lipoapoptosis with lipid accumulation. Hepatic lipotoxicity causes multiple hepatic damages in NAFLD and has a directly effect on the progression from NAFLD to nonalcoholic steatohepatitis (NASH). This study confirmed that the natural compound skatole improves various damages to hepatocytes caused by lipotoxicity in hyperlipidemic conditions. To induce lipotoxicity, we exposed HepG2, SNU-449, and Huh7 cells to palmitic acid, a saturated fatty acid, and confirmed the protective effect of skatole. Skatole inhibited fat accumulation in the hepatocytes, reduced ER and oxidative stress, and recovered insulin resistance and glucose uptake. Importantly, skatole reduced lipoapoptosis by regulating caspase activity. In conclusion, skatole ameliorated multiple types of hepatocyte damage induced by lipotoxicity in the presence of excess free fatty acids.
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Zgarbová E, Vrzal R. Skatole: A thin red line between its benefits and toxicity. Biochimie 2022; 208:1-12. [PMID: 36586563 DOI: 10.1016/j.biochi.2022.12.014] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 12/30/2022]
Abstract
Skatole (3-methylindole) is a heterocyclic compound naturally found in the feces of vertebrates and is produced by certain flowers. Skatole has been used in specific products of the perfume industry or as a flavor additive in ice cream. Additionally, skatole is formed by tryptophan pyrolysis of tobacco and has been demonstrated to be a mutagen. Skatole-induced pulmonotoxicity was reliably described in ruminants and rodents, but no studies have been conducted in humans. Initially, we provide basic knowledge and a historical overview of skatole. Then, skatole bacterial formation in the intestine is described, and the importance of the microbiome during this process is evaluated. Increased skatole concentrations could serve as a marker for intestinal disease development. Therefore, the human molecular targets of skatole that may have significant effects on various processes in the human body are described. Ultimately, we suggest a link between skatole intestinal formation in humans and skatole-induced pulmonotoxicity, which should be explored further in the future.
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Affiliation(s)
- Eliška Zgarbová
- Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71, Olomouc, Czech Republic
| | - Radim Vrzal
- Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71, Olomouc, Czech Republic.
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Gorelik O, Rogad A, Holoidovsky L, Meijler MM, Sal-Man N. Indole intercepts the communication between enteropathogenic E. coli and Vibrio cholerae. Gut Microbes 2022; 14:2138677. [PMID: 36519445 PMCID: PMC9635540 DOI: 10.1080/19490976.2022.2138677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Reported numbers of diarrheal samples exhibiting co-infections or multiple infections, with two or more infectious agents, are rising, likely due to advances in bacterial diagnostic techniques. Bacterial species detected in these samples include Vibrio cholerae (V. cholerae) and enteropathogenic Escherichia coli (EPEC), which infect the small intestine and are associated with high mortality rates. It has previously been reported that EPEC exhibit enhanced virulence in the presence of V. cholerae owing to their ability to sense and respond to elevated concentrations of cholera autoinducer 1 (CAI-1), which is the primary quorum-sensing (QS) molecule produced by V. cholerae. In this study, we examined this interspecies bacterial communication in the presence of indole, a major microbiome-derived metabolite found at high concentrations in the human gut. Interestingly, we discovered that although indole did not affect bacterial growth or CAI-1 production, it impaired the ability of EPEC to enhance its virulence activity in response to the presence of V. cholerae. Furthermore, the co-culture of EPEC and V. cholerae in the presence of B. thetaiotaomicron, an indole-producing commensal bacteria, ablated the enhancement of EPEC virulence. Together, these results suggest that microbiome compositions or diets that influence indole gut concentrations may differentially impact the virulence of pathogens and their ability to sense and respond to competing bacteria.
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Affiliation(s)
- Orna Gorelik
- The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Alona Rogad
- The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Lara Holoidovsky
- Department of Chemistry, the National Institute for Biotechnology in the Negev Ben-Gurion University of the Negev, Be’er Sheva, Israel
| | - Michael M. Meijler
- Department of Chemistry, the National Institute for Biotechnology in the Negev Ben-Gurion University of the Negev, Be’er Sheva, Israel
| | - Neta Sal-Man
- The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel,CONTACT Neta Sal-Man The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
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10
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Effect of Different Coffee Brews on Tryptophan Metabolite-Induced Cytotoxicity in HT-29 Human Colon Cancer Cells. Antioxidants (Basel) 2022; 11:antiox11122458. [PMID: 36552667 PMCID: PMC9774627 DOI: 10.3390/antiox11122458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/07/2022] [Accepted: 12/13/2022] [Indexed: 12/15/2022] Open
Abstract
Coffee consumption positively influences colon health. Conversely, high levels of tryptophan metabolites such as skatole released from intestinal putrefactive fermentation in the presence of excessive dietary animal protein intake, and gut microbiota alterations, may have several adverse effects, including the development of colorectal cancer. Therefore, this study aimed to elucidate the potential protective effects of coffee in the presence of different skatole levels. The results showed that skatole exposure induced reduced cell viability and oxidative stress in the HT-29 human colon cancer cell line. However, co-treatment of cells with skatole and coffee samples was able to reduce ROS production (up to 45% for espresso) compared to cells not treated with coffee. Real-time PCR analysis highlighted that treating HT-29 cells with skatole increased the levels of inflammatory cytokines and chemokines TNF-α, IL-1β, IL-8, and IL12, whereas exposure to coffee extracts in cells that were pretreated with skatole showed anti-inflammatory effects with decreased levels of these cytokines. These findings demonstrate that coffee may counteract the adverse effects of putrefactive compounds by modulating oxidative stress and exerting anti-inflammatory activity in colonocytes, thus suggesting that coffee intake could improve health conditions in the presence of altered intestinal microbiota metabolism.
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Sun H, Wang M, Liu Y, Wu P, Yao T, Yang W, Yang Q, Yan J, Yang B. Regulation of flagellar motility and biosynthesis in enterohemorrhagic Escherichia coli O157:H7. Gut Microbes 2022; 14:2110822. [PMID: 35971812 PMCID: PMC9387321 DOI: 10.1080/19490976.2022.2110822] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
ABSTARCTEnterohemorrhagic Escherichia coli (EHEC) O157:H7 is a human pathogen that causes a variety of diseases, such as hemorrhagic colitis and lethal hemolytic uremic syndrome. Flagellum-dependent motility plays diverse roles in the pathogenesis of EHEC O157:H7, including its migration to an optimal host site, adherence and colonization, survival at the infection site, and post-infection dispersal. However, it is very expensive for cellular economy in terms of the number of genes and the energy required for flagellar biosynthesis and functioning. Furthermore, the flagellar filament bears strong antigenic properties that induce a strong host immune response. Consequently, the flagellar gene expression and biosynthesis are highly regulated to occur at the appropriate time and place by different regulatory influences. The present review focuses on the regulatory mechanisms of EHEC O157:H7 motility and flagellar biosynthesis, especially in terms of flagellar gene regulation by environmental factors, regulatory proteins, and small regulatory RNAs.
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Affiliation(s)
- Hongmin Sun
- TEDA Institute of Biological Sciences and Biotechnology, Nankai University, TEDA, Tianjin, China
| | - Min Wang
- TEDA Institute of Biological Sciences and Biotechnology, Nankai University, TEDA, Tianjin, China
| | - Yutao Liu
- TEDA Institute of Biological Sciences and Biotechnology, Nankai University, TEDA, Tianjin, China
| | - Pan Wu
- TEDA Institute of Biological Sciences and Biotechnology, Nankai University, TEDA, Tianjin, China
| | - Ting Yao
- TEDA Institute of Biological Sciences and Biotechnology, Nankai University, TEDA, Tianjin, China
| | - Wen Yang
- TEDA Institute of Biological Sciences and Biotechnology, Nankai University, TEDA, Tianjin, China
| | - Qian Yang
- TEDA Institute of Biological Sciences and Biotechnology, Nankai University, TEDA, Tianjin, China
| | - Jun Yan
- TEDA Institute of Biological Sciences and Biotechnology, Nankai University, TEDA, Tianjin, China
| | - Bin Yang
- TEDA Institute of Biological Sciences and Biotechnology, Nankai University, TEDA, Tianjin, China,CONTACT Bin Yang TEDA Institute of Biological Sciences and Biotechnology, Nankai University, TEDA, Tianjin300457, P. R. China
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12
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Perry EK, Meirelles LA, Newman DK. From the soil to the clinic: the impact of microbial secondary metabolites on antibiotic tolerance and resistance. Nat Rev Microbiol 2022; 20:129-142. [PMID: 34531577 PMCID: PMC8857043 DOI: 10.1038/s41579-021-00620-w] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/02/2021] [Indexed: 02/08/2023]
Abstract
Secondary metabolites profoundly affect microbial physiology, metabolism and stress responses. Increasing evidence suggests that these molecules can modulate microbial susceptibility to commonly used antibiotics; however, secondary metabolites are typically excluded from standard antimicrobial susceptibility assays. This may in part account for why infections by diverse opportunistic bacteria that produce secondary metabolites often exhibit discrepancies between clinical antimicrobial susceptibility testing results and clinical treatment outcomes. In this Review, we explore which types of secondary metabolite alter antimicrobial susceptibility, as well as how and why this phenomenon occurs. We discuss examples of molecules that opportunistic and enteric pathogens either generate themselves or are exposed to from their neighbours, and the nuanced impacts these molecules can have on tolerance and resistance to certain antibiotics.
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Affiliation(s)
- Elena K Perry
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Lucas A Meirelles
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Dianne K Newman
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
- Division of Geological and Planetary Sciences, California Institute of Technology, Pasadena, CA, USA.
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13
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Abstract
Gastrointestinal microbes respond to biochemical metabolites that coordinate their behaviors. Here, we demonstrate that bacterial indole functions as a multifactorial mitigator of Klebsiella grimontii and Klebsiella oxytoca pathogenicity. These closely related microbes produce the enterotoxins tilimycin and tilivalline; cytotoxin-producing strains are the causative agent of antibiotic-associated hemorrhagic colitis and have been associated with necrotizing enterocolitis of premature infants. We demonstrate that carbohydrates induce cytotoxin synthesis while concurrently repressing indole biosynthesis. Conversely, indole represses cytotoxin production. In both cases, the alterations stemmed from differential transcription of npsA and npsB, key genes involved in tilimycin biosynthesis. Indole also enhances conversion of tilimycin to tilivalline, an indole analog with reduced cytotoxicity. In this context, we established that tilivalline, but not tilimycin, is a strong agonist of pregnane X receptor (PXR), a master regulator of xenobiotic detoxification and intestinal inflammation. Tilivalline binding upregulated PXR-responsive detoxifying genes and inhibited tubulin-directed toxicity. Bacterial indole, therefore, acts in a multifunctional manner to mitigate cytotoxicity by Klebsiella spp.: suppression of toxin production, enhanced conversion of tilimycin to tilivalline, and activation of PXR. IMPORTANCE The human gut harbors a complex community of microbes, including several species and strains that could be commensals or pathogens depending on context. The specific environmental conditions under which a resident microbe changes its relationship with a host and adopts pathogenic behaviors, in many cases, remain poorly understood. Here, we describe a novel communication network involving the regulation of K. grimontii and K. oxytoca enterotoxicity. Bacterial indole was identified as a central modulator of these colitogenic microbes by suppressing bacterial toxin (tilimycin) synthesis and converting tilimycin to tilivalline while simultaneously activating a host receptor, PXR, as a means of mitigating tissue cytotoxicity. On the other hand, fermentable carbohydrates were found to inhibit indole biosynthesis and enhance toxin production. This integrated network involving microbial, host, and metabolic factors provides a contextual framework to better understand K. oxytoca complex pathogenicity.
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"The quantitative determination of indolic microbial tryptophan metabolites in human and rodent samples: A systematic review". J Chromatogr B Analyt Technol Biomed Life Sci 2021; 1186:123008. [PMID: 34735972 DOI: 10.1016/j.jchromb.2021.123008] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 10/18/2021] [Indexed: 02/08/2023]
Abstract
Concentrations reported for indolic microbial metabolites of tryptophan in human and rodent brain, cerebrospinal fluid, plasma, saliva and feces were compiled and discussed. A systematic review of the literature was accomplished by key word searches of Pubmed, Google Scholar and the Human Metabolome Data Base (HMDB), and by searching bibliographies of identified publications including prior reviews. The review was prompted by the increasing appreciation of the physiological importance of the indolic compounds in human health and disease. The compounds included were indoleacetic acid (IAA), indole propionic acid (IPA), indoleacrylic acid (IACR), indolelactic acid (ILA) indolepyruvic acid (IPY), indoleacetaldehyde (IAALD), indolealdehyde (IALD), tryptamine (TAM), indole (IND) and skatole (SKT). The undertaking aimed to vet and compare existing reports, to resolve apparent discrepancies, to draw biological inferences from the consideration of multiple analytes across sample types, to survey the analytical methodologies used, and to point out areas in need of greater attention.
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15
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Mertowska P, Mertowski S, Wojnicka J, Korona-Głowniak I, Grywalska E, Błażewicz A, Załuska W. A Link between Chronic Kidney Disease and Gut Microbiota in Immunological and Nutritional Aspects. Nutrients 2021; 13:3637. [PMID: 34684638 PMCID: PMC8540836 DOI: 10.3390/nu13103637] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/14/2021] [Accepted: 10/15/2021] [Indexed: 02/07/2023] Open
Abstract
Chronic kidney disease (CKD) is generally progressive and irreversible, structural or functional renal impairment for 3 or more months affecting multiple metabolic pathways. Recently, the composition, dynamics, and stability of a patient's microbiota has been noted to play a significant role during disease onset or progression. Increasing urea concentration during CKD can lead to an acceleration of the process of kidney injury leading to alterations in the intestinal microbiota that can increase the production of gut-derived toxins and alter the intestinal epithelial barrier. A detailed analysis of the relationship between the role of intestinal microbiota and the development of inflammation within the symbiotic and dysbiotic intestinal microbiota showed significant changes in kidney dysfunction. Several recent studies have determined that dietary factors can significantly influence the activation of immune cells and their mediators. Moreover, dietary changes can profoundly affect the balance of gut microbiota. The aim of this review is to present the importance and factors influencing the differentiation of the human microbiota in the progression of kidney diseases, such as CKD, IgA nephropathy, idiopatic nephropathy, and diabetic kidney disease, with particular emphasis on the role of the immune system. Moreover, the effects of nutrients, bioactive compounds on the immune system in development of chronic kidney disease were reviewed.
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Affiliation(s)
- Paulina Mertowska
- Department of Experimental Immunology, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland; (P.M.); (S.M.); (E.G.)
| | - Sebastian Mertowski
- Department of Experimental Immunology, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland; (P.M.); (S.M.); (E.G.)
| | - Julia Wojnicka
- Department of Pathobiochemistry and Interdisciplinary Applications of Ion Chromatography, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (J.W.); (A.B.)
| | - Izabela Korona-Głowniak
- Department of Pharmaceutical Microbiology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland
| | - Ewelina Grywalska
- Department of Experimental Immunology, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland; (P.M.); (S.M.); (E.G.)
| | - Anna Błażewicz
- Department of Pathobiochemistry and Interdisciplinary Applications of Ion Chromatography, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (J.W.); (A.B.)
| | - Wojciech Załuska
- Department of Nephrology, Medical University of Lublin, 8 Jaczewskiego Street, 20-954 Lublin, Poland;
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Han H, Safe S, Jayaraman A, Chapkin RS. Diet-Host-Microbiota Interactions Shape Aryl Hydrocarbon Receptor Ligand Production to Modulate Intestinal Homeostasis. Annu Rev Nutr 2021; 41:455-478. [PMID: 34633858 PMCID: PMC8667662 DOI: 10.1146/annurev-nutr-043020-090050] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The aryl hydrocarbon receptor (AhR) is a ligand-activated basic-helix-loop-helix transcription factor that binds structurally diverse ligands and senses cues from environmental toxicants and physiologically relevant dietary/microbiota-derived ligands. The AhR is an ancient conserved protein and is widely expressed across different tissues in vertebrates and invertebrates. AhR signaling mediates a wide range of cellular functions in a ligand-, cell type-, species-, and context-specific manner. Dysregulation of AhR signaling is linked to many developmental defects and chronic diseases. In this review, we discuss the emerging role of AhR signaling in mediating bidirectional host-microbiome interactions. We also consider evidence showing the potential for the dietary/microbial enhancement ofhealth-promoting AhR ligands to improve clinical pathway management in the context of inflammatory bowel diseases and colon tumorigenesis.
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Affiliation(s)
- Huajun Han
- Program in Integrative Nutrition and Complex Diseases and Department of Nutrition, Texas A&M University, College Station, Texas 77843, USA;
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, Texas 77843, USA
| | - Stephen Safe
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, Texas 77843, USA
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843, USA
| | - Arul Jayaraman
- Department of Chemical Engineering, Texas A&M University, College Station, Texas 77843, USA
| | - Robert S Chapkin
- Program in Integrative Nutrition and Complex Diseases and Department of Nutrition, Texas A&M University, College Station, Texas 77843, USA;
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, Texas 77843, USA
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17
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Hoshiko Y, Nishiyama Y, Moriya T, Kadokami K, López-Jácome LE, Hirano R, García-Contreras R, Maeda T. Quinolone Signals Related to Pseudomonas Quinolone Signal-Quorum Sensing Inhibits the Predatory Activity of Bdellovibrio bacteriovorus. Front Microbiol 2021; 12:722579. [PMID: 34566925 PMCID: PMC8461301 DOI: 10.3389/fmicb.2021.722579] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 08/12/2021] [Indexed: 12/12/2022] Open
Abstract
Bdellovibrio bacteriovorus is one of the predatory bacteria; therefore, it can act as a novel “living antibiotic,” unlike the current antibiotics. Here the predation of Escherichia coli by B. bacteriovorus was inhibited in the presence of Pseudomonas aeruginosa. This study investigated whether P. aeruginosa-induced predation inhibition is associated with bacterial quorum sensing (QS). Each las, rhl, or pqs QS mutant in P. aeruginosa was used to check the predatory activity of E. coli cells using B. bacteriovorus. As a result, the predatory activity of B. bacteriovorus increased in a mutant pqs QS system, whereas wild-type PA14 inhibited the predatory activity. Moreover, the addition of 4-hydroxy-2-heptylquinoline (HHQ) or the analog triggered the low predatory activity of B. bacteriovorus and killed B. bacteriovorus cells. Therefore, a defensive action of P. aeruginosa against B. bacteriovorus is activated by the pqs QS system, which produces some quinolone compounds such as HHQ.
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Affiliation(s)
- Yuki Hoshiko
- Department of Biological Functions Engineering, Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Kitakyushu, Japan
| | - Yoshito Nishiyama
- Department of Biological Functions Engineering, Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Kitakyushu, Japan
| | - Tae Moriya
- Department of Biological Functions Engineering, Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Kitakyushu, Japan
| | - Kiwao Kadokami
- Institute of Environmental Science and Technology, The University of Kitakyushu, Kitakyushu, Japan
| | - Luis Esaú López-Jácome
- Department of Microbiology and Parasitology, Faculty of Medicine, UNAM, Mexico City, Mexico.,Laboratory of Infectology, National Institute of Rehabilitation Luis Guillermo Ibarra Ibarra, Mexico City, Mexico
| | - Ryutaro Hirano
- Department of Biological Functions Engineering, Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Kitakyushu, Japan
| | | | - Toshinari Maeda
- Department of Biological Functions Engineering, Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Kitakyushu, Japan
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18
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Samuelson DR, Gu M, Shellito JE, Molina PE, Taylor CM, Luo M, Welsh DA. Pulmonary immune cell trafficking promotes host defense against alcohol-associated Klebsiella pneumonia. Commun Biol 2021; 4:997. [PMID: 34426641 PMCID: PMC8382828 DOI: 10.1038/s42003-021-02524-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 08/05/2021] [Indexed: 12/15/2022] Open
Abstract
The intestinal microbiota generates many different metabolites which are critical for the regulation of host signaling pathways. In fact, a wide-range of diseases are associated with increased levels of local or systemic microbe-derived metabolites. In contrast, certain bacterial metabolites, such as tryptophan metabolites, are known to contribute to both local and systemic homeostasis. Chronic alcohol consumption is accompanied by alterations to intestinal microbial communities, and their functional capacities. However, little is known about the role of alcohol-associated dysbiosis on host defense against bacterial pneumonia. Our previous work using fecal transplantation demonstrated that alcohol-associated intestinal dysbiosis, independent of ethanol consumption, increased susceptibility to Klebsiella pneumonia. Here, we demonstrate that intestinal microbiota treatments mitigate the increased risk of alcohol-associated pneumonia. Treatment with the microbial metabolite indole or with probiotics reduced pulmonary and extrapulmonary bacterial burden, restored immune responses, and improved cellular trafficking required for host defense. Protective effects were, in part, mediated by aryl hydrocarbon receptors (AhR), as inhibition of AhR diminished the protective effects. Thus, alcohol appears to impair the production/processing of tryptophan catabolites resulting in immune dysregulation and impaired cellular trafficking. These data support microbiota therapeutics as novel strategies to mitigate the increased risk for alcohol-associated bacterial pneumonia. Samuelson et al show that alcohol impairs the production/processing of microbial metabolites, specifically tryptophan catabolites, resulting in immune dysregulation and impaired cellular trafficking for optimal host defense. The metabolite, indole, or probiotics making indole metabolites mitigate alcohol-induced susceptibility to Klebsiella-associated pneumonia, and that the mechanisms are partially dependent on AhR.
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Affiliation(s)
- Derrick R Samuelson
- Department of Internal Medicine, Section of Pulmonary/Critical Care & Allergy/Immunology, Louisiana State University Health Sciences Center, New Orleans, LA, USA. .,Department of Internal Medicine, Division of Pulmonary, Critical Care, & Sleep, University of Nebraska Medical Center, Omaha, NE, USA.
| | - Min Gu
- Department of Internal Medicine, Section of Pulmonary/Critical Care & Allergy/Immunology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Judd E Shellito
- Department of Internal Medicine, Section of Pulmonary/Critical Care & Allergy/Immunology, Louisiana State University Health Sciences Center, New Orleans, LA, USA.,Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Patricia E Molina
- Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Christopher M Taylor
- Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Meng Luo
- Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - David A Welsh
- Department of Internal Medicine, Section of Pulmonary/Critical Care & Allergy/Immunology, Louisiana State University Health Sciences Center, New Orleans, LA, USA.,Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
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Kumar P, Lee JH, Lee J. Diverse roles of microbial indole compounds in eukaryotic systems. Biol Rev Camb Philos Soc 2021; 96:2522-2545. [PMID: 34137156 PMCID: PMC9290978 DOI: 10.1111/brv.12765] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 06/07/2021] [Accepted: 06/08/2021] [Indexed: 02/06/2023]
Abstract
Indole and its derivatives are widespread across different life forms, functioning as signalling molecules in prokaryotes and with more diverse roles in eukaryotes. A majority of indoles found in the environment are attributed to bacterial enzymes converting tryptophan into indole and its derivatives. The involvement of indoles among lower organisms as an interspecies and intraspecies signal is well known, with many reports showing that inter‐kingdom interactions involving microbial indole compounds are equally important as they influence defence systems and even the behaviour of higher organisms. This review summarizes recent advances in our understanding of the functional properties of indole and indole derivatives in diverse eukaryotes. Furthermore, we discuss current perspectives on the role of microbial indoles in human diseases such as diabetes, obesity, atherosclerosis, and cancers. Deciphering the function of indoles as biomarkers of metabolic state will facilitate the formulation of diet‐based treatments and open unique therapeutic opportunities.
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Affiliation(s)
- Prasun Kumar
- School of Chemical Engineering, Yeungnam University, 280 Daehak-Ro, Gyeongsan, 38541, Republic of Korea
| | - Jin-Hyung Lee
- School of Chemical Engineering, Yeungnam University, 280 Daehak-Ro, Gyeongsan, 38541, Republic of Korea
| | - Jintae Lee
- School of Chemical Engineering, Yeungnam University, 280 Daehak-Ro, Gyeongsan, 38541, Republic of Korea
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20
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Spichak S, Bastiaanssen TFS, Berding K, Vlckova K, Clarke G, Dinan TG, Cryan JF. Mining microbes for mental health: Determining the role of microbial metabolic pathways in human brain health and disease. Neurosci Biobehav Rev 2021; 125:698-761. [PMID: 33675857 DOI: 10.1016/j.neubiorev.2021.02.044] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 02/22/2021] [Accepted: 02/25/2021] [Indexed: 12/12/2022]
Abstract
There is increasing knowledge regarding the role of the microbiome in modulating the brain and behaviour. Indeed, the actions of microbial metabolites are key for appropriate gut-brain communication in humans. Among these metabolites, short-chain fatty acids, tryptophan, and bile acid metabolites/pathways show strong preclinical evidence for involvement in various aspects of brain function and behaviour. With the identification of neuroactive gut-brain modules, new predictive tools can be applied to existing datasets. We identified 278 studies relating to the human microbiota-gut-brain axis which included sequencing data. This spanned across psychiatric and neurological disorders with a small number also focused on normal behavioural development. With a consistent bioinformatics pipeline, thirty-five of these datasets were reanalysed from publicly available raw sequencing files and the remainder summarised and collated. Among the reanalysed studies, we uncovered evidence of disease-related alterations in microbial metabolic pathways in Alzheimer's Disease, schizophrenia, anxiety and depression. Amongst studies that could not be reanalysed, many sequencing and technical limitations hindered the discovery of specific biomarkers of microbes or metabolites conserved across studies. Future studies are warranted to confirm our findings. We also propose guidelines for future human microbiome analysis to increase reproducibility and consistency within the field.
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Affiliation(s)
- Simon Spichak
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; APC Microbiome Institute, University College Cork, Cork, Ireland
| | - Thomaz F S Bastiaanssen
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; APC Microbiome Institute, University College Cork, Cork, Ireland
| | - Kirsten Berding
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; APC Microbiome Institute, University College Cork, Cork, Ireland
| | - Klara Vlckova
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; APC Microbiome Institute, University College Cork, Cork, Ireland
| | - Gerard Clarke
- APC Microbiome Institute, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - Timothy G Dinan
- APC Microbiome Institute, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - John F Cryan
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; APC Microbiome Institute, University College Cork, Cork, Ireland.
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21
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Knudsen C, Neyrinck AM, Leyrolle Q, Baldin P, Leclercq S, Rodriguez J, Beaumont M, Cani PD, Bindels LB, Lanthier N, Delzenne NM. Hepatoprotective Effects of Indole, a Gut Microbial Metabolite, in Leptin-Deficient Obese Mice. J Nutr 2021; 151:1507-1516. [PMID: 33693866 PMCID: PMC8169809 DOI: 10.1093/jn/nxab032] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 10/30/2020] [Accepted: 01/28/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The gut microbiota plays a role in the occurrence of nonalcoholic fatty liver disease (NAFLD), notably through the production of bioactive metabolites. Indole, a bacterial metabolite of tryptophan, has been proposed as a pivotal metabolite modulating inflammation, metabolism, and behavior. OBJECTIVES The aim of our study was to mimic an upregulation of intestinal bacterial indole production and to evaluate its potential effect in vivo in 2 models of NAFLD. METHODS Eight-week-old leptin-deficient male ob/ob compared with control ob/+ mice (experiment 1), and 4-5-wk-old C57BL/6JRj male mice fed a low-fat (LF, 10 kJ%) compared with a high-fat (HF, 60 kJ%) diet (experiment 2), were given plain water or water supplemented with a physiological dose of indole (0.5 mM, n ≥6/group) for 3 wk and 3 d, respectively. The effect of the treatments on the liver, intestine, adipose tissue, brain, and behavior was assessed. RESULTS Indole reduced hepatic expression of genes involved in inflammation [C-C motif chemokine ligand 2 (Ccl2), C-X-C motif chemokine ligand 2 (Cxcl2); 3.3- compared with 5.0-fold, and 2.4- compared with 3.3-fold of control ob/+ mice, respectively, P < 0.05], and in macrophage activation [Cd68, integrin subunit α X (Itgax); 2.1- compared with 2.5-fold, and 5.0- compared with 6.4-fold of control ob/+ mice, respectively, P < 0.01] as well as markers of hepatic damage (alaninine aminotransferase; -32%, P < 0.001) regardless of genotype in experiment 1. Indole had no effect on hepatic inflammation in mice fed the LF or HF diet in experiment 2. Indole did not change hepatic lipid content, anxiety-like behavior, or inflammation in the ileum, adipose tissue, and brain in experiment 1. CONCLUSIONS Our results support the efficacy of indole to reduce hepatic damage and associated inflammatory response and macrophage activation in ob/ob mice. These modifications appear to be attributable to direct effects of indole on the liver, rather than through effects on the adipose tissue or intestinal barrier.
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Affiliation(s)
- Christelle Knudsen
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
- GenPhySE, Université de Toulouse, INRAE, ENVT, 31320, Castanet Tolosan, France
| | - Audrey M Neyrinck
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Quentin Leyrolle
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Pamela Baldin
- Service d'Anatomie Pathologique Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Sophie Leclercq
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
- Institute of Neuroscience, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Julie Rodriguez
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Martin Beaumont
- GenPhySE, Université de Toulouse, INRAE, ENVT, 31320, Castanet Tolosan, France
| | - Patrice D Cani
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
- WELBIO–Walloon Excellence in Life Sciences and BIOtechnology, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Laure B Bindels
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Nicolas Lanthier
- Service d'Hépato-gastroentérologie, Cliniques universitaires Saint-Luc, Brussels, Belgium
- Laboratory of Gastroenterology and Hepatology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Nathalie M Delzenne
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
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22
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Bui TPN, de Vos WM. Next-generation therapeutic bacteria for treatment of obesity, diabetes, and other endocrine diseases. Best Pract Res Clin Endocrinol Metab 2021; 35:101504. [PMID: 33785319 DOI: 10.1016/j.beem.2021.101504] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The human gut microbiota has appeared as an important factor affecting host health and intestinal bacteria have recently emerged as potential therapeutics to treat diabetes and other endocrine diseases. These mainly anaerobic bacteria have been identified either via comparative "omics" analysis of the intestinal microbiota in healthy and diseased subjects or of data collected by fecal microbiota transplantation studies. Both approaches require advanced and in-depth sequencing technologies to perform massive genomic screening to select bacteria with potential benefits. It has been shown that these potentially therapeutic bacteria can either produce bioactive products that directly influence the host patho-physiology and endocrine systems or produce specific signaling molecules that may do so. These bioactive compounds can be formed via degradation of dietary or host-derived components or the conversion of intermediate compounds produced by fermentation of intestinal bacteria. Several of these bacteria have shown causality in preclinical models and entered clinical phase studies, while their mode of action is being analyzed. In this review, we summarize the research on the most promising bacterial candidates with therapeutic properties with a specific focus on diabetes.
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Affiliation(s)
- Thi Phuong Nam Bui
- Laboratory of Microbiology, Wageningen University, Stippeneng 4, 6708, WE, Wageningen, the Netherlands; Caelus Pharmaceuticals BV, 3474, KG, Zegveld, the Netherlands
| | - Willem M de Vos
- Laboratory of Microbiology, Wageningen University, Stippeneng 4, 6708, WE, Wageningen, the Netherlands; Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
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23
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Huang J, Tong J, Zhang P, Zhou Y, Cui Y, Tan S, Wang Z, Yang F, Kochunov P, Chiappelli J, Tian B, Tian L, Tan Y, Hong LE. Effects of neuroactive metabolites of the tryptophan pathway on working memory and cortical thickness in schizophrenia. Transl Psychiatry 2021; 11:198. [PMID: 33795641 PMCID: PMC8016899 DOI: 10.1038/s41398-021-01311-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 02/19/2021] [Accepted: 03/11/2021] [Indexed: 01/10/2023] Open
Abstract
A number of tryptophan metabolites known to be neuroactive have been examined for their potential associations with cognitive deficits in schizophrenia. Among these metabolites, kynurenic acid (KYNA), 5-hydroxyindole (5-HI), and quinolinic acid (QUIN) are documented in their diverse effects on α-7 nicotinic acetylcholine receptor (α7nAChR) and/or N-methyl-D-aspartate receptor (NMDAR), two of the receptor types thought to contribute to cognitive impairment in schizophrenia. In this study, serum levels of KYNA, 5-HI, and QUIN were measured in 195 patients with schizophrenia and in 70 healthy controls using liquid chromatography-tandem mass spectrometry; cognitive performance in MATRICS Consensus Cognitive Battery and cortical thickness measured by magnetic resonance imaging were obtained. Patients with schizophrenia had significantly lower serum KYNA (p < 0.001) and QUIN (p = 0.02) levels, and increased 5-HI/KYNA (p < 0.001) and QUIN/KYNA ratios (p < 0.001) compared with healthy controls. Multiple linear regression showed that working memory was positively correlated with serum 5-HI levels (t = 2.10, p = 0.04), but inversely correlated with KYNA concentrations (t = -2.01, p = 0.05) in patients. Patients with high 5-HI and low KYNA had better working memory than other subgroups (p = 0.01). Higher 5-HI levels were associated with thicker left lateral orbitofrontal cortex (t = 3.71, p = 2.94 × 10-4) in patients. The different effects of 5-HI and KYNA on working memory may appear consistent with their opposite receptor level mechanisms. Our findings appear to provide a new insight into the dynamic roles of tryptophan pathway metabolites on cognition, which may benefit novel therapeutic development that targets cognitive impairment in schizophrenia.
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Affiliation(s)
- Junchao Huang
- grid.414351.60000 0004 0530 7044Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China
| | - Jinghui Tong
- grid.414351.60000 0004 0530 7044Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China
| | - Ping Zhang
- grid.414351.60000 0004 0530 7044Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China
| | - Yanfang Zhou
- grid.414351.60000 0004 0530 7044Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China
| | - Yimin Cui
- grid.411472.50000 0004 1764 1621Department of Pharmacy, Peking University First Hospital, Beijing, China
| | - Shuping Tan
- grid.414351.60000 0004 0530 7044Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China
| | - Zhiren Wang
- grid.414351.60000 0004 0530 7044Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China
| | - Fude Yang
- grid.414351.60000 0004 0530 7044Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China
| | - Peter Kochunov
- grid.411024.20000 0001 2175 4264Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD USA
| | - Joshua Chiappelli
- grid.411024.20000 0001 2175 4264Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD USA
| | - Baopeng Tian
- grid.414351.60000 0004 0530 7044Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China
| | - Li Tian
- grid.10939.320000 0001 0943 7661Faculty of Medicine, Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Yunlong Tan
- Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China.
| | - L. Elliot Hong
- grid.411024.20000 0001 2175 4264Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD USA
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Qayed M, Michonneau D, Socié G, Waller EK. Indole derivatives, microbiome and graft versus host disease. Curr Opin Immunol 2021; 70:40-47. [PMID: 33647539 PMCID: PMC8466652 DOI: 10.1016/j.coi.2021.02.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 02/05/2021] [Accepted: 02/08/2021] [Indexed: 02/07/2023]
Abstract
Graft versus host disease is a life-threatening complication following allogeneic hematopoietic stem cell transplantation driven by donor T cells reacting against disparate host antigens. Immune homeostasis within the gut plays a major role in the graft versus host response. Gut microbiota and its metabolites impact gut integrity, inflammation and immune activation within the gut. This review will focus on the role of indoles, a product of microbiota metabolism, on gut homeostasis and our current understanding on how that modulates graft versus host disease.
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Affiliation(s)
- Muna Qayed
- Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
- Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
- Corresponding author: Edmund K. Waller MD, PhD, FACP, Professor of Medicine and Oncology, Winship Cancer Institute Emory University, Atlanta, Georgia 30322; Phone 404-727-4995; Fax 404-778-5530
| | - David Michonneau
- Hematology Transplantation, Saint Louis Hospital, 1 avenue Claude Vellefaux, 75010 Paris, France
- Université de Paris, INSERM U976, F-75010 Paris, France
| | - Gerard Socié
- Hematology Transplantation, Saint Louis Hospital, 1 avenue Claude Vellefaux, 75010 Paris, France
- Université de Paris, INSERM U976, F-75010 Paris, France
| | - Edmund K. Waller
- Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
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25
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Gut Microbiota-Derived Metabolites in the Development of Diseases. ACTA ACUST UNITED AC 2021; 2021:6658674. [PMID: 33505541 PMCID: PMC7815404 DOI: 10.1155/2021/6658674] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 12/12/2020] [Accepted: 12/30/2020] [Indexed: 02/08/2023]
Abstract
Gut microbiota is increasingly recognized as a metabolic organ essential for human health. Compelling evidences show a variety set of links between diets and gut microbial homeostasis. Changes in gut microbial flora would probably contribute to the development of certain diseases such as diabetes, heart disease, allergy, and psychiatric diseases. In addition to the composition of gut microbiota, the metabolites derived from gut microbiota have emerged as a pivotal regulator in diseases development. Since high-fat and high-protein diets substantially affect the gut microbial ecology and human health, the current review summarizes the gut microbiota-derived metabolites such as short-chain fatty acids (SCFAs), amino acids, and their derivatives and highlights the mechanisms underlying the host responses to these bioactive substances.
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Sun XZ, Zhao DY, Zhou YC, Wang QQ, Qin G, Yao SK. Alteration of fecal tryptophan metabolism correlates with shifted microbiota and may be involved in pathogenesis of colorectal cancer. World J Gastroenterol 2020; 26:7173-7190. [PMID: 33362375 PMCID: PMC7723673 DOI: 10.3748/wjg.v26.i45.7173] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 10/12/2020] [Accepted: 11/02/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gut tryptophan (Trp) metabolites are produced by microbiota and/or host metabolism. Some of them have been proven to promote or inhibit colorectal cancer (CRC) in vitro and animal models. We hypothesized that there is an alteration of gut Trp metabolism mediated by microbiota and that it might be involved in the pathogenesis of cancer in patients with CRC. AIM To investigate the features of Trp metabolism in CRC and the correlation between fecal Trp metabolites and gut microbiota. METHODS Seventy-nine patients with colorectal neoplastic lesions (33 with colon adenoma and 46 with sporadic CRC) and 38 healthy controls (HCs) meeting the inclusion and exclusion criteria were included in the study. Their demographic and clinical features were collected. Fecal Trp, kynurenine (KYN), and indoles (metabolites of Trp metabolized by gut microbiota) were examined by ultraperformance liquid chromatography coupled to tandem mass spectrometry. Gut barrier marker and indoleamine 2,3-dioxygenase 1 (IDO1) mRNA were analyzed by quantitative real-time polymerase chain reaction. Zonula occludens-1 (ZO-1) protein expression was analyzed by immunohistochemistry. The gut microbiota was detected by 16S ribosomal RNA gene sequencing. Correlations between fecal metabolites and other parameters were examined in all patients. RESULTS The absolute concentration of KYN [1.51 (0.70, 3.46) nmol/g vs 0.81 (0.64, 1.57) nmol/g, P = 0.036] and the ratio of KYN to Trp [7.39 (4.12, 11.72) × 10-3 vs 5.23 (1.86, 7.99) × 10-3, P = 0.032] were increased in the feces of patients with CRC compared to HCs, while the indoles to Trp ratio was decreased [1.34 (0.70, 2.63) vs 2.46 (1.25, 4.10), P = 0.029]. The relative ZO-1 mRNA levels in patients with CRC (0.27 ± 0.24) were significantly lower than those in HCs (1.00 ± 0.31) (P < 0.001), and the relative IDO1 mRNA levels in patients with CRC [1.65 (0.47-2.46)] were increased (P = 0.035). IDO1 mRNA levels were positively associated with the KYN/Trp ratio (r = 0.327, P = 0.003). ZO-1 mRNA and protein levels were positively correlated with the indoles/Trp ratio (P = 0.035 and P = 0.009, respectively). In addition, the genera Asaccharobacter (Actinobacteria) and Parabacteroides (Bacteroidetes), and members of the phylum Firmicutes (Clostridium XlVb, Fusicatenibacter, Anaerofilum, and Anaerostipes) decreased in CRC and exhibited a positive correlation with indoles in all subjects. CONCLUSION Alteration of fecal Trp metabolism mediated by microbiota is associated with intestinal barrier function and tissue Trp metabolism, and may be involved in the pathogenesis of CRC.
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Affiliation(s)
- Xi-Zhen Sun
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Dong-Yan Zhao
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Yuan-Chen Zhou
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
- Peking University China-Japan Friendship School of Clinical Medicine, Peking University, Beijing 100029, China
| | - Qian-Qian Wang
- Peking University China-Japan Friendship School of Clinical Medicine, Peking University, Beijing 100029, China
| | - Geng Qin
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Shu-Kun Yao
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
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Abstract
Increasing evidence suggests a significant role for microbiota dependent metabolites and co-metabolites, acting as aryl hydrocarbon receptor (AHR) ligands, to facilitate bidirectional communication between the host and the microbiota and thus modulate physiology. Such communication is particularly evident within the gastrointestinal tract. Through binding to or activating the AHR, these metabolites play fundamental roles in various physiological processes and likely contribute to the maintenance of intestinal homeostasis. In recent years, tryptophan metabolites were screened to identify physiologically relevant AHR ligands or activators. The discovery of specific microbiota-derived indole-based metabolites as AHR ligands may provide insight concerning how these metabolites affect interactions between gut microbiota and host intestinal homeostasis and how this relates to chronic GI disease and overall health. A greater understanding of the mechanisms that modulate the production of such metabolites and associated AHR activity may be utilized to effectively treat inflammatory diseases and promote human health. Here, we review microbiota-derived AHR ligands generated from tryptophan that modulate host-gut microbiota interactions and discuss possible intervention strategies for potential therapies in the future.
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Affiliation(s)
- Fangcong Dong
- Department of Veterinary and Biomedical Sciences and the Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA
| | - Gary H. Perdew
- Department of Veterinary and Biomedical Sciences and the Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA,CONTACT Gary H. Perdew The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA16802, USA
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Dharmawardana N, Goddard T, Woods C, Watson DI, Butler R, Ooi EH, Yazbeck R. Breath methane to hydrogen ratio as a surrogate marker of intestinal dysbiosis in head and neck cancer. Sci Rep 2020; 10:15010. [PMID: 32929151 PMCID: PMC7490703 DOI: 10.1038/s41598-020-72115-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 08/13/2020] [Indexed: 01/30/2023] Open
Abstract
Exhaled breath compounds can non-invasively detect head and neck squamous cell carcinoma (HNSCC). Here we investigated exhaled compounds related to intestinal bacterial carbohydrate fermentation. Fasting breath samples were collected into 3 litre FlexFoil PLUS bags from patients awaiting a biopsy procedure for suspected HNSCC. Samples were analysed using a Syft selected ion flow-tube mass spectrometer and a Quintron BreathTracker. Two tailed non-parametric significance testing was conducted with corrections for multiple imputations. 74 patients were diagnosed (histological) with HNSCC and 61 patients were benign (controls). The methane to hydrogen ratio was significantly different between cancer and non-cancer controls (p = 0.0440). This ratio increased with tumour stage with a significant difference between T1 and T4 tumours (p = 0.0259). Hydrogen levels were significantly higher in controls who were smokers (p = 0.0129), with no smoking dependent methane changes. There were no differences in short chain fatty acids between groups. Exhaled compounds of intestinal carbohydrate fermentation can detect HNSCC patients. These findings suggest a modified carbohydrate fermentation profile in HNSCC patients that is tumour stage and smoking status dependent.
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Affiliation(s)
- Nuwan Dharmawardana
- Department of Otorhinolaryngology-Head and Neck Surgery, Flinders Medical Centre, Bedford Park, Australia.
- Discipline of Surgery, College of Medicine and Public Health, Flinders University, Bedford Park, Australia.
| | - Thomas Goddard
- Department of Respiratory and Sleep Medicine, Women's and Children's Hospital, Adelaide, Australia
| | - Charmaine Woods
- Department of Otorhinolaryngology-Head and Neck Surgery, Flinders Medical Centre, Bedford Park, Australia
- Discipline of Surgery, College of Medicine and Public Health, Flinders University, Bedford Park, Australia
| | - David I Watson
- Discipline of Surgery, College of Medicine and Public Health, Flinders University, Bedford Park, Australia
| | - Ross Butler
- Discipline of Surgery, College of Medicine and Public Health, Flinders University, Bedford Park, Australia
| | - Eng H Ooi
- Department of Otorhinolaryngology-Head and Neck Surgery, Flinders Medical Centre, Bedford Park, Australia
- Discipline of Surgery, College of Medicine and Public Health, Flinders University, Bedford Park, Australia
| | - Roger Yazbeck
- Discipline of Surgery, College of Medicine and Public Health, Flinders University, Bedford Park, Australia
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Maiti S, Grivas G, Choi K, Dai W, Ding Y, Acosta DP, Hahn J, Jayaraman A. MODELING INTER-KINGDOM REGULATION OF INFLAMMATORY SIGNALING IN HUMAN INTESTINAL EPITHELIAL CELLS. Comput Chem Eng 2020; 140. [PMID: 32669746 DOI: 10.1016/j.compchemeng.2020.106954] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The human gastrointestinal (GI) tract is colonized by a highly diverse and complex microbial community (i.e., microbiota). The microbiota plays an important role in the development of the immune system, specifically mediating inflammatory responses, however the exact mechanisms are poorly understood. We have developed a mathematical model describing the effect of indole on host inflammatory signaling in HCT-8 human intestinal epithelial cells. In this model, indole modulates transcription factor nuclear factor κ B (NF-κB) and produces the chemokine interleukin-8 (IL-8) through the activation of the aryl hydrocarbon receptor (AhR). Phosphorylated NF-κB exhibits dose and time-dependent responses to indole concentrations and IL-8 production shows a significant down-regulation for 0.1 ng/mL TNF-α stimulation. The model shows agreeable simulation results with the experimental data for IL-8 secretion and normalized NF-κB values. Our results suggest that microbial metabolites such as indole can modulate inflammatory signaling in HTC-8 cells through receptor-mediated processes.
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Affiliation(s)
- Shreya Maiti
- Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, TX
| | - Genevieve Grivas
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY
| | - Kyungoh Choi
- Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, TX
| | - Wei Dai
- Department of Chemical & Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY
| | - Yufang Ding
- Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, TX
| | | | - Juergen Hahn
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY.,Department of Chemical & Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY
| | - Arul Jayaraman
- Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, TX
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Williams KB, Bischof J, Lee FJ, Miller KA, LaPalme JV, Wolfe BE, Levin M. Regulation of axial and head patterning during planarian regeneration by a commensal bacterium. Mech Dev 2020; 163:103614. [PMID: 32439577 DOI: 10.1016/j.mod.2020.103614] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Accepted: 05/06/2020] [Indexed: 02/08/2023]
Abstract
Some animals, such as planaria, can regenerate complex anatomical structures in a process regulated by genetic and biophysical factors, but additional external inputs into regeneration remain to be uncovered. Microbial communities inhabiting metazoan organisms are important for metabolic, immune, and disease processes, but their instructive influence over host structures remains largely unexplored. Here, we show that Aquitalea sp. FJL05, an endogenous commensal bacterium of Dugesia japonica planarians, and one of the small molecules it produces, indole, can influence axial and head patterning during regeneration, leading to regeneration of permanently two-headed animals. Testing the impact of indole on planaria tissues via RNA sequencing, we find that indole alters the regenerative outcomes in planarians through changes in expression to patterning genes, including a downregulation of Wnt pathway genes. These data provide a unique example of the product of a commensal bacterium modulating transcription of patterning genes to affect the host's anatomical structure during regeneration.
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Affiliation(s)
| | - Johanna Bischof
- Allen Discovery Center, Tufts University, Medford, MA, United States of America
| | - Frederick J Lee
- Allen Discovery Center, Tufts University, Medford, MA, United States of America
| | - Kelsie A Miller
- Allen Discovery Center, Tufts University, Medford, MA, United States of America
| | - Jennifer V LaPalme
- Allen Discovery Center, Tufts University, Medford, MA, United States of America
| | - Benjamin E Wolfe
- Allen Discovery Center, Tufts University, Medford, MA, United States of America
| | - Michael Levin
- Allen Discovery Center, Tufts University, Medford, MA, United States of America.
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31
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Boon N, Kaur M, Aziz A, Bradnick M, Shibayama K, Eguchi Y, Lund PA. The Signaling Molecule Indole Inhibits Induction of the AR2 Acid Resistance System in Escherichia coli. Front Microbiol 2020; 11:474. [PMID: 32351457 PMCID: PMC7174508 DOI: 10.3389/fmicb.2020.00474] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 03/04/2020] [Indexed: 12/19/2022] Open
Abstract
Induction of the AR2 acid response system of Escherichia coli occurs at a moderately low pH (pH 5.5) and leads to high levels of resistance to pH levels below 2.5 in the presence of glutamate. Induction is mediated in part by the EvgAS two component system. Here, we show that the bacterial signaling molecule indole inhibits the induction of key promoters in the AR2 system and blocks the development of glutamate-dependent acid resistance. The addition of tryptophan, the precursor for indole biosynthesis, had the same effects, and this block was relieved in a tnaA mutant, which is unable to synthesize indole. Expression of a constitutively active EvgS protein was able to relieve the inhibition caused by indole, consistent with EvgS being inhibited directly or indirectly by indole. Indole had no effect on autophosphorylation of the isolated cytoplasmic domain of EvgS. This is consistent with a model where indole directly or indirectly affects the ability of EvgS to detect its inducing signal or to transduce this information across the cytoplasmic membrane. The inhibitory activity of indole on the AR2 system is not related to its ability to act as an ionophore, and, conversely, the ionophore CCCP had no effect on acid-induced AR2 promoter activity, showing that the proton motive force is unlikely to be a signal for induction of the AR2 system.
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Affiliation(s)
- Nathaniel Boon
- School of Biosciences and Institute of Microbiology and Infection, University of Birmingham, Birmingham, United Kingdom
| | - Manpreet Kaur
- School of Biosciences and Institute of Microbiology and Infection, University of Birmingham, Birmingham, United Kingdom
| | - Amina Aziz
- School of Biosciences and Institute of Microbiology and Infection, University of Birmingham, Birmingham, United Kingdom
| | - Morissa Bradnick
- School of Biosciences and Institute of Microbiology and Infection, University of Birmingham, Birmingham, United Kingdom
| | - Kenta Shibayama
- Department of Science and Technology on Food Safety, Faculty of Biology-Oriented Science and Technology, Kindai University, Wakayama, Japan
| | - Yoko Eguchi
- Department of Science and Technology on Food Safety, Faculty of Biology-Oriented Science and Technology, Kindai University, Wakayama, Japan
| | - Peter A Lund
- School of Biosciences and Institute of Microbiology and Infection, University of Birmingham, Birmingham, United Kingdom
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The Emergence of Insect Odorant Receptor-Based Biosensors. BIOSENSORS-BASEL 2020; 10:bios10030026. [PMID: 32192133 PMCID: PMC7146604 DOI: 10.3390/bios10030026] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 03/11/2020] [Accepted: 03/12/2020] [Indexed: 12/28/2022]
Abstract
The olfactory receptor neurons of insects and vertebrates are gated by odorant receptor (OR) proteins of which several members have been shown to exhibit remarkable sensitivity and selectivity towards volatile organic compounds of significant importance in the fields of medicine, agriculture and public health. Insect ORs offer intrinsic amplification where a single binding event is transduced into a measurable ionic current. Consequently, insect ORs have great potential as biorecognition elements in many sensor configurations. However, integrating these sensing components onto electronic transducers for the development of biosensors has been marginal due to several drawbacks, including their lipophilic nature, signal transduction mechanism and the limited number of known cognate receptor-ligand pairs. We review the current state of research in this emerging field and highlight the use of a group of indole-sensitive ORs (indolORs) from unexpected sources for the development of biosensors.
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33
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Mitchell RJ, Mun W, Mabekou SS, Jang H, Choi SY. Compounds affecting predation by and viability of predatory bacteria. Appl Microbiol Biotechnol 2020; 104:3705-3713. [DOI: 10.1007/s00253-020-10530-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 03/01/2020] [Accepted: 03/05/2020] [Indexed: 12/13/2022]
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Orazi G, O'Toole GA. "It Takes a Village": Mechanisms Underlying Antimicrobial Recalcitrance of Polymicrobial Biofilms. J Bacteriol 2019; 202:e00530-19. [PMID: 31548277 PMCID: PMC6932244 DOI: 10.1128/jb.00530-19] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Chronic infections are frequently caused by polymicrobial biofilms. Importantly, these infections are often difficult to treat effectively in part due to the recalcitrance of biofilms to antimicrobial therapy. Emerging evidence suggests that polymicrobial interactions can lead to dramatic and unexpected changes in the ability of antibiotics to eradicate biofilms and often result in decreased antimicrobial efficacy in vitro In this review, we discuss the influence of polymicrobial interactions on the antibiotic susceptibility of biofilms, and we highlight the studies that first documented the shifted antimicrobial susceptibilities of mixed-species cultures. Recent studies have identified several mechanisms underlying the recalcitrance of polymicrobial biofilm communities, including interspecies exchange of antibiotic resistance genes, β-lactamase-mediated inactivation of antibiotics, changes in gene expression induced by metabolites and quorum sensing signals, inhibition of the electron transport chain, and changes in properties of the cell membrane. In addition to elucidating multiple mechanisms that contribute to the altered drug susceptibility of polymicrobial biofilms, these studies have uncovered novel ways in which polymicrobial interactions can impact microbial physiology. The diversity of findings discussed highlights the importance of continuing to investigate the efficacy of antibiotics against biofilm communities composed of different combinations of microbial species. Together, the data presented here illustrate the importance of studying microbes as part of mixed-species communities rather than in isolation. In light of our greater understanding of how interspecies interactions alter the efficacy of antimicrobial agents, we propose that the methods for measuring the drug susceptibility of polymicrobial infections should be revisited.
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Affiliation(s)
- Giulia Orazi
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
| | - George A O'Toole
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
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35
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Harvie RM, Tuck CJ, Schultz M. Evaluation of lactulose, lactose, and fructose breath testing in clinical practice: A focus on methane. JGH OPEN 2019; 4:198-205. [PMID: 32280765 PMCID: PMC7144793 DOI: 10.1002/jgh3.12240] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 07/13/2019] [Indexed: 12/17/2022]
Abstract
Background and Aim Breath testing (BT) is used to identify carbohydrate malabsorption and small intestine bacterial overgrowth. Measuring methane alongside hydrogen is advocated to reduce false-negative studies, but the variability of methane production is unknown. The aim of this study is to examine the effect of high methane production on hydrogen excretion after ingesting lactulose, fructose, or lactose. Methods A retrospective audit was performed of patients with gastrointestinal symptoms who underwent BT. Following a low fermentable carbohydrate diet for 24-h, a fasting BT before consuming 35 ml lactulose, 35 g fructose, or lactose in 200 ml water, followed by BT every 10-15 min for up to 3-h, was performed. A positive test was defined as a ≥20 ppm rise of hydrogen or methane from baseline. A high methane producer had an initial reading of ≥5 ppm. Breath hydrogen and methane production were measured as area under the curve. Chi-squared tests were used to compare proportions of those meeting the cut-off criteria. Results Of patients, 26% (28/106) were high methane producers at their initial lactulose test. The test-retest repeatability of methane production was high, with the same methane production status before ingesting lactose in all (70/70) and before ingesting fructose in most (71/73). Methane production was highly variable during testing, with 38% (10/26) having ≥1 reading lower than baseline. Hydrogen produced by high or low methane producers did not differ (1528 [960-3645] ppm min vs 2375 [1810-3195] ppm min [P = 0.11]). Symptoms and breath test results were not positively related. Conclusion The validity of including an increase of ≥20 ppm methane to identify carbohydrate malabsorption or small intestine bacterial overgrowth should be questioned due to the variability of readings during testing.
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Affiliation(s)
- Ruth M Harvie
- Department of Medicine, Dunedin School of Medicine University of Otago Dunedin New Zealand
| | - Caroline J Tuck
- Gastrointestinal Disease Research Unit, Kingston General Hospital Queen's University Kingston Ontario Canada
| | - Michael Schultz
- Department of Medicine, Dunedin School of Medicine University of Otago Dunedin New Zealand.,Gastroenterology Otago Ltd., Marinoto Clinic Mercy Hospital Dunedin New Zealand
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36
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Muku GE, Murray IA, Perdew GH. Activation of the Ah Receptor Modulates Gastrointestinal Homeostasis and the Intestinal Microbiome. ACTA ACUST UNITED AC 2019. [DOI: 10.1007/s40495-019-00197-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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37
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Abstract
Microbial establishment within the gastrointestinal (GI) tract requires surveillance of the gut biogeography. The gut microbiota coordinates behaviors by sensing host- or microbiota-derived signals. Here we show for the first time that microbiota-derived indole is highly prevalent in the lumen compared to the intestinal tissue. This difference in indole concentration plays a key role in modulating virulence gene expression of the enteric pathogens enterohemorrhagic Escherichia coli (EHEC) and Citrobacter rodentium Indole decreases expression of genes within the locus of enterocyte effacement (LEE) pathogenicity island, which is essential for these pathogens to form attaching and effacing (AE) lesions on enterocytes. We synthetically altered the concentration of indole in the GI tracts of mice by employing mice treated with antibiotics to deplete the microbiota and reconstituted with indole-producing commensal Bacteroides thetaiotaomicron (B. theta) or a B. theta ΔtnaA mutant (does not produce indole) or by engineering an indole-producing C. rodentium strain. This allowed us to assess the role of self-produced versus microbiota-produced indole, and the results show that decreased indole concentrations promote bacterial pathogenesis, while increased levels of indole decrease bacterial virulence gene expression. Moreover, we identified the bacterial membrane-bound histidine sensor kinase (HK) CpxA as an indole sensor. Enteric pathogens sense a gradient of indole concentrations in the gut to probe different niches and successfully establish an infection.IMPORTANCE Pathogens sense and respond to several small molecules within the GI tract to modulate expression of their virulence repertoire. Indole is a signaling molecule produced by the gut microbiota. Here we show that indole concentrations are higher in the lumen, where the microbiota is present, than in the intestinal tissue. The enteric pathogens EHEC and C. rodentium sense indole to downregulate expression of their virulence genes, as a read-out of the luminal compartment. We also identified the bacterial membrane-bound HK CpxA as an indole sensor. This regulation ensures that EHEC and C. rodentium express their virulence genes only at the epithelial lining, which is the niche they colonize.
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38
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Swimm A, Giver CR, DeFilipp Z, Rangaraju S, Sharma A, Ulezko Antonova A, Sonowal R, Capaldo C, Powell D, Qayed M, Kalman D, Waller EK. Indoles derived from intestinal microbiota act via type I interferon signaling to limit graft-versus-host disease. Blood 2018; 132:2506-2519. [PMID: 30257880 PMCID: PMC6284212 DOI: 10.1182/blood-2018-03-838193] [Citation(s) in RCA: 114] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 09/19/2018] [Indexed: 01/05/2023] Open
Abstract
The intestinal microbiota in allogeneic bone marrow transplant (allo-BMT) recipients modulates graft-versus-host disease (GVHD), a systemic inflammatory state initiated by donor T cells that leads to colitis, a key determinant of GVHD severity. Indole or indole derivatives produced by tryptophan metabolism in the intestinal microbiota limit intestinal inflammation caused by diverse stressors, so we tested their capacity to protect against GVHD in murine major histocompatibility complex-mismatched models of allo-BMT. Indole effects were assessed by colonization of allo-BMT recipient mice with tryptophanase positive or negative strains of Escherichia coli, or, alternatively, by exogenous administration of indole-3-carboxaldehyde (ICA), an indole derivative. Treatment with ICA limited gut epithelial damage, reduced transepithelial bacterial translocation, and decreased inflammatory cytokine production, reducing GVHD pathology and GVHD mortality, but did not compromise donor T-cell-mediated graft-versus-leukemia responses. ICA treatment also led to recipient-strain-specific tolerance of engrafted T cells. Transcriptional profiling and gene ontology analysis indicated that ICA administration upregulated genes associated with the type I interferon (IFN1) response, which has been shown to protect against radiation-induced intestinal damage and reduce subsequent GVHD pathology. Accordingly, protective effects of ICA following radiation exposure were abrogated in mice lacking IFN1 signaling. Taken together, these data indicate that indole metabolites produced by the intestinal microbiota act via type I IFNs to limit intestinal inflammation and damage associated with myeloablative chemotherapy or radiation exposure and acute GVHD, but preserve antitumor responses, and may provide a therapeutic option for BMT patients at risk for GVHD.
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Affiliation(s)
- Alyson Swimm
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA
| | - Cynthia R Giver
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA
| | - Zachariah DeFilipp
- Blood and Marrow Transplant Program, Massachusetts General Hospital, Boston, MA
| | - Sravanti Rangaraju
- Department of Hematology and Oncology, Indiana University, Indianapolis, IN
| | - Akshay Sharma
- Pediatric Hematology and Oncology, St. Jude Children's Research Hospital, Memphis, TN
| | - Alina Ulezko Antonova
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA
| | - Robert Sonowal
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA
| | - Christopher Capaldo
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA
| | - Domonica Powell
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA
- Immunology and Molecular Pathogenesis Graduate Program, Emory University School of Medicine, Atlanta, GA; and
| | - Muna Qayed
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Department of Pediatrics, Emory University, Atlanta, GA
| | - Daniel Kalman
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA
| | - Edmund K Waller
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA
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Huc T, Konop M, Onyszkiewicz M, Podsadni P, Szczepańska A, Turło J, Ufnal M. Colonic indole, gut bacteria metabolite of tryptophan, increases portal blood pressure in rats. Am J Physiol Regul Integr Comp Physiol 2018; 315:R646-R655. [PMID: 29847162 DOI: 10.1152/ajpregu.00111.2018] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Portal hypertension (PH) is a potentially life-threatening condition. We investigated the effects of indole and dietary tryptophan, a substrate for gut bacterial production of indole, on portal blood pressure (PBP), portal blood flow (PBF), and arterial blood pressure (ABP) in Sprague-Dawley rats (SD) and SD with PH induced by liver cirrhosis (SD-PH). Hemodynamics were recorded in anesthetized male 28-wk-old SD and SD-PH at baseline and after the administration of either a vehicle or indole into the colon. Blood levels of tryptophan and its bacterial metabolites were evaluated using chromatography coupled with mass spectrometry. Indole at lower doses increased PBP and PBF. Indole at higher doses produced a transient increase in PBP, which was accompanied by a decrease in ABP. Portal blood levels of indole, indole-3-propionic, indole-3-lactic, and indole-3-acetic acids were higher in SD-PH, suggesting an increased gut-blood barrier permeability. Rats on a tryptophan-rich diet showed a significantly higher PBP and portal blood level of indoles than rats on a tryptophan-free diet. In conclusion, a tryptophan-rich diet and intracolonic indole increase PBP and portal blood level of indole. Rats with PH show an increased penetration of indoles from the colon to the circulation. Intracolonic indole production may be of therapeutic importance in PH.
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Affiliation(s)
- Tomasz Huc
- Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw , Warsaw , Poland
| | - Marek Konop
- Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw , Warsaw , Poland
| | - Maksymilian Onyszkiewicz
- Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw , Warsaw , Poland
| | - Piotr Podsadni
- Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw , Warsaw , Poland
| | - Agnieszka Szczepańska
- Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw , Warsaw , Poland
| | - Jadwiga Turło
- Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw , Warsaw , Poland
| | - Marcin Ufnal
- Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw , Warsaw , Poland
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Cyanide Production by Chromobacterium piscinae Shields It from Bdellovibrio bacteriovorus HD100 Predation. mBio 2017; 8:mBio.01370-17. [PMID: 29259082 PMCID: PMC5736907 DOI: 10.1128/mbio.01370-17] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Predation of Chromobacterium piscinae by Bdellovibrio bacteriovorus HD100 was inhibited in dilute nutrient broth (DNB) but not in HEPES. Experiments showed that the effector responsible was present in the medium, as cell-free supernatants retained the ability to inhibit predation, and that the effector was not toxic to B. bacteriovorus. Violacein, a bisindole secondary metabolite produced by C. piscinae, was not responsible. Further characterization of C. piscinae found that this species produces sufficient concentrations of cyanide (202 µM) when grown in DNB to inhibit the predatory activity of B. bacteriovorus, but that in HEPES, the cyanide concentrations were negligible (19 µM). The antagonistic role of cyanide was further confirmed, as the addition of hydroxocobalamin, which chelates cyanide, allowed predation to proceed. The activity of cyanide against B. bacteriovorus was found to be twofold, depending on the life cycle stage of this predator. For the attack-phase predatory cells, cyanide caused the cells to lose motility and tumble, while for intraperiplasmic predators, development and lysis of the prey cell were halted. These findings suggest that cyanogenesis in nature may be employed by the bacterial strains that produce this compound to prevent and reduce their predation by B. bacteriovorus. Bacterial predators actively attack, kill, and enter the periplasm of susceptible Gram-negative bacteria, where they consume the prey cell components. To date, the activity of B. bacteriovorus HD100 has been demonstrated against more than 100 human pathogens. As such, this strain and others are being considered as potential alternatives or supplements to conventional antibiotics. However, the production of secondary metabolites by prey bacteria is known to mitigate, and even abolish, predation by bacterivorous nematodes and protists. With the exception of indole, which was shown to inhibit predation, the effects of bacterial secondary metabolites on B. bacteriovorus and its activities have not been considered. Consequently, we undertook this study to better understand the mechanisms that bacterial strains employ to inhibit predation by B. bacteriovorus HD100. We report here that cyanogenic bacterial strains can inhibit predation and show that cyanide affects both attack-phase predators and those within prey, i.e., in the bdelloplast.
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Qu Y, Ma Q, Liu Z, Wang W, Tang H, Zhou J, Xu P. Unveiling the biotransformation mechanism of indole in a Cupriavidus sp. strain. Mol Microbiol 2017; 106:905-918. [PMID: 28963777 DOI: 10.1111/mmi.13852] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/27/2017] [Indexed: 01/13/2023]
Abstract
Indole, an important signaling molecule as well as a typical N-heterocyclic aromatic pollutant, is widespread in nature. However, the biotransformation mechanisms of indole are still poorly studied. Here, we sought to unlock the genetic determinants of indole biotransformation in strain Cupriavidus sp. SHE based on genomics, proteomics and functional studies. A total of 177 proteins were notably altered (118 up- and 59 downregulated) in cells grown in indole mineral salt medium when compared with that in sodium citrate medium. RT-qPCR and gene knockout assays demonstrated that an indole oxygenase gene cluster was responsible for the indole upstream metabolism. A functional indole oxygenase, termed IndA, was identified in the cluster, and its catalytic efficiency was higher than those of previously reported indole oxidation enzymes. Furthermore, the indole downstream metabolism was found to proceed via the atypical CoA-thioester pathway rather than conventional gentisate and salicylate pathways. This unusual pathway was catalyzed by a conserved 2-aminobenzoyl-CoA gene cluster, among which the 2-aminobenzoyl-CoA ligase initiated anthranilate transformation. This study unveils the genetic determinants of indole biotransformation and will provide new insights into our understanding of indole biodegradation in natural environments and its functional studies.
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Affiliation(s)
- Yuanyuan Qu
- State Key Laboratory of Fine Chemicals, Key Laboratory of Industrial Ecology and Environmental Engineering (Ministry of Education), School of Environmental Science and Technology, Dalian University of Technology, Dalian 116024, People's Republic of China
| | - Qiao Ma
- State Key Laboratory of Fine Chemicals, Key Laboratory of Industrial Ecology and Environmental Engineering (Ministry of Education), School of Environmental Science and Technology, Dalian University of Technology, Dalian 116024, People's Republic of China
| | - Ziyan Liu
- State Key Laboratory of Fine Chemicals, Key Laboratory of Industrial Ecology and Environmental Engineering (Ministry of Education), School of Environmental Science and Technology, Dalian University of Technology, Dalian 116024, People's Republic of China
| | - Weiwei Wang
- State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, People's Republic of China
| | - Hongzhi Tang
- State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, People's Republic of China
| | - Jiti Zhou
- State Key Laboratory of Fine Chemicals, Key Laboratory of Industrial Ecology and Environmental Engineering (Ministry of Education), School of Environmental Science and Technology, Dalian University of Technology, Dalian 116024, People's Republic of China
| | - Ping Xu
- State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, People's Republic of China
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Zhang S, Zhang W, Liu N, Song T, Liu H, Zhao X, Xu W, Li C. Indole reduces the expression of virulence related genes in Vibrio splendidus pathogenic to sea cucumber Apostichopus japonicus. Microb Pathog 2017; 111:168-173. [PMID: 28867630 DOI: 10.1016/j.micpath.2017.08.032] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 08/06/2017] [Accepted: 08/30/2017] [Indexed: 12/24/2022]
Abstract
Indole is a metabolite of tryptophan that can be synthesized by various bacteria. In the present study, production of indole by Vibrio splendidus Vs was determined using Kovac's reagent, and m/z was further determined by HPLC-MS. Extracellular indole reached a maximum concentration of 160 μM, when OD600 of V. splendidus Vs was approximately 0.9. In addition, glucose could reduce indole level, and 1% (m/v) glucose could reduce the mRNA level of tnaA, the gene encoding tryptophanase, down to 0.2%. To investigate the effects of indole on the mRNA levels of virulence related genes of V. splendidus Vs, mRNA levels of vsm, vsh and ABC respectively related to protease activity, haemolytic activity and ABC transporter ATP-binding protein were determined. Exogenous indole supplemented at a concentration of 125 μΜ could respectively down regulate the mRNA level of vsm, vsh and ABC to 16%, 13% and 11%. Meanwhile, indole could alter the expressions of immune related gene in Apostichopus japonicus. When coelomocytes were co-cultured with exogenous indole at a concentration of 125 μΜ, the mRNA level of Ajp105 and AjLBP/BPI1, were up regulated by 1.6-fold and 2.1-fold, respectively. Combined all the results in our study suggested that indole could alter the expressions of the virulence related genes in pathogenic V. splendidus Vs as well as the immune related genes in A. japonicus.
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Affiliation(s)
- Shanshan Zhang
- School of Marine Sciences, Ningbo University, Ningbo 315211, PR China
| | - Weiwei Zhang
- School of Marine Sciences, Ningbo University, Ningbo 315211, PR China
| | - Ningning Liu
- School of Marine Sciences, Ningbo University, Ningbo 315211, PR China
| | - Tongxiang Song
- School of Marine Sciences, Ningbo University, Ningbo 315211, PR China
| | - Huijie Liu
- School of Marine Sciences, Ningbo University, Ningbo 315211, PR China
| | - Xuelin Zhao
- School of Marine Sciences, Ningbo University, Ningbo 315211, PR China
| | - Wei Xu
- Louisiana State University, Agricultural Center, USA
| | - Chenghua Li
- School of Marine Sciences, Ningbo University, Ningbo 315211, PR China; Louisiana State University, Agricultural Center, USA.
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Indole-Induced Reversion of Intrinsic Multiantibiotic Resistance in Lysobacter enzymogenes. Appl Environ Microbiol 2017. [PMID: 28625984 DOI: 10.1128/aem.00995-17] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Lysobacter species are a group of environmental bacteria that are emerging as a new source of antibiotics. One characteristic of Lysobacter is intrinsic resistance to multiple antibiotics, which had not been studied. To understand the resistance mechanism, we tested the effect of blocking two-component regulatory systems (TCSs) on the antibiotic resistance of Lysobacter enzymogenes, a prolific producer of antibiotics. Upon treatment with LED209, an inhibitor of the widespread TCS QseC/QseB, L. enzymogenes produced a large amount of an unknown metabolite that was barely detectable in the untreated culture. Subsequent structural elucidation by nuclear magnetic resonance (NMR) unexpectedly revealed that the metabolite was indole. Indole production was also markedly induced by adrenaline, a known modulator of QseC/QseB. Next, we identified two TCS genes, L. enzymogenesqseC (Le-qseC) and Le-qseB, in L. enzymogenes and found that mutations of Le-qseC and Le-qseB also led to a dramatic increase in indole production. We then chemically synthesized a fluorescent indole probe that could label the cells. While the Le-qseB (cytoplasmic response regulator) mutant was clearly labeled by the probe, the Le-qseC (membrane sensor) mutant was not labeled. It was reported previously that indole can enhance antibiotic resistance in bacteria. Therefore, we tested if the dramatic increase in the level of indole production in L. enzymogenes upon blocking of Le-qseC and Le-qseB would lead to enhanced antibiotic resistance. Surprisingly, we found that indole caused the intrinsically multiantibiotic-resistant bacterium L. enzymogenes to become susceptible. Point mutations at conserved amino acids in Le-QseC also led to antibiotic susceptibility. Because indole is known as an interspecies signal, these findings may have implications.IMPORTANCE The environmental bacterium Lysobacter is a new source of antibiotic compounds and exhibits intrinsic antibiotic resistance. Here, we found that the inactivation of a two-component regulatory system (TCS) by an inhibitor or by gene deletion led to a remarkable increase in the level of production of a metabolite in L. enzymogenes, and this metabolite was identified to be indole. We chemically synthesized a fluorescent indole probe and found that it could label the wild type and a mutant of the TCS cytoplasmic response regulator but not a mutant of the TCS membrane sensor. Indole treatment caused the intrinsically multidrug-resistant bacterium L. enzymogenes to be susceptible to antibiotics. Mutations of the TCS sensor also led to antibiotic susceptibility. Because indole is known as an interspecies signal between gut microbiota and mammalian hosts, the observation that indole could render intrinsically resistant L. enzymogenes susceptible to common antibiotics may have implications.
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Steinmeyer S, Howsmon DP, Alaniz RC, Hahn J, Jayaraman A. Empirical modeling of T cell activation predicts interplay of host cytokines and bacterial indole. Biotechnol Bioeng 2017; 114:2660-2667. [PMID: 28667749 DOI: 10.1002/bit.26371] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 06/21/2017] [Accepted: 06/30/2017] [Indexed: 12/24/2022]
Abstract
Adoptive transfer of anti-inflammatory FOXP3+ Tregs has gained attention as a new therapeutic strategy for auto-inflammatory disorders such as Inflammatory Bowel Disease. The isolated cells are conditioned in vitro to obtain a sufficient number of anti-inflammatory FOXP3+ Tregs that can be reintroduced into the patient to potentially reduce the pathologic inflammatory response. Previous evidence suggests that microbiota metabolites can potentially condition cells during the in vitro expansion/differentiation step. However, the number of combinations of cytokines and metabolites that can be varied is large, preventing a purely experimental investigation which would determine optimal cell therapeutic outcomes. To address this problem, a combined experimental and modeling approached is investigated here: an artificial neural network model was trained to predict the steady-state T cell population phenotype after differentiation with a variety of host cytokines and the microbial metabolite indole. This artificial neural network model was able to both reliably predict the phenotype of these T cell populations and also uncover unexpected conditions for optimal Treg differentiation that were subsequently verified experimentally. Biotechnol. Bioeng. 2017;114: 2660-2667. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Shelby Steinmeyer
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, College Station, Texas
| | - Daniel P Howsmon
- Department of Chemical & Biological Engineering, Rensselaer Polytechnic Institute, 110 Eighth St., CBIS # 4213, Troy, New York, 12180.,Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York
| | - Robert C Alaniz
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, College Station, Texas
| | - Juergen Hahn
- Department of Chemical & Biological Engineering, Rensselaer Polytechnic Institute, 110 Eighth St., CBIS # 4213, Troy, New York, 12180.,Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York.,Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, New York
| | - Arul Jayaraman
- Department of Chemical Engineering, Texas A&M University, 3122 TAMU Room 200, College Station, Texas, 77843
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Lee JH, Kim YG, Kim M, Kim E, Choi H, Kim Y, Lee J. Indole-associated predator-prey interactions between the nematode Caenorhabditis elegans and bacteria. Environ Microbiol 2017; 19:1776-1790. [PMID: 28028877 DOI: 10.1111/1462-2920.13649] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 12/14/2016] [Accepted: 12/17/2016] [Indexed: 12/29/2022]
Abstract
Indole is an intercellular and interkingdom signalling molecule found in diverse ecological niches. Caenorhabditis elegans is a bacterivorous nematode that lives in soil and compost environments and a useful model host for studies of host-microbe interactions. Although various bacteria and some plants produce large quantities of extracellular indole, little is known about the effects of indole, its derivatives, or of indole-producing bacteria on the behaviours of C. elegans or other animals. Here, they show that C. elegans senses and moves toward indole and several indole-producing bacteria, but avoids non-indole producing pathogenic bacteria. Furthermore, it was found indole-producing and non-indole-producing bacteria exert divergent effects on the egg-laying behaviour of C. elegans, and that various indole derivatives also modulate chemotaxis, egg-laying behaviour and the survival of C. elegans. In contrast, indole at high concentration can kill C. elegans, which in turn, has the ability to detoxify indole by oxidation and glucosylation. Transcriptional analysis showed indole markedly up-regulated the gene expressions of cytochrome P450s, UDP-glucuronosyltransferases and glutathione S-transferase, which well explained the modification of indole by C. elegans while indole down-regulated the expressions of collagen and F-box genes. Their findings suggest that indole and its derivatives are important signalling molecules during bacteria-nematode interactions.
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Affiliation(s)
- Jin-Hyung Lee
- School of Chemical Engineering, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Yong-Guy Kim
- School of Chemical Engineering, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Minsu Kim
- School of Chemical Engineering, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Eonmi Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Hyukjae Choi
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Younghoon Kim
- Department of Animal Science, Chonbuk National University, Jeonju, 54896, Republic of Korea
| | - Jintae Lee
- School of Chemical Engineering, Yeungnam University, Gyeongsan, 38541, Republic of Korea
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Fernstrom JD. A Perspective on the Safety of Supplemental Tryptophan Based on Its Metabolic Fates. J Nutr 2016; 146:2601S-2608S. [PMID: 27934651 DOI: 10.3945/jn.115.228643] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Revised: 01/12/2016] [Accepted: 03/04/2016] [Indexed: 11/14/2022] Open
Abstract
Over the past 50 y, tryptophan has been ingested in amounts well in excess of its dietary requirement. This use is based on extensive findings that ingesting tryptophan increases brain tryptophan concentrations, which stimulates the synthesis and release of the neurotransmitter serotonin, from which it is derived. Such increases in serotonin function may improve mood and sleep. However, tryptophan ingestion has other effects, such as increasing serotonin production in the gut, increasing serotonin concentrations in blood, stimulating the production of the hormone melatonin (a tryptophan metabolite), stimulating tryptophan metabolism via the kynurenine pathway, and possibly stimulating the production of tryptophan metabolites in the gut microbiome. Several of the kynurenine metabolites have actions on excitatory glutamate receptors in the gut and brain and on cells of the immune system. In addition, metabolites of tryptophan produced by colonic bacteria are reported to cause adverse effects in some species. This review examines each of these tryptophan pathways to determine if any of the metabolites increase after tryptophan ingestion, and if so, whether effects are seen on target body functions. In this regard, recent research suggests that it may be useful to examine kynurenine pathway metabolites and some microbial tryptophan metabolites to determine whether supplemental tryptophan consumption increases their concentrations in the body and amplifies their actions.
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Affiliation(s)
- John D Fernstrom
- Departments of Psychiatry, and Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA
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47
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Ellis JE, Star A. Carbon Nanotube Based Gas Sensors toward Breath Analysis. Chempluschem 2016; 81:1248-1265. [DOI: 10.1002/cplu.201600478] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Indexed: 12/25/2022]
Affiliation(s)
- James E. Ellis
- Department of Chemistry; University of Pittsburgh; Pittsburgh PA 15260 USA
| | - Alexander Star
- Department of Chemistry; University of Pittsburgh; Pittsburgh PA 15260 USA
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48
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Lai Y, Xu Z, Yan A. A novel regulatory circuit to control indole biosynthesis protectsEscherichia colifrom nitrosative damages during the anaerobic respiration of nitrate. Environ Microbiol 2016; 19:598-610. [DOI: 10.1111/1462-2920.13527] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 09/08/2016] [Indexed: 01/09/2023]
Affiliation(s)
- Yong Lai
- School of Biological Sciences; The University of Hong Kong; Hong Kong SAR
| | - Zeling Xu
- School of Biological Sciences; The University of Hong Kong; Hong Kong SAR
| | - Aixin Yan
- School of Biological Sciences; The University of Hong Kong; Hong Kong SAR
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Fecal Indole as a Biomarker of Susceptibility to Cryptosporidium Infection. Infect Immun 2016; 84:2299-306. [PMID: 27245413 DOI: 10.1128/iai.00336-16] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Accepted: 05/22/2016] [Indexed: 01/16/2023] Open
Abstract
Cryptosporidium causes significant diarrhea worldwide, especially among children and immunocompromised individuals, and no effective drug treatment is currently available for those who need it most. In this report, previous volunteer infectivity studies have been extended to examine the association between fecal indole and indole-producing (IP) gut microbiota on the outcome of a Cryptosporidium infection. Fecal indole concentrations (FICs) of 50 subjects and 19 taxa of common gut microbiota, including six IP taxa (11 subjects) were determined in stool samples collected before and after a challenge with Cryptosporidium oocysts. At the baseline, the mean FIC (± the standard deviation) was 1.66 ± 0.80 mM in those who became infected after a challenge versus 3.20 ± 1.23 mM in those who remained uninfected (P = 0.0001). Only 11.1% of the subjects with a FIC of >2.5 mM became infected after a challenge versus 65.2% of the subjects with a FIC of <2.5 mM. In contrast, the FICs of infected subjects at the baseline or during diarrhea were not correlated with infection intensity or disease severity. The relative abundances (percent) of Escherichia coli, Bacillus spp., and Clostridium spp. were greater ≥2.5-fold in volunteers with a baseline FIC of >2.5 mM, while those of Bacteroides pyogenes, B. fragilis, and Akkermansia muciniphila were greater in those with a baseline FIC of <2.5 mM. These data indicate that some IP bacteria, or perhaps indole alone, can influence the ability of Cryptosporidium to establish an infection. Thus, preexisting indole levels in the gut join the oocyst dose and immune status as important factors that determine the outcome of Cryptosporidium exposure.
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50
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McKenney ES, Kendall MM. Microbiota and pathogen 'pas de deux': setting up and breaking down barriers to intestinal infection. Pathog Dis 2016; 74:ftw051. [PMID: 27252177 PMCID: PMC5985477 DOI: 10.1093/femspd/ftw051] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 02/04/2016] [Accepted: 05/24/2016] [Indexed: 02/07/2023] Open
Abstract
The gut microbiota plays essential roles in human health and disease. In this review, we focus on the role of the intestinal microbiota in promoting resistance to infection by bacterial pathogens as well as how pathogens overcome this barrier. We discuss how the resident microbiota restricts growth and colonization of invading pathogens by limiting availability of nutrients and through generation of a hostile environment. Additionally, we examine how microbiota-derived signaling molecules interfere with bacterial virulence. In turn, we discuss how pathogens exploit non-competitive metabolites to replicate in vivo as well as to precisely control virulence and cause disease. This bacterial two step of creating and overcoming challenges important in preventing and establishing infection highlights the complexities of elucidating interactions between the commensal bacteria and pathogens. Better understanding of microbiota-pathogen interplay will have significant implications for developing novel therapeutics to treat infectious diseases.
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Affiliation(s)
- Elizabeth S McKenney
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Melissa M Kendall
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
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