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Shrestha A, Gonzales JL, Beingesser J, Uzal FA, McClane BA. Processing of Clostridium perfringens Enterotoxin by Intestinal Proteases. Toxins (Basel) 2025; 17:170. [PMID: 40278668 DOI: 10.3390/toxins17040170] [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: 02/10/2025] [Revised: 03/20/2025] [Accepted: 03/26/2025] [Indexed: 04/26/2025] Open
Abstract
C. perfringens type F isolates are a leading cause of food poisoning and antibiotic-associated diarrhea. Type F isolate virulence requires production of C. perfringens enterotoxin [CPE], which acts by forming large pore complexes in host cell plasma membranes. During GI disease, CPE is produced in the intestines when type F strains undergo sporulation. The toxin is then released into the intestinal lumen when the mother cell lyses at the completion of sporulation. Once present in the lumen, CPE encounters proteases. This study examined the in vitro, ex vivo, and in vivo processing of CPE by intestinal proteases and the effects of this processing on CPE activity. Results using purified trypsin or mouse intestinal contents detected the rapid cleavage of CPE to a major band of ~32 kDa and studies with Caco-2 cells showed that this processed CPE still forms large complexes and retains cytotoxic activity. When mouse small intestinal loops were challenged with CPE, the toxin caused intestinal histologic damage, despite rapid proteolytic processing of most CPE to 32 kDa within 15 min. Intestinal large CPE complexes became more stable with longer treatment times. These results indicate that CPE processing involving trypsin occurs in the intestines and the processed toxin retains enterotoxicity.
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Affiliation(s)
- Archana Shrestha
- Department of Microbiology and Molecular Genetics, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15219, USA
| | - Jessica L Gonzales
- California Animal Health and Food Safety Laboratory, School of Veterinary Medicine, University of California Davis, San Bernardino, CA 92408, USA
| | - Juliann Beingesser
- California Animal Health and Food Safety Laboratory, School of Veterinary Medicine, University of California Davis, San Bernardino, CA 92408, USA
| | - Francisco A Uzal
- California Animal Health and Food Safety Laboratory, School of Veterinary Medicine, University of California Davis, San Bernardino, CA 92408, USA
| | - Bruce A McClane
- Department of Microbiology and Molecular Genetics, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15219, USA
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Kaur N, Kumar P, Dhami M, Aran KR. Antibiotic-induced gut dysbiosis: unraveling the gut-heart axis and its impact on cardiovascular health. Mol Biol Rep 2025; 52:319. [PMID: 40095156 DOI: 10.1007/s11033-025-10425-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 03/10/2025] [Indexed: 03/19/2025]
Abstract
Cardiovascular diseases (CVDs) remain the major cause of morbidity and mortality amongst people of all ages across the world. Research suggests that the initiation and progression of CVDs are associated with antibiotic-induced gut dysbiosis. Antibiotics are primarily intended to be used to treat bacterial infections, which can alter gut microbiota (GM) composition, by lowering the abundance of beneficial bacteria, like Firmicutes, Bacteroidetes, and increasing the profusion of Enterobacteriaceae, leading to harm on gut health. Additionally, it reduces short-chain fatty acids (SCFAs) and bile acid metabolism, increases trimethylamine N-oxide (TMAO) production, intestinal permeability allowing lipopolysaccharide (LPS) and TMAO into systemic circulation. SCFAs play a key role in lipid metabolism, inflammation, and strengthening of the intestinal barrier, and participate in CVDs through FFAR2 and FFAR3 receptors, whereas dysbiosis reduces SCFAs levels and worsens these effects. TMAO enhances oxidative stress, inflammation, endothelial dysfunction, and cholesterol dysregulation, thus worsening CVDs. Furthermore, LPS develops systemic inflammation, insulin resistance, and endothelial dysfunction by activating the NF-κB pathway. Dysbiosis also affects bile acid synthesis, disrupting lipid and glucose metabolism, further participating in the progression of CVDs. This article aims to explore the role of gut dysbiosis in various CVDs, including congenital heart disease, hypertension, valvular heart disease, coronary heart disease, and heart failure. Furthermore, this article aims to bridge the knowledge gap regarding the gut-heart axis by exploring how antibiotics alter the gut microbiota homeostasis, further contributing to the development of CVDs and therapeutic interventions that reduce cardiovascular risks and restore the gut microbiota homeostasis.
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Affiliation(s)
- Navpreet Kaur
- Department of Pharmacy Practice, ISF College of Pharmacy, Moga, Punjab, India
| | - Pankaj Kumar
- Department of Pharmacology, Himachal Institute of Pharmaceutical Education and Research (HIPER), Tehsil-Nadaun, Hamirpur, Himachal Pradesh, 177033, India
| | - Mahadev Dhami
- Bhimdatta Polytechnic Institute, Patan, Baitadi, 10200, Nepal
| | - Khadga Raj Aran
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India.
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Sun L, Zhu F, Chen Y, Shi Y, Wang H, Yu Y, Lu Z, Chen Y. Genomic characterization of healthcare-associated ST5 MRSA causing severe pseudomembranous enteritis in intensive care unit. BMC Infect Dis 2025; 25:208. [PMID: 39939973 PMCID: PMC11823201 DOI: 10.1186/s12879-025-10573-7] [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: 11/19/2024] [Accepted: 01/29/2025] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND Methicillin resistant Staphylococcus aureus (MRSA) is one of the main causes of hospital-acquired infections, but the diagnosis of MRSA pseudomembranous enteritis has faded in recent years. Here, we reported a pseudomembranous enteritis case in a young male patient caused by ST5 MRSA. METHODS Clinical data of the patient were collected from medical records. Mass spectrometry identification, antimicrobial susceptibility testing, whole genome sequencing, as well as resistance and virulence genes detection of MRSA strain were performed. RESULTS A 27-year-old young man with acute pancreatitis and septic shock in the intensive care unit passed large volume of intestine-like "stool" with more than 200 centimetres in length. A large number of Gram-positive cocci was persistently found in the stool samples. Histopathological examination of the intestine-like stool revealed that this stool was actually pseudomembrane, consisting of fibrinous exudate, inflammatory cells and clusters of gram-positive cocci adjacent to the luminal border. The patient was suspected for diagnosis of pseudomembranous enteritis. Stool and gastric juice cultures were positive for MRSA. These strains belonged to ST5-SCCmec II-t311, and harbored abundant virulence genes, especially enterotoxin genes. They contained not only sea, sec3, sel, but an enterotoxin gene cluster (egc, seg, sei, sem, sen, seo, yent1 and yent2), which may serve as an enterotoxin gene nursery. Besides, the strains were related to the isolates of the same hospital between 2013 and 2015, and there may be nosocomial transmission. CONCLUSIONS The severe clinical symptoms in this patient and the described virulence genes all suggested that these ST5 strains belonged to a kind of hypervirulent MRSA lineage. At the same time, the analysis of cgMLST indicated that there might be nosocomial transmission, which required the society to pay more attention to this highly virulent nosocomial clone.
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Affiliation(s)
- Lu Sun
- Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Feiteng Zhu
- Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Yiyi Chen
- Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Yue Shi
- Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, Zhejiang, China
- Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Haiping Wang
- Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Yunsong Yu
- Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Zhihua Lu
- Department of Intensive Care Unit, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
| | - Yan Chen
- Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, Zhejiang, China.
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Shrestha A, Gonzales JL, Beingesser J, Uzal FA, McClane BA. Processing of Clostridium perfringens Enterotoxin by Intestinal Proteases. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.11.637699. [PMID: 39990433 PMCID: PMC11844521 DOI: 10.1101/2025.02.11.637699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/25/2025]
Abstract
C. perfringens type F isolates are a leading cause of food poisoning and antibiotic-associated diarrhea. Type F isolate virulence requires production of C. perfringens enterotoxin [CPE], which acts by forming large pore complexes in host cell plasma membranes. During disease, CPE is produced in the intestines when type F strains undergo sporulation. The toxin is then released into the intestinal lumen when the mother cell lyses at the completion of sporulation. Once present in the lumen, CPE encounters intestinal proteases. This study examined in vitro, ex vivo and in vivo processing of CPE by intestinal proteases and the effects of this processing on CPE activity. Results using purified trypsin or mouse intestinal contents detected rapid cleavage of CPE to a major band of ~32 kDa and studies with Caco-2 cells showed this processed CPE still forms large complexes and retains cytotoxic activity. When mouse small intestinal loops were challenged with CPE, the toxin caused intestinal histologic damage despite rapid proteolytic processing of most CPE to 32 kDa within 15 min. Intestinal large CPE complexes became more stable with longer treatment times. These results indicate that CPE processing involving trypsin occurs in the intestines and the processed toxin retains enterotoxicity.
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Affiliation(s)
- Archana Shrestha
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA USA 15219
| | - Jessica L. Gonzales
- California Animal Health and Food Safety Laboratory, School of Veterinary Medicine, University of California Davis, San Bernardino CA 92408
| | - Juliann Beingesser
- California Animal Health and Food Safety Laboratory, School of Veterinary Medicine, University of California Davis, San Bernardino CA 92408
| | - Francisco A. Uzal
- California Animal Health and Food Safety Laboratory, School of Veterinary Medicine, University of California Davis, San Bernardino CA 92408
| | - Bruce A. McClane
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA USA 15219
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Xu X, Zhang H, Meng K, Cai H, Liu W, Song L, Zhang Z, Zhu Q, Han X, Han Y, Yang P. Limosilactobacillus reuteri ZY15 Alleviates Intestinal Inflammation and Barrier Dysfunction via AKT/mTOR/HIF-1α/RORγt/IL-17 Signaling and the Gut Microbiota in ETEC K88-Challenged Mice. Antioxidants (Basel) 2025; 14:58. [PMID: 39857392 PMCID: PMC11763039 DOI: 10.3390/antiox14010058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 12/27/2024] [Accepted: 01/03/2025] [Indexed: 01/27/2025] Open
Abstract
Limosilactobacillus reuteri, a recognized probiotic, improves intestinal health in animals, but the mechanism remains unclear. This study investigates the mechanisms by which L. reuteri ZY15, isolated from healthy pig feces, mitigates intestinal barrier damage and inflammation caused by oxidative stress in Enterotoxigenic Escherichia coli (ETEC) K88-challenged mice. The results indicated that L. reuteri ZY15 increased antioxidant capacity by reducing serum reactive oxygen species (ROS) and superoxide dismutase (SOD) levels. L. reuteri ZY15 enhanced the intestinal barrier by upregulating mucin 1, mucin 2, occludin, zonula occludens-1 (ZO-1), and claudin-1 expressions in protein and mRNA levels. It significantly alleviated intestinal inflammation by reducing the proinflammatory cytokines interleukin-1β (IL-1β), interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin-17 (IL-17) mRNA and protein levels. Notably, L. reuteri ZY15 suppressed intestinal inflammation by inhibiting AKT/mTOR/HIF-1α/RORγt/IL-17 pathway activation. Additionally, it significantly altered the structure of gut microorganisms by enriching Akkermansia and Clostridia_UCG.014, and thereby re-establishing colonization resistance and alleviating ETEC K88-induced intestinal barrier damage and inflammation in mice. Taken together, our findings reveal the protective mechanism of L. reuteri ZY15 in mice challenged with ETEC K88 by regulating AKT/mTOR/HIF-1α/RORγt/IL-17 signaling and microbial imbalance. Leveraging these properties, live L. reuteri ZY15 offers a promising alternative treatment for Escherichia coli-induced diarrhea in weaned piglets.
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Affiliation(s)
- Xin Xu
- Key Laboratory of Feed Biotechnology of Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (X.X.); (K.M.); (H.C.); (W.L.); (L.S.); (Z.Z.); (Q.Z.); (X.H.)
| | - Hongwei Zhang
- Chengde Academy of Agriculture and Forestry Sciences, Chengde 067000, China;
| | - Kun Meng
- Key Laboratory of Feed Biotechnology of Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (X.X.); (K.M.); (H.C.); (W.L.); (L.S.); (Z.Z.); (Q.Z.); (X.H.)
| | - Hongying Cai
- Key Laboratory of Feed Biotechnology of Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (X.X.); (K.M.); (H.C.); (W.L.); (L.S.); (Z.Z.); (Q.Z.); (X.H.)
| | - Weiwei Liu
- Key Laboratory of Feed Biotechnology of Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (X.X.); (K.M.); (H.C.); (W.L.); (L.S.); (Z.Z.); (Q.Z.); (X.H.)
| | - Liye Song
- Key Laboratory of Feed Biotechnology of Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (X.X.); (K.M.); (H.C.); (W.L.); (L.S.); (Z.Z.); (Q.Z.); (X.H.)
| | - Zihan Zhang
- Key Laboratory of Feed Biotechnology of Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (X.X.); (K.M.); (H.C.); (W.L.); (L.S.); (Z.Z.); (Q.Z.); (X.H.)
| | - Qijun Zhu
- Key Laboratory of Feed Biotechnology of Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (X.X.); (K.M.); (H.C.); (W.L.); (L.S.); (Z.Z.); (Q.Z.); (X.H.)
| | - Xiling Han
- Key Laboratory of Feed Biotechnology of Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (X.X.); (K.M.); (H.C.); (W.L.); (L.S.); (Z.Z.); (Q.Z.); (X.H.)
| | - Yunsheng Han
- Key Laboratory of Feed Biotechnology of Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (X.X.); (K.M.); (H.C.); (W.L.); (L.S.); (Z.Z.); (Q.Z.); (X.H.)
| | - Peilong Yang
- Key Laboratory of Feed Biotechnology of Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China; (X.X.); (K.M.); (H.C.); (W.L.); (L.S.); (Z.Z.); (Q.Z.); (X.H.)
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Hsia CH, Su HY, Chen YH, Chuang HC, Chien YW. Effects of probiotics in elderly hospitalized tube-fed patients with antibiotics use. BMC Gastroenterol 2024; 24:467. [PMID: 39702125 DOI: 10.1186/s12876-024-03561-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 12/12/2024] [Indexed: 12/21/2024] Open
Abstract
BACKGROUND Several studies revealed the beneficial effects of probiotics against the incidence of antibiotic-associated diarrhea of hospitalized patients but it is rarely to assess the nutrition status. This study investigated the effects of probiotics in elderly hospitalized tube-fed patients with antibiotics use and is the first study that concerns the nutritional status among these patients. METHODS Elderly hospitalized tube-fed patients who were using antibiotics were recruited. Probiotics were given within 48 h after their first antibiotic therapy, and then twice daily 2 h after consuming antibiotics and a meal; the probiotics were continued to use for an additional 7 days after completion of antibiotics therapy. Anthropometric data, laboratory data, medication records, nutritional status, nutrition intake and data on stool form were collected. RESULTS Twenty-nine patients served as probiotic group. 11 patients completed the study in both groups. In probiotic group, the stool form was found to exhibit no significant differences between the beginning and end of antibiotics therapy (5.5 ± 0.8 vs 5.1 ± 1.1, p = 0.21), but the stool frequency significantly decreased (2.0 ± 1.0 vs 1.6 ± 0.7, p = 0.05). In control group, the stool form between the beginning and end of antibiotics therapy exhibited significant improvement (5.6 ± 1.4 vs 4.5 ± 1.4, p = 0.01), but not in the frequency (2.7 ± 2.1 vs 2.4 ± 1.5, p = 0.1). The initial NRS 2002 score of the probiotic and control groups were similar. (3.6 ± 1.7 vs 3.7 ± 1.8, p = 1.00), and their nutrition status both significantly improved during the last visit before discharged (2.6 ± 0.9 vs 2.9 ± 1.3). CONCLUSION Probiotic supplementation in elderly hospitalized tube-fed patients significantly reduced stool frequency during antibiotic treatment. Improvements in stool form were observed only during the follow-up period. Nutritional status remained stable, with patients' nutritional needs adequately met throughout the study.
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Affiliation(s)
- Chu-Hsuan Hsia
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei, 11031, Taiwan, ROC
- Department of Dietetics, Taipei Medical University Hospital, Taipei, 11031, Taiwan, ROC
- Nutrition Research Center, Taipei Medical University Hospital, Taipei, 11031, Taiwan, ROC
| | - Hsiu-Yueh Su
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei, 11031, Taiwan, ROC
- Department of Dietetics, Taipei Medical University Hospital, Taipei, 11031, Taiwan, ROC
- Nutrition Research Center, Taipei Medical University Hospital, Taipei, 11031, Taiwan, ROC
| | - Yue-Hwa Chen
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei, 11031, Taiwan, ROC
- School of Food Safety, Taipei Medical University, Taipei, 11031, Taiwan, ROC
- TMU Research Center for Digestive Medicine, Taipei Medical University, Taipei, 11031, Taiwan
- Research Center of Food Safety Inspection and Function Development, Taipei Medical University, Taipei, 11031, Taiwan, ROC
| | - Han-Chuan Chuang
- Department of Infectious Disease, Taipei Medical University Hospital, Taipei, 11031, Taiwan, ROC
| | - Yi-Wen Chien
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei, 11031, Taiwan, ROC.
- TMU Research Center for Digestive Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
- Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei, 11031, Taiwan, ROC.
- Nutrition Research Center, Taipei Medical University Hospital, Taipei, 11031, Taiwan, ROC.
- Research Center of Geriatric Nutrition, College of Nutrition, Taipei Medical University, Taipei, 11031, Taiwan, ROC.
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7
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Fu S, Yu R, Yang B, Han X, Xu Y, Miao J. Hypoxia-inducible lipid droplet-associated protein (HILPDA) and cystathionine β-synthase (CBS) co-contribute to protecting intestinal epithelial cells from Staphylococcus aureus via regulating lipid droplets formation. Biochim Biophys Acta Mol Cell Biol Lipids 2024; 1869:159558. [PMID: 39173873 DOI: 10.1016/j.bbalip.2024.159558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Revised: 08/06/2024] [Accepted: 08/19/2024] [Indexed: 08/24/2024]
Abstract
Despite Staphylococcus aureus (S. aureus) being a highly studied zoontic bacterium, its enteropathogenicity remains elusive. Herein, our findings demonstrated that S. aureus infection led to the accumulation of lipid droplets (LDs) in intestinal epithelial cells, accompanied by marked elevation inflammatory response that ultimately decreases intracellular bacterial load. The aforestated phenomenon may be partly attributed to the up-regulation of hypoxia-inducible lipid droplet-associated protein (HILPDA) and the concomitant down-regulation of cystathionine β-synthase (CBS) protein. Moreover, S. aureus infection up-regulated the expression of HILPDA, thereby promoting LDs accumulation, and down-regulated that of CBS, consequently inhibiting microsomal triglyceride transfer protein (MTTP) expression. This process may suppress the transport of LDs to the extracellular environment, further contributing to the formation of intracellular LDs. In summary, the results of this study provide significant insights into the intricate mechanisms through which the host organism combats pathogens and maintains the balance of sulfur and lipid metabolism. These findings not only enhance our understanding of the host's defense mechanisms but also offer promising avenues for the development of novel strategies to combat intestinal infectious diseases.
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Affiliation(s)
- Shaodong Fu
- MOE Joint International Research Laboratory of Animal Health and Food Safety, Key Laboratory of Animal Physiology & Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Rui Yu
- MOE Joint International Research Laboratory of Animal Health and Food Safety, Key Laboratory of Animal Physiology & Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Bo Yang
- MOE Joint International Research Laboratory of Animal Health and Food Safety, Key Laboratory of Animal Physiology & Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Xiangan Han
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China
| | - Yuanyuan Xu
- MOE Joint International Research Laboratory of Animal Health and Food Safety, Key Laboratory of Animal Physiology & Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Jinfeng Miao
- MOE Joint International Research Laboratory of Animal Health and Food Safety, Key Laboratory of Animal Physiology & Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
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Hamchand R, Wang K, Song D, Palm NW, Crawford JM. Mucosal sugars delineate pyrazine vs pyrazinone autoinducer signaling in Klebsiella oxytoca. Nat Commun 2024; 15:8902. [PMID: 39406708 PMCID: PMC11480411 DOI: 10.1038/s41467-024-53185-6] [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: 03/15/2024] [Accepted: 10/03/2024] [Indexed: 10/18/2024] Open
Abstract
Virulent Klebsiella oxytoca strains are associated with gut and lung pathologies, yet our understanding of the molecular signals governing pathogenesis remains limited. Here, we characterized a family of K. oxytoca pyrazine and pyrazinone autoinducers and explored their roles in microbial and host signaling. We identified the human mucin capping sugar Neu5Ac as a selective elicitor of leupeptin, a protease inhibitor prevalent in clinical lung isolates of K. oxytoca, and leupeptin-derived pyrazinone biosynthesis. Additionally, we uncovered a separate pyrazine pathway, regulated by general carbohydrate metabolism, derived from a broadly conserved PLP-dependent enzyme. While both pyrazine and pyrazinone signaling induce iron acquisition responses, including enterobactin biosynthesis, pyrazinone signaling enhances yersiniabactin virulence factor production and selectively activates the proinflammatory human histamine receptor H4 (HRH4). Our findings suggest that the availability of specific carbohydrates delineates distinct autoinducer pathways in K. oxytoca that may have differential effects on bacterial virulence and host immune responses.
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Affiliation(s)
- Randy Hamchand
- Department of Chemistry, Yale University, New Haven, CT, USA
- Institute of Biomolecular Design & Discovery, Yale University, West Haven, CT, USA
| | - Kevin Wang
- Institute of Biomolecular Design & Discovery, Yale University, West Haven, CT, USA
| | - Deguang Song
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
| | - Noah W Palm
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
| | - Jason M Crawford
- Department of Chemistry, Yale University, New Haven, CT, USA.
- Institute of Biomolecular Design & Discovery, Yale University, West Haven, CT, USA.
- Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA.
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9
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Chen X, Xie X, Sun N, Liu X, Liu J, Zhang W, Cao Y. Gut microbiota-derived butyrate improved acute leptospirosis in hamster via promoting macrophage ROS mediated by HDAC3 inhibition. mBio 2024; 15:e0190624. [PMID: 39287437 PMCID: PMC11481532 DOI: 10.1128/mbio.01906-24] [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: 06/21/2024] [Accepted: 09/03/2024] [Indexed: 09/19/2024] Open
Abstract
Leptospirosis is a re-emerging worldwide zoonotic disease. Infected patients and animals often exhibit intestinal symptoms. Mounting evidence suggests that host immune responses to bacterial infection are closely associated with intestinal homeostasis. Our previous research has shown that the gut microbiota can protect the host from acute leptospirosis, while the specific bacterial metabolic mediators participating in the pathogenesis remain to be identified. Short-chain fatty acids (SCFAs) are metabolites produced mainly by the gut microbiota that play a role in immune regulation. However, whether SCFAs are the key to protecting the host against leptospirosis and the underlying regulatory mechanisms are unknown. In this study, our results showed that the SCFA butyrate is involved in ameliorating leptospirosis. The depletion of SCFAs by antibiotic cocktail treatment reduced survival time after Leptospira infection while supplementation with butyrate but not acetate or propionate significantly amelioration of leptospirosis. In vitro experiments showed that butyrate treatment enhanced the intracellular bactericidal activity mediated by reactive oxygen species (ROS) production. Mechanistically, butyrate functions as a histone deacetylase 3 inhibitor (HDAC3i) to promote ROS production via monocarboxylate transporter (MCT). The protection of butyrate against acute leptospirosis mediated by ROS was also proven in vivo. Collectively, our data provide evidence that the butyrate-MCT-HDAC3i-ROS signaling axis is a potential therapeutic target for acute leptospirosis. Our work not only interprets the microbial metabolite signaling involved in transkingdom interactions between the host and gut microbiota but also provides a possible target for developing a prevention strategy for acute leptospirosis. IMPORTANCE Leptospirosis is a worldwide zoonotic disease caused by Leptospira. An estimated 1 million people are infected with leptospirosis each year. Studies have shown that healthy gut microbiota can protect the host against leptospirosis but the mechanism is not clear. This work elucidated the mechanism of gut microbiota protecting the host against acute leptospirosis. Here, we find that butyrate, a metabolite of gut microbiota, can improve the survival rate of hamsters with leptospirosis by promoting the bactericidal activity of macrophages. Mechanistically, butyrate upregulates reactive oxygen species (ROS) levels after macrophage infection with Leptospira by inhibiting HDAC3. This work confirms the therapeutic potential of butyrate in preventing acute leptospirosis and provides evidence for the benefits of the macrophage-HDAC3i-ROS axis.
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Affiliation(s)
- Xi Chen
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Xufeng Xie
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Ni Sun
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Xin Liu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Jiuxi Liu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Wenlong Zhang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Yongguo Cao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, China
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, China
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10
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Visternicu M, Rarinca V, Burlui V, Halitchi G, Ciobică A, Singeap AM, Dobrin R, Mavroudis I, Trifan A. Investigating the Impact of Nutrition and Oxidative Stress on Attention Deficit Hyperactivity Disorder. Nutrients 2024; 16:3113. [PMID: 39339712 PMCID: PMC11435085 DOI: 10.3390/nu16183113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 08/30/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
Background/Objectives: Attention deficit hyperactivity disorder (ADHD) is the most common childhood-onset neurodevelopmental disorder, characterized by difficulty maintaining attention, impulsivity, and hyperactivity. While the cause of this disorder is still unclear, recent studies have stated that heredity is important in the development of ADHD. This is linked to a few comorbidities, including depression, criminal behavior, and anxiety. Although genetic factors influence ADHD symptoms, there are also non-genetic factors, one of which is oxidative stress (OS), which plays a role in the pathogenesis and symptoms of ADHD. This review aims to explore the role of OS in ADHD and its connection to antioxidant enzyme levels, as well as the gut-brain axis (GBA), focusing on diet and its influence on ADHD symptoms, particularly in adults with comorbid conditions. Methods: The literature search included the main available databases (e.g., Science Direct, PubMed, and Google Scholar). Articles in the English language were taken into consideration and our screening was conducted based on several words such as "ADHD", "oxidative stress", "diet", "gut-brain axis", and "gut microbiota." The review focused on studies examining the link between oxidative stress and ADHD, the role of the gut-brain axis, and the potential impact of dietary interventions. Results: Oxidative stress plays a critical role in the development and manifestation of ADHD symptoms. Studies have shown that individuals with ADHD exhibit reduced levels of key antioxidant enzymes, including glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD), as well as a diminished total antioxidant status (TOS) compared to healthy controls. Additionally, there is evidence of a close bidirectional interaction between the nervous system and gut microbiota, mediated by the gut-brain axis. This relationship suggests that dietary interventions targeting gut health may influence ADHD symptoms and related comorbidities. Conclusions: Oxidative stress and the gut-brain axis are key factors in the pathogenesis of ADHD, particularly in adults with comorbid conditions. A better understanding of these mechanisms could lead to more targeted treatments, including dietary interventions, to mitigate ADHD symptoms. Further research is required to explore the therapeutic potential of modulating oxidative stress and gut microbiota in the management of ADHD.
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Affiliation(s)
- Malina Visternicu
- Faculty of Biology, "Alexandru Ioan Cuza" University of Iași, Carol I Avenue, No. 20A, 700505 Iași, Romania
- "Ioan Haulica" Institute, Apollonia University, Pacurari Street 11, 700511 Iași, Romania
| | - Viorica Rarinca
- "Ioan Haulica" Institute, Apollonia University, Pacurari Street 11, 700511 Iași, Romania
- Department of Biology, Faculty of Biology, "Alexandru Ioan Cuza" University of Iași, Carol I Avenue, No. 20A, 700505 Iași, Romania
- Doctoral School of Geosciences, Faculty of Geography and Geology, "Alexandru Ioan Cuza" University of Iași, Carol I Avenue, No. 20A, 700505 Iași, Romania
| | - Vasile Burlui
- "Ioan Haulica" Institute, Apollonia University, Pacurari Street 11, 700511 Iași, Romania
| | - Gabriela Halitchi
- "Ioan Haulica" Institute, Apollonia University, Pacurari Street 11, 700511 Iași, Romania
| | - Alin Ciobică
- "Ioan Haulica" Institute, Apollonia University, Pacurari Street 11, 700511 Iași, Romania
- Department of Biology, Faculty of Biology, "Alexandru Ioan Cuza" University of Iași, Carol I Avenue, No. 20A, 700505 Iași, Romania
- CENEMED Platform for Interdisciplinary Research, "Grigore T. Popa" University of Medicine and Pharmacy of Iasi, University Street No. 16, 700115 Iași, Romania
- Academy of Romanian Scientists, No. 54, Independence Street, Sector 5, 050094 Bucharest, Romania
| | - Ana-Maria Singeap
- Department of Gastroenterology, "Grigore T. Popa" University of Medicine and Pharmacy of Iasi, University Street No. 16, 700115 Iași, Romania
- Institute of Gastroenterology and Hepatology, "St. Spiridon" University Hospital, 700115 Iași, Romania
| | - Romeo Dobrin
- Institute of Psychiatry "Socola", 36 Bucium Street, 700282 Iași, Romania
- Department of Psychiatry, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy of Iasi, University Street No. 16, 700115 Iași, Romania
| | - Ioannis Mavroudis
- Department of Neurology, Leeds Teaching Hospitals, NHS Trust, Leeds LS2 9JT, UK
- Faculty of Medicine, Leeds University, Leeds LS2 9JT, UK
| | - Anca Trifan
- Department of Gastroenterology, "Grigore T. Popa" University of Medicine and Pharmacy of Iasi, University Street No. 16, 700115 Iași, Romania
- Institute of Gastroenterology and Hepatology, "St. Spiridon" University Hospital, 700115 Iași, Romania
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11
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Uttarwar RG, Mekonnen SA, Van Beeck W, Wang A, Finnegan P, Roberts RF, Merenstein D, Slupsky CM, Marco ML. Effects of Bifidobacterium animalis subsp. lactis BB-12 and yogurt on mice during oral antibiotic administration. Microbiol Res 2024; 286:127794. [PMID: 38852301 DOI: 10.1016/j.micres.2024.127794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 05/24/2024] [Accepted: 05/29/2024] [Indexed: 06/11/2024]
Abstract
Probiotics have the potential to prevent disruptions to normal gastrointestinal function caused by oral antibiotic use. In this study, we examined the capacity of Bifidobacterium animalis subspecies lactis BB-12 (BB-12) and yogurt, separately and combined, to mitigate the effects of the antibiotic amoxicillin-clavulanate (AMC) on the gut microbiota and metabolomes of C57BL/6 J mice. Male and female mice were administered either BB-12, yogurt, BB-12 in yogurt, or saline for 10 days concurrent with the inclusion of AMC in the drinking water. Male mice exposed to AMC exhibited significant reductions (p<0.05) in body weight over the course of the study compared to sham (no AMC) controls whereas no such effects were observed for female mice. AMC administration resulted in rapid alterations to the intestinal microbiota in both sexes irrespective of BB-12 or yogurt treatment, including significant (p<0.05) losses in bacterial cell numbers and changes in microbial alpha-diversity and beta-diversity in the feces and cecal contents. The effects of AMC on the gut microbiota were observed within one day of administration and the bacterial contents continued to change over time, showing a succession marked by rapid reductions in Muribaculaceae and Lachnospiraceae and temporal increases in proportions of Acholeplasmataceae (day 1) and Streptococcaceae and Leuconostocaceae (day 5). By day 10 of AMC intake, high proportions of Gammaproteobacteria assigned as Erwiniaceae or Enterobacteriaceae (average of 63 %), were contained in the stools and were similarly enriched in the cecum. The cecal contents of mice given AMC harbored significantly reduced concentrations of (branched) short-chain fatty acids (SCFA), aspartate, and other compounds, whereas numerous metabolites, including formate, lactate, and several amino acids and amino acid derivatives were significantly enriched. Despite the extensive impact of AMC, starting at day 7 of the study, the body weights of male mice given yogurt or BB-12 (in saline) with AMC were similar to the healthy controls. BB-12 (in saline) and yogurt intake was associated with increased Streptococcaceae and both yogurt and BB-12 resulted in lower proportions of Erwiniaceae in the fecal and cecal contents. The cecal contents of mice fed BB-12 in yogurt contained levels of formate, glycine, and glutamine that were equivalent to the sham controls. These findings highlight the potential of BB-12 and yogurt to mitigate antibiotic-induced gut dysbiosis.
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Affiliation(s)
- Ruchita G Uttarwar
- Department of Food Science & Technology, University of California, Davis, USA
| | - Solomon A Mekonnen
- Department of Food Science & Technology, University of California, Davis, USA
| | - Wannes Van Beeck
- Department of Food Science & Technology, University of California, Davis, USA
| | - Aidong Wang
- Department of Food Science & Technology, University of California, Davis, USA; Department of Nutrition, University of California, Davis, CA, USA
| | - Peter Finnegan
- Department of Food Science & Technology, University of California, Davis, USA
| | | | - Daniel Merenstein
- Department of Family Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Carolyn M Slupsky
- Department of Food Science & Technology, University of California, Davis, USA; Department of Nutrition, University of California, Davis, CA, USA
| | - Maria L Marco
- Department of Food Science & Technology, University of California, Davis, USA.
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12
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Ba X, Jin Y, Ning X, Gao Y, Li W, Li Y, Wang Y, Zhou J. Clostridium perfringens in the Intestine: Innocent Bystander or Serious Threat? Microorganisms 2024; 12:1610. [PMID: 39203452 PMCID: PMC11356505 DOI: 10.3390/microorganisms12081610] [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: 07/02/2024] [Revised: 07/31/2024] [Accepted: 08/02/2024] [Indexed: 09/03/2024] Open
Abstract
The Clostridium perfringens epidemic threatens biosecurity and causes significant economic losses. C. perfringens infections are linked to more than one hundred million cases of food poisoning annually, and 8-60% of susceptible animals are vulnerable to infection, resulting in an economic loss of more than 6 hundred million USD. The enzymes and toxins (>20 species) produced by C. perfringens play a role in intestinal colonization, immunological evasion, intestinal micro-ecosystem imbalance, and intestinal mucosal disruption, all influencing host health. In recent decades, there has been an increase in drug resistance in C. perfringens due to antibiotic misuse and bacterial evolution. At the same time, traditional control interventions have proven ineffective, highlighting the urgent need to develop and implement new strategies and approaches to improve intervention targeting. Therefore, an in-depth understanding of the spatial and temporal evolutionary characteristics, transmission routes, colonization dynamics, and pathogenic mechanisms of C. perfringens will aid in the development of optimal therapeutic strategies and vaccines for C. perfringens management. Here, we review the global epidemiology of C. perfringens, as well as the molecular features and roles of various virulence factors in C. perfringens pathogenicity. In addition, we emphasize measures to prevent and control this zoonotic disease to reduce the transmission and infection of C. perfringens.
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Affiliation(s)
- Xuli Ba
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China; (X.B.); (Y.J.); (X.N.); (W.L.)
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China; (Y.L.); (Y.W.)
| | - Youshun Jin
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China; (X.B.); (Y.J.); (X.N.); (W.L.)
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China; (Y.L.); (Y.W.)
| | - Xuan Ning
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China; (X.B.); (Y.J.); (X.N.); (W.L.)
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China; (Y.L.); (Y.W.)
| | - Yidan Gao
- State Key Laboratory of Grassland Agro-Ecosystems, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou 730020, China;
| | - Wei Li
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China; (X.B.); (Y.J.); (X.N.); (W.L.)
| | - Yunhui Li
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China; (Y.L.); (Y.W.)
| | - Yihan Wang
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China; (Y.L.); (Y.W.)
| | - Jizhang Zhou
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China; (X.B.); (Y.J.); (X.N.); (W.L.)
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China; (Y.L.); (Y.W.)
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13
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Camargo A, Bohorquez L, López DP, Ferrebuz-Cardozo A, Castellanos-Rozo J, Díaz-Ovalle J, Rada M, Camargo M, Ramírez JD, Muñoz M. Clostridium perfringens in central Colombia: frequency, toxin genes, and risk factors. Gut Pathog 2024; 16:32. [PMID: 38965598 PMCID: PMC11225238 DOI: 10.1186/s13099-024-00629-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 06/28/2024] [Indexed: 07/06/2024] Open
Abstract
Clostridium perfringens is an opportunistic bacterium that causes intestinal diseases in both humans and animals. This study aimed to assess the frequency of C. perfringens and the presence of toxin-encoding genes in fecal samples from individuals with or without gastrointestinal symptoms in the Department of Boyacá, Colombia. Additionally, risk factors associated with carriage and disease development were analyzed. A total of 114 stool samples were analyzed using a molecular test based on specific polymerase chain reaction (PCR) targeting 16S-rRNA and alpha toxin (cpa) genes. For individuals with a positive result for the PCR test, stool samples were cultured on Tryptose Sulfite Cycloserine (TSC) agar. Two to five colonies forming units were selected based on phenotypic characteristics, resulting in 56 bacterial isolates. These isolates were then analyzed for toxin-coding genes associated with gastrointestinal diseases. In addition, sociodemographic and clinical data from 77 individuals were also analyzed. The overall frequency of C. perfringens was 19.3% (n = 22/114). The detection frequency in 77 individuals with clinical data was 16.6% (n = 5/30) among symptomatic individuals and 21.2% (n = 10/47) among asymptomatic individuals. All 56 isolates obtained carried the cpa gene, while cpb2 was present in 10.7% (n = 6/56); cpe and cpb genes were not detected. Notably, diabetes and autoimmune diseases are significantly associated with an increased risk of C. perfringens detection (adjusted OR 8.41: 95% CI 1.32-35.89). This study highlights an elevated frequency of C. perfringens and the presence of the cpb2 gene in asymptomatic individuals compared with their symptomatic counterparts. These findings offer insights into the distribution and virulence factors of C. perfringens at a micro-geographical level. This information supports the need for developing tailored prevention strategies based on local characteristics to promote active surveillance programs based on molecular epidemiology.
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Affiliation(s)
- Anny Camargo
- Centro de Investigaciones en Microbiología y Biotecnología-UR (CIMBIUR), Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia
- Universidad de Boyacá, Tunja, Colombia
| | - Laura Bohorquez
- Centro de Investigaciones en Microbiología y Biotecnología-UR (CIMBIUR), Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia
| | | | | | | | | | | | - Milena Camargo
- Centro de Investigaciones en Microbiología y Biotecnología-UR (CIMBIUR), Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia
- Centro de Tecnología en Salud (CETESA), Innovaseq SAS, Funza, Cundinamarca, Colombia
| | - Juan David Ramírez
- Centro de Investigaciones en Microbiología y Biotecnología-UR (CIMBIUR), Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia
- Molecular Microbiology Laboratory, Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Marina Muñoz
- Centro de Investigaciones en Microbiología y Biotecnología-UR (CIMBIUR), Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia.
- Instituto de Biotecnología-UN (IBUN), Universidad Nacional de Colombia, Bogotá, Colombia.
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14
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Zhang S, Tang S, Liu Z, Lv H, Cai X, Zhong R, Chen L, Zhang H. Baicalin restore intestinal damage after early-life antibiotic therapy: the role of the MAPK signaling pathway. Pharmacol Res 2024; 204:107194. [PMID: 38663526 DOI: 10.1016/j.phrs.2024.107194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 04/09/2024] [Accepted: 04/22/2024] [Indexed: 04/30/2024]
Abstract
Antibiotic related intestinal injury in early life affects subsequent health and susceptibility. Here, we employed weaned piglets as a model to investigate the protective effects of baicalin against early-life antibiotic exposure-induced microbial dysbiosis. Piglets exposed to lincomycin showed a marked reduction in body weight (p < 0.05) and deterioration of jejunum intestinal morphology, alongside an increase in antibiotic-resistant bacteria such as Staphylococcus, Dolosicoccus, Escherichia-Shigella, and Raoultella. In contrast, baicalin treatment resulted in body weights, intestinal morphology, and microbial profiles that closely resembled those of the control group (p > 0.05), with a significant increase in norank_f_Muribaculaceae and Prevotellaceae_NK3B31_group colonization compared with lincomycin group (p < 0.05). Further analysis through fecal microbial transplantation into mice revealed that lincomycin exposure led to significant alterations in intestinal morphology and microbial composition, notably increasing harmful microbes and decreasing beneficial ones such as norank_Muribaculaceae and Akkermansia (p < 0.05). This shift was associated with an increase in harmful metabolites and disruption of the calcium signaling pathway gene expression. Conversely, baicalin supplementation not only counteracted these effects but also enhanced beneficial metabolites and regulated genes within the MAPK signaling pathway (MAP3K11, MAP4K2, MAPK7, MAPK13) and calcium channel proteins (ORA13, CACNA1S, CACNA1F and CACNG8), suggesting a mechanism through which baicalin mitigates antibiotic-induced intestinal and microbial disturbances. These findings highlight baicalin's potential as a plant extract-based intervention for preventing antibiotic-related intestinal injury and offer new targets for therapeutic strategies.
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Affiliation(s)
- Shunfen Zhang
- State Key Laboratory of Animal Nutrition and Feeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Shanlong Tang
- State Key Laboratory of Animal Nutrition and Feeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Zhengqun Liu
- State Key Laboratory of Animal Nutrition and Feeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Tianjin Key Laboratory of Animal Molecular Breeding and Biotechnology, Tianjin Engineering Research Center of Animal Healthy Farming, Institute of Animal Science and Veterinary, Tianjin Academy of Agricultural Sciences, Tianjin 300381, China
| | - Huiyuan Lv
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China; Beijing Centre Biology Co., Ltd., Daxing District, Beijing 102218, China
| | - Xueying Cai
- Department of Critical Care, Hangzhou First People's Hospital, Hangzhou 310003, China
| | - Ruqing Zhong
- State Key Laboratory of Animal Nutrition and Feeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
| | - Liang Chen
- State Key Laboratory of Animal Nutrition and Feeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
| | - Hongfu Zhang
- State Key Laboratory of Animal Nutrition and Feeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China
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15
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Yao X, Nie W, Chen X, Zhang J, Wei J, Qiu Y, Liu K, Shao D, Liu H, Ma Z, Li Z, Li B. Two Enterococcus faecium Isolates Demonstrated Modulating Effects on the Dysbiosis of Mice Gut Microbiota Induced by Antibiotic Treatment. Int J Mol Sci 2024; 25:5405. [PMID: 38791443 PMCID: PMC11121104 DOI: 10.3390/ijms25105405] [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: 02/29/2024] [Revised: 05/02/2024] [Accepted: 05/08/2024] [Indexed: 05/26/2024] Open
Abstract
Broad-spectrum antibiotics are frequently used to treat bacteria-induced infections, but the overuse of antibiotics may induce the gut microbiota dysbiosis and disrupt gastrointestinal tract function. Probiotics can be applied to restore disturbed gut microbiota and repair abnormal intestinal metabolism. In the present study, two strains of Enterococcus faecium (named DC-K7 and DC-K9) were isolated and characterized from the fecal samples of infant dogs. The genomic features of E. faecium DC-K7 and DC-K9 were analyzed, the carbohydrate-active enzyme (CAZyme)-encoding genes were predicted, and their abilities to produce short-chain fatty acids (SCFAs) were investigated. The bacteriocin-encoding genes in the genome sequences of E. faecium DC-K7 and DC-K9 were analyzed, and the gene cluster of Enterolysin-A, which encoded a 401-amino-acid peptide, was predicted. Moreover, the modulating effects of E. faecium DC-K7 and DC-K9 on the gut microbiota dysbiosis induced by antibiotics were analyzed. The current results demonstrated that oral administrations of E. faecium DC-K7 and DC-K9 could enhance the relative abundances of beneficial microbes and decrease the relative abundances of harmful microbes. Therefore, the isolated E. faecium DC-K7 and DC-K9 were proven to be able to alter the gut microbiota dysbiosis induced by antibiotic treatment.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Zongjie Li
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai 200241, China; (X.Y.); (W.N.); (X.C.); (J.Z.); (J.W.); (Y.Q.); (K.L.); (D.S.); (H.L.); (Z.M.)
| | - Beibei Li
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai 200241, China; (X.Y.); (W.N.); (X.C.); (J.Z.); (J.W.); (Y.Q.); (K.L.); (D.S.); (H.L.); (Z.M.)
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16
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Deihim B, Masoudipour P. Antibiotic resistance of enteropathogenic bacteria in a teaching hospital in North Khuzestan during a three-year period. J Family Med Prim Care 2024; 13:2073-2077. [PMID: 38948633 PMCID: PMC11213378 DOI: 10.4103/jfmpc.jfmpc_1594_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 12/07/2023] [Accepted: 01/09/2024] [Indexed: 07/02/2024] Open
Abstract
Introduction Gastrointestinal infections affect many people annually. The most common bacterial agents involved in these infections are enteropathogenic bacteria and in the continuation of using broad-spectrum antibiotics, Clostridium difficile-associated diarrhea is involved, especially in hospitalized patients. The aim of the present study was to investigate the pattern of antibiotic resistance among enteropathogenic bacteria. Materials and Methods In this cross-sectional study, 163 samples of patients with diarrhea in Dezful Ganjavian Hospital were examined. The samples were cultured in MacConkey, Hektoen enteric agar and GN broth, and cycloserine cefoxitin fructose agar media and incubated under standard conditions. In order to identify enteropathogenic bacteria, biochemical tests and serological confirmatory tests were used. Antibiotic resistance pattern of the isolates was investigated by Kirby-Bauer disk diffusion susceptibility test. Results The frequency of pathogenic bacteria includes 41.1% of Shigella flexneri, followed by 41.1% of S. sonnei, 6.7% of Enteropathogenic E. coli, 5.5% of Salmonella enterica Serogroup B, and 5.5% of Shigella dysenteriae. The results revealed a total of 46 patients with orders regarding C. difficile culture, no C. difficile was isolated from the samples. The studied isolates showed the highest resistance to trimethoprim-sulfamethoxazole, and ceftriaxone (88.3%), and the most effective antibiotic in the treatment of patients was ciprofloxacin with 86% sensitivity. Conclusion Susceptibility to antibiotics was different among the isolates, which shows that the early identification of the infection agent and the selection of the correct antibiotic treatment are effective in improving the gastrointestinal infection and preventing the spread of the infection.
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Affiliation(s)
- Behnaz Deihim
- Infectious and Tropical Diseases Research Center, Dezful University of Medical Sciences, Dezful, Iran
- Department of Bacteriology and Virology, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran
| | - Parisa Masoudipour
- Department of Microbiology, Tertiary Ganjavian Hospital, Dezful University of Medical Sciences, Dezful, Iran
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17
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Mehdizadeh Gohari I, Gonzales JL, Uzal FA, McClane BA. Overexpressing the cpr1953 Orphan Histidine Kinase Gene in the Absence of cpr1954 Orphan Histidine Kinase Gene Expression, or Vice Versa, Is Sufficient to Obtain Significant Sporulation and Strong Production of Clostridium perfringens Enterotoxin or Spo0A by Clostridium perfringens Type F Strain SM101. Toxins (Basel) 2024; 16:195. [PMID: 38668620 PMCID: PMC11053440 DOI: 10.3390/toxins16040195] [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: 03/13/2024] [Revised: 04/03/2024] [Accepted: 04/10/2024] [Indexed: 04/29/2024] Open
Abstract
The CPR1953 and CPR1954 orphan histidine kinases profoundly affect sporulation initiation and Clostridium perfringens enterotoxin (CPE) production by C. perfringens type F strain SM101, whether cultured in vitro (modified Duncan-Strong sporulation medium (MDS)) or ex vivo (mouse small intestinal contents (MIC)). To help distinguish whether CPR1953 and CPR1954 act independently or in a stepwise manner to initiate sporulation and CPE production, cpr1953 and cpr1954 null mutants of SM101 were transformed with plasmids carrying the cpr1954 or cpr1953 genes, respectively, causing overexpression of cpr1954 in the absence of cpr1953 expression and vice versa. RT-PCR confirmed that, compared to SM101, the cpr1953 mutant transformed with a plasmid encoding cpr1954 expressed cpr1954 at higher levels while the cpr1954 mutant transformed with a plasmid encoding cpr1953 expressed higher levels of cpr1953. Both overexpressing strains showed near wild-type levels of sporulation, CPE toxin production, and Spo0A production in MDS or MIC. These findings suggest that CPR1953 and CPR1954 do not function together in a step-wise manner, e.g., as a novel phosphorelay. Instead, it appears that, at natural expression levels, the independent kinase activities of both CPR1953 and CPR1954 are necessary for obtaining sufficient Spo0A production and phosphorylation to initiate sporulation and CPE production.
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Affiliation(s)
- Iman Mehdizadeh Gohari
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA;
| | - Jessica L. Gonzales
- California Animal Health and Food Safety Laboratory System, School of Veterinary Medicine, University of California Davis, San Bernardino, CA 92408, USA; (J.L.G.); (F.A.U.)
| | - Francisco A. Uzal
- California Animal Health and Food Safety Laboratory System, School of Veterinary Medicine, University of California Davis, San Bernardino, CA 92408, USA; (J.L.G.); (F.A.U.)
| | - Bruce A. McClane
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA;
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Bhardwaj G, Riadi Y, Afzal M, Bansal P, Kaur H, Deorari M, Tonk RK, Almalki WH, Kazmi I, Alzarea SI, Kukreti N, Thangavelu L, Saleem S. The hidden threat: Environmental toxins and their effects on gut microbiota. Pathol Res Pract 2024; 255:155173. [PMID: 38364649 DOI: 10.1016/j.prp.2024.155173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/23/2024] [Accepted: 01/24/2024] [Indexed: 02/18/2024]
Abstract
The human gut microbiota (GM), which consists of a complex and diverse ecosystem of bacteria, plays a vital role in overall wellness. However, the delicate balance of this intricate system is being compromised by the widespread presence of environmental toxins. The intricate connection between contaminants in the environment and human well-being has garnered significant attention in recent times. Although many environmental pollutants and their toxicity have been identified and studied in laboratory settings and animal models, there is insufficient data concerning their relevance to human physiology. Consequently, research on the toxicity of environmental toxins in GM has gained prominence in recent years. Various factors, such as air pollution, chemicals, heavy metals, and pesticides, have a detrimental impact on the composition and functioning of the GM. This comprehensive review aims to comprehend the toxic effects of numerous environmental pollutants, including antibiotics, endocrine-disrupting chemicals, heavy metals, and pesticides, on GM by examining recent research findings. The current analysis concludes that different types of environmental toxins can lead to GM dysbiosis and have various potential adverse effects on the well-being of animals. We investigate the alterations to the GM composition induced by contaminants and their impact on overall well-being, providing a fresh perspective on research related to pollutant exposure.
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Affiliation(s)
- Gautam Bhardwaj
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, Pushp Vihar sector-3, M-B Road, New Delhi 110017, India
| | - Yassine Riadi
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj 11942, Saudi Arabia
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Pooja Bansal
- Department of Biotechnology and Genetics, Jain (Deemed-to-be) University, Bengaluru, Karnataka 560069, India; Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan 303012, India
| | - Harpreet Kaur
- School of Basic & Applied Sciences, Shobhit University, Gangoh, Uttar Pradesh 247341, India; Department of Health & Allied Sciences, Arka Jain University, Jamshedpur, Jharkhand 831001, India
| | - Mahamedha Deorari
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Rajiv Kumar Tonk
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, Pushp Vihar sector-3, M-B Road, New Delhi 110017, India.
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, 21589 Jeddah, Saudi Arabia
| | - Sami I Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, 72341 Sakaka, Aljouf, Saudi Arabia
| | - Neelima Kukreti
- School of Pharmacy, Graphic Era Hill University, Dehradun 248007, India
| | - Lakshmi Thangavelu
- Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India
| | - Shakir Saleem
- Department of Public Health. College of Health Sciences, Saudi Electronic University, Riyadh, Saudi Arabia.
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19
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Huang H, Li L, Wu M, Liu Z, Zhao Y, Peng J, Ren X, Chen S. Antibiotics and antibiotic-associated diarrhea: a real-world disproportionality study of the FDA adverse event reporting system from 2004 to 2022. BMC Pharmacol Toxicol 2023; 24:73. [PMID: 38049920 PMCID: PMC10694877 DOI: 10.1186/s40360-023-00710-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 11/17/2023] [Indexed: 12/06/2023] Open
Abstract
BACKGROUND Our study aimed to assess the risk signals of antibiotic-associated diarrhea (AAD) caused by various antibiotics using real-world data and provide references for safe clinical applications. METHODS We analyzed data extracted from the FDA Adverse Event Reporting System (FAERS) database, covering the period from the first quarter of 2004 to the third quarter of 2022. We computed the reporting odds ratio (ROR) for each antibiotic or antibiotic class to compare the signal difference. Furthermore, we also examined the differences in the onset times and outcomes of AAD caused by various antibiotics. RESULTS A total of 5,397 reports met the inclusion requirements. Almost all antibiotics, except tobramycin and minocycline (ROR 0.98; 95%CI: 0.64-1.51 and 0.42; 95%CI: 0.16-1.11, respectively), showed a significant correlation with AAD. The analysis of the correlation between different classes of antibiotics and AAD revealed that lincomycins (ROR 29.19; 95%CI: 27.06-31.50), third-generation cephalosporins (ROR 15.96; 95%CI: 14.58-17.47), and first/second generation cephalosporins (ROR 15.29; 95%CI: 13.74-17.01) ranked the top three. The ROR values for antibiotics from the same class of antibiotics also varied greatly, with the ROR values for third-generation cephalosporins ranging from 9.97 to 58.59. There were also differences in ROR values between β-lactamase inhibitors and their corresponding β-lactamase drugs, such as amoxicillin-clavulanate (ROR = 13.31; 95%CI: 12.09-14.65) and amoxicillin (ROR = 6.50; 95%CI: 5.69-7.44). 91.35% of antibiotics have an onset time of less than four weeks. CONCLUSIONS There is a significant correlation between almost all antibiotics and AAD, particularly lincomycins and β-lactam antibiotics, as well as a different correlation within the same class. These findings offer valuable evidence for selecting antibiotics appropriately.
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Affiliation(s)
- Haining Huang
- Department of Clinical Pharmacy, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Lanfang Li
- Department of Clinical Pharmacy, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Mingli Wu
- Department of Clinical Pharmacy, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Zhen Liu
- Department of Clinical Pharmacy, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Yanyan Zhao
- Department of Clinical Pharmacy, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Jing Peng
- Department of Clinical Pharmacy, Affiliated Hospital of Jining Medical University, Jining, Shandong, China.
| | - Xiaolei Ren
- Data Center, Affiliated Hospital of Jining Medical University, Jining, Shandong, China.
| | - Shuai Chen
- Department of Pathology, Affiliated Hospital of Jining Medical University, Jining, Shandong, China.
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20
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Poto R, Laniro G, de Paulis A, Spadaro G, Marone G, Gasbarrini A, Varricchi G. Is there a role for microbiome-based approach in common variable immunodeficiency? Clin Exp Med 2023; 23:1981-1998. [PMID: 36737487 PMCID: PMC9897624 DOI: 10.1007/s10238-023-01006-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 01/18/2023] [Indexed: 02/05/2023]
Abstract
Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by low levels of serum immunoglobulins and increased susceptibility to infections, autoimmune disorders and cancer. CVID embraces a plethora of heterogeneous manifestations linked to complex immune dysregulation. While CVID is thought to be due to genetic defects, the exact cause of this immune disorder is unknown in the large majority of cases. Compelling evidences support a linkage between the gut microbiome and the CVID pathogenesis, therefore a potential for microbiome-based treatments to be a therapeutic pathway for this disorder. Here we discuss the potential of treating CVID patients by developing a gut microbiome-based personalized approach, including diet, prebiotics, probiotics, postbiotics and fecal microbiota transplantation. We also highlight the need for a better understanding of microbiota-host interactions in CVID patients to prime the development of improved preventive strategies and specific therapeutic targets.
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Affiliation(s)
- Remo Poto
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy
- World Allergy Organization (WAO), Center of Excellence, 80131, Naples, Italy
- Department of Oncology and Molecular Medicine, Istituto Superiore Di Sanità (ISS), Rome, Italy
| | - Gianluca Laniro
- Digestive Disease Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
- Department of Translational Medicine and Surgery, Catholic University of Rome, Rome, Italy
| | - Amato de Paulis
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy
- World Allergy Organization (WAO), Center of Excellence, 80131, Naples, Italy
| | - Giuseppe Spadaro
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy
- World Allergy Organization (WAO), Center of Excellence, 80131, Naples, Italy
| | - Gianni Marone
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy
- World Allergy Organization (WAO), Center of Excellence, 80131, Naples, Italy
- Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council, 80131, Naples, Italy
| | - Antonio Gasbarrini
- Digestive Disease Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
- Department of Translational Medicine and Surgery, Catholic University of Rome, Rome, Italy
| | - Gilda Varricchi
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy.
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy.
- World Allergy Organization (WAO), Center of Excellence, 80131, Naples, Italy.
- Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council, 80131, Naples, Italy.
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21
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Xu B, Shaoyong W, Wang L, Yang C, Chen T, Jiang X, Yan R, Jiang Z, Zhang P, Jin M, Wang Y. Gut-targeted nanoparticles deliver specifically targeted antimicrobial peptides against Clostridium perfringens infections. SCIENCE ADVANCES 2023; 9:eadf8782. [PMID: 37774026 PMCID: PMC10541502 DOI: 10.1126/sciadv.adf8782] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 08/25/2023] [Indexed: 10/01/2023]
Abstract
Specifically targeted antimicrobial peptides (STAMPs) are novel alternatives to antibiotics, whereas the development of STAMPs for colonic infections is hindered by limited de novo design efficiency and colonic bioavailability. In this study, we report an efficient de novo STAMP design strategy that combines a traversal design, machine learning model, and phage display technology to identify STAMPs against Clostridium perfringens. STAMPs could physically damage C. perfringens, eliminate biofilms, and self-assemble into nanoparticles to entrap pathogens. Further, a gut-targeted engineering particle vaccine (EPV) was used for STAMPs delivery. In vivo studies showed that both STAMP and EPV@STAMP effectively limited C. perfringens infections and then reduced inflammatory response. Notably, EPV@STAMP exhibited stronger protection against colonic infections than STAMPs alone. Moreover, 16S ribosomal RNA sequencing showed that both STAMPs and EPV@STAMP facilitated the recovery of disturbed gut microflora. Collectively, our work may accelerate the development of the discovery and delivery of precise antimicrobials.
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Affiliation(s)
- Bocheng Xu
- National Engineering Research Center for Green Feed and Healthy Breeding, Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Institute of Feed Science, Zhejiang University, Hangzhou 310058, China
| | - Weike Shaoyong
- National Engineering Research Center for Green Feed and Healthy Breeding, Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Institute of Feed Science, Zhejiang University, Hangzhou 310058, China
| | - Lin Wang
- National Engineering Research Center for Green Feed and Healthy Breeding, Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Institute of Feed Science, Zhejiang University, Hangzhou 310058, China
| | - Chen Yang
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310007, China
| | - Tingjun Chen
- College of Animal Science, Zhejiang University; Hangzhou 310058, China
| | - Xiao Jiang
- National Engineering Research Center for Green Feed and Healthy Breeding, Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Institute of Feed Science, Zhejiang University, Hangzhou 310058, China
| | - Rong Yan
- National Engineering Research Center for Green Feed and Healthy Breeding, Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Institute of Feed Science, Zhejiang University, Hangzhou 310058, China
| | - Zipeng Jiang
- National Engineering Research Center for Green Feed and Healthy Breeding, Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Institute of Feed Science, Zhejiang University, Hangzhou 310058, China
| | - Pan Zhang
- College of Animal Science, Zhejiang University; Hangzhou 310058, China
| | - Mingliang Jin
- National Engineering Research Center for Green Feed and Healthy Breeding, Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Institute of Feed Science, Zhejiang University, Hangzhou 310058, China
| | - Yizhen Wang
- National Engineering Research Center for Green Feed and Healthy Breeding, Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Institute of Feed Science, Zhejiang University, Hangzhou 310058, China
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22
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Éliás AJ, Barna V, Patoni C, Demeter D, Veres DS, Bunduc S, Erőss B, Hegyi P, Földvári-Nagy L, Lenti K. Probiotic supplementation during antibiotic treatment is unjustified in maintaining the gut microbiome diversity: a systematic review and meta-analysis. BMC Med 2023; 21:262. [PMID: 37468916 DOI: 10.1186/s12916-023-02961-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 06/26/2023] [Indexed: 07/21/2023] Open
Abstract
BACKGROUND Probiotics are often used to prevent antibiotic-induced low-diversity dysbiosis, however their effect is not yet sufficiently summarized in this regard. We aimed to investigate the effects of concurrent probiotic supplementation on gut microbiome composition during antibiotic therapy. METHODS We performed a systematic review and meta-analysis of randomized controlled trials reporting the differences in gut microbiome diversity between patients on antibiotic therapy with and without concomitant probiotic supplementation. The systematic search was performed in three databases (MEDLINE (via PubMed), Embase, and Cochrane Central Register of Controlled Trials (CENTRAL)) without filters on 15 October 2021. A random-effects model was used to estimate pooled mean differences (MD) with 95% confidence intervals (CI). This review was registered on PROSPERO (CRD42021282983). RESULTS Of 11,769 identified articles, 15 were eligible in the systematic review and 5 in the meta-analyses. Quantitative data synthesis for Shannon (MD = 0.23, 95% CI: [(-)0.06-0.51]), Chao1 (MD = 11.59 [(-)18.42-41.60]) and observed OTUs (operational taxonomic unit) (MD = 17.15 [(-)9.43-43.73]) diversity indices revealed no significant difference between probiotic supplemented and control groups. Lacking data prevented meta-analyzing other diversity indices; however, most of the included studies reported no difference in the other reported α- and ß-diversity indices between the groups. Changes in the taxonomic composition varied across the eligible studies but tended to be similar in both groups. However, they showed a potential tendency to restore baseline levels in both groups after 3-8 weeks. This is the first meta-analysis and the most comprehensive review of the topic to date using high quality methods. The limited number of studies and low sample sizes are the main limitations of our study. Moreover, there was high variability across the studies regarding the indication of antibiotic therapy and the type, dose, and duration of antimicrobials and probiotics. CONCLUSIONS Our results showed that probiotic supplementation during antibiotic therapy was not found to be influential on gut microbiome diversity indices. Defining appropriate microbiome diversity indices, their standard ranges, and their clinical relevance would be crucial.
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Affiliation(s)
- Anna Júlia Éliás
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Doctoral School of Health Sciences, Semmelweis University, Budapest, Hungary
| | - Viktória Barna
- Faculty of Health Sciences, Semmelweis University, Budapest, Hungary
| | - Cristina Patoni
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Dóra Demeter
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Military Hospital Medical Centre, Hungarian Defense Forces, Budapest, Hungary
| | - Dániel Sándor Veres
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary
| | - Stefania Bunduc
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- Fundeni Clinical Institute, Bucharest, Romania
| | - Bálint Erőss
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Institute of Pancreatic Diseases, Semmelweis University, Budapest, Hungary
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Péter Hegyi
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Institute of Pancreatic Diseases, Semmelweis University, Budapest, Hungary
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - László Földvári-Nagy
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary.
- Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, Budapest, Hungary.
| | - Katalin Lenti
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, Budapest, Hungary
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23
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Zhang CE, Yu XH, Cui YT, Wang HJ, Chen X, Ma XJ, Li H, Su JR, Ma ZJ, Huang LQ. Shengjiang Xiexin Decoction ameliorates antibiotic-associated diarrhea by altering the gut microbiota and intestinal metabolic homeostasis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 113:154737. [PMID: 36905867 DOI: 10.1016/j.phymed.2023.154737] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 02/24/2023] [Accepted: 02/28/2023] [Indexed: 06/18/2023]
Abstract
BACKGROUND Antibiotic-associated diarrhea (AAD) has had a significant increase in the last years, with limited available effective therapies. Shengjiang Xiexin Decoction (SXD), a classic traditional Chinese medicine formula for treating diarrhea, is a promising alternative for reducing the incidence of AAD. PURPOSE This study aimed to explore the therapeutic effect of SXD on AAD and to investigate its potential therapeutic mechanism by integrated analysis of the gut microbiome and intestinal metabolic profile. METHODS 16S rRNA sequencing analysis of the gut microbiota and untargeted-metabolomics analysis of feces were performed. The mechanism was further explored by fecal microbiota transplantation (FMT). RESULTS SXD could effectively ameliorate AAD symptoms and restore intestinal barrier function. In addition, SXD could significantly improve the diversity of the gut microbiota and accelerate the recovery of the gut microbiota. At the genus level, SXD significantly increased the relative abundance of Bacteroides spp (p < 0.01) and decreased the relative abundance of Escherichia_Shigela spp (p < 0.001). Untargeted metabolomics showed that SXD significantly improved gut microbiota and host metabolic function, particularly bile acid metabolism and amino acid metabolism. CONCLUSION This study demonstrated that SXD could extensively modulate the gut microbiota and intestinal metabolic homeostasis to treat AAD.
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Affiliation(s)
- Cong-En Zhang
- Department of Pharmacy, Beijing Friendsip Hospital, Capital Medical University, 100050, Beijing, China
| | - Xiao-Hong Yu
- Department of Pharmacy, Beijing Friendsip Hospital, Capital Medical University, 100050, Beijing, China
| | - Yu-Tao Cui
- Department of Pharmacy, Beijing Friendsip Hospital, Capital Medical University, 100050, Beijing, China
| | - Huan-Jun Wang
- Department of Pharmacy, Beijing Friendsip Hospital, Capital Medical University, 100050, Beijing, China
| | - Xi Chen
- Department of Pharmacy, Beijing Friendsip Hospital, Capital Medical University, 100050, Beijing, China
| | - Xiao-Jing Ma
- Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Hui Li
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Jian-Rong Su
- Clinical Laboratory Center, Beijing Friendship Hospital, Capital Medical University, 100050, Beijing, China
| | - Zhi-Jie Ma
- Department of Pharmacy, Beijing Friendsip Hospital, Capital Medical University, 100050, Beijing, China.
| | - Lu-Qi Huang
- Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
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24
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Rafey A, Jahan S, Farooq U, Akhtar F, Irshad M, Nizamuddin S, Parveen A. Antibiotics Associated With Clostridium difficile Infection. Cureus 2023; 15:e39029. [PMID: 37323360 PMCID: PMC10266117 DOI: 10.7759/cureus.39029] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/15/2023] [Indexed: 06/17/2023] Open
Abstract
Introduction Clostridium difficile (C. difficile) is one of the major causes of diarrhea transmitted by the fecal-oral route. C. difficile type BI/NAP1/027 is responsible for the most severe C. difficile infection (CDI). It is a major cause of antibiotic-associated diarrhea followed by Clostridium perfringens, Staphylococcus aureus,and Klebsiella oxytoca. Historically, clindamycin, cephalosporins, penicillins, and fluoroquinolones were related to CDI. We conducted this study to evaluate the antibiotics associated with CDI in recent times. Methods We conducted a retrospective, single-center study over a period of eight years. A total of 58 patients were enrolled in the study. Patients with diarrhea and positive C. difficile toxin in stool were evaluated for antibiotics given, age, presence of malignancy, previous hospital stay for more than three days in the last three months, and any comorbidities. Results Among patients who developed CDI, prior antibiotics for at least four days duration were given in 93% (54/58) of patients. The most common antibiotics associated with C. difficile infection were piperacillin/tazobactam in 77.60% (45/58), meropenem in 27.60% (16/58), vancomycin in 20.70% (12/58), ciprofloxacin in 17.20% (10/58), ceftriaxone in 16% (9/58), and levofloxacin in 14% (8/58) of patients, respectively. Seven percent (7%) of patients with CDI did not receive any prior antibiotics. Solid organ malignancy was present in 67.20% and hematological malignancy in 27.60% of CDI patients. Ninety-eight percent (98%, 57/58) of patients treated with proton pump inhibitors, 93% of patients with a previous hospital stay for more than three days, 24% of patients with neutropenia, 20.1% of patients aged more than 65 years, 14% of patients with diabetes mellitus, and 12% of patients with chronic kidney disease also developed C. difficile infection. Conclusion The antibiotics associated with C. difficile infection are piperacillin/tazobactam, meropenem, vancomycin, ciprofloxacin, ceftriaxone, and levofloxacin. Other risk factors for CDI are proton pump inhibitor use, prior hospital admission, solid organ malignancy, neutropenia, diabetes mellitus (DM), and chronic kidney disease (CKD).
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Affiliation(s)
- Abdur Rafey
- Department of Internal Medicine and Infectious Diseases, Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, PAK
| | - Shah Jahan
- Department of Internal Medicine, Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, PAK
| | - Umer Farooq
- Department of Internal Medicine, Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, PAK
| | - Furqana Akhtar
- Department of Infectious Diseases, Bahria International Hospital, Lahore, PAK
| | - Memoona Irshad
- Department of Infectious Diseases, Aga Khan University Hospital, Karachi, PAK
| | - Summiya Nizamuddin
- Department of Microbiology, Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, PAK
| | - Azra Parveen
- Department of Internal Medicine and Infectious Diseases, Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, PAK
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25
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Pan H, Chen X, Wang P, Peng J, Li J, Ding K. Effects of Nemacystus decipiens polysaccharide on mice with antibiotic associated diarrhea and colon inflammation. Food Funct 2023; 14:1627-1635. [PMID: 36688462 DOI: 10.1039/d1fo02813h] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Antibiotic associated diarrhea (AAD) is a common side effect of antibiotic therapy in which gut microbiota plays an important role in the disease. However, the function of gut microbiota in this disease is still not entirely clear. Polysaccharides have shown strong activity in shaping gut microbiota. Whether the polysaccharide can intervene with the microbiota to improve ADD has not been determined. In this study, we extract crude polysaccharides from Nemacystus decipiens (N. decipiens), a traditional Chinese medicine (TCM), named NDH0. The crude polysaccharide NDH0 might significantly relieve the symptom of mice with AAD, including a reduction in body weight, shortening of cecum index and the infiltration of inflammatory cells into the colon. NDH0-treated mice exhibited more abundant gut microbial diversity; significantly increased the abundance of Muribaculum, Lactobacillus, and Bifidobacterium and decreased the abundance of Enterobacter and Clostridioides at genus level. NDH0 treatment down-regulated the level of pro-inflammatory cytokines, including IL-1β and IL-6 in colon tissue. NDH0 protected the integrity of colon tissues and partially inactivated the related inflammation pathway by maintaining occludin and SH2-containing Inositol 5'-Phosphatase (SHIP). NDH0 could alleviate symptoms of diarrhea by modulating gut microbiota composition, improving intestinal integrity and reducing inflammation. The underlying protective mechanism was to reduce the abundance of opportunistic pathogens and maintain SHIP protein expression. Collectively, our results demonstrated the role of NDH0 as a potential intestinal protective agent in gut dysbiosis.
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Affiliation(s)
- Haoyu Pan
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Road, Shanghai, 201203, China.,Glycochemistry and Glycobiology Lab, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China.,University of Chinese Academy of Science, No. 19A Yuquan Road, Beijing, 100049, China
| | - Xia Chen
- Glycochemistry and Glycobiology Lab, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China.,University of Chinese Academy of Science, No. 19A Yuquan Road, Beijing, 100049, China
| | - PeiPei Wang
- Glycochemistry and Glycobiology Lab, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China.,University of Chinese Academy of Science, No. 19A Yuquan Road, Beijing, 100049, China
| | - Junfeng Peng
- Glycochemistry and Glycobiology Lab, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China.,University of Chinese Academy of Science, No. 19A Yuquan Road, Beijing, 100049, China.,Shanghai Changzheng Hospital, Naval Medical University, No.415 Fengyang Road, Shanghai, 200003, China
| | - Judong Li
- Glycochemistry and Glycobiology Lab, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China.,University of Chinese Academy of Science, No. 19A Yuquan Road, Beijing, 100049, China.,Shanghai Changzheng Hospital, Naval Medical University, No.415 Fengyang Road, Shanghai, 200003, China
| | - Kan Ding
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Road, Shanghai, 201203, China.,Glycochemistry and Glycobiology Lab, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China.,University of Chinese Academy of Science, No. 19A Yuquan Road, Beijing, 100049, China
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Bassotti G, Fruganti A, Stracci F, Marconi P, Fettucciari K. Cytotoxic synergism of Clostridioides difficile toxin B with proinflammatory cytokines in subjects with inflammatory bowel diseases. World J Gastroenterol 2023; 29:582-596. [PMID: 36742168 PMCID: PMC9896618 DOI: 10.3748/wjg.v29.i4.582] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 12/03/2022] [Accepted: 12/27/2022] [Indexed: 01/20/2023] Open
Abstract
Clostridioides difficile (C. difficile) is progressively colonizing humans and animals living with humans. During this process, hypervirulent strains and mutated toxin A and B of C. difficile (TcdA and TcdB) are originating and developing. While in healthy subjects colonization by C. difficile becomes a risk after the use of antibiotics that alter the microbiome, other categories of people are more susceptible to infection and at risk of relapse, such as those with inflammatory bowel disease (IBD). Recent in vitro studies suggest that this increased susceptibility could be due to the strong cytotoxic synergism between TcdB and proinflammatory cytokines the tumor necrosis factor-alpha and interferon-gamma (CKs). Therefore, in subjects with IBD the presence of an inflammatory state in the colon could be the driver that increases the susceptibility to C. difficile infection and its progression and relapses. TcdB is internalized in the cell via three receptors: chondroitin sulphate proteoglycan 4; poliovirus receptor-like 3; and Wnt receptor frizzled family. Chondroitin sulphate proteoglycan 4 and Wnt receptor frizzled family are involved in cell death by apoptosis or necrosis depending on the concentration of TcdB and cell types, while poliovirus receptor-like 3 induces only necrosis. It is possible that cytokines could also induce a greater expression of receptors for TcdB that are more involved in necrosis than in apoptosis. Therefore, in subjects with IBD there are the conditions: (1) For greater susceptibility to C. difficile infection, such as the inflammatory state, and abnormalities of the microbiome and of the immune system; (2) for the enhancement of the cytotoxic activity of TcdB +Cks; and (3) for a greater expression of TcdB receptors stimulated by cytokines that induce cell death by necrosis rather than apoptosis. The only therapeutic approach currently possible in IBD patients is monitoring of C. difficile colonization for interventions aimed at reducing tumor necrosis factor-alpha and interferon-gamma levels when the infection begins. The future perspective is to generate bacteriophages against C. difficile for targeted therapy.
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Affiliation(s)
- Gabrio Bassotti
- Department of Medicine and Surgery, Gastroenterology, Hepatology & Digestive Endoscopy Section University of Perugia Medical School, Piazza Lucio Severi, Perugia 06132, Italy, and Santa Maria della Misericordia Hospital, Gastroenterology & Hepatology Unit Perugia 06156, Italy
| | - Alessandro Fruganti
- School of Biosciences and Veterinary Medicine, University of Camerino, Matelica 62024, Italy
| | - Fabrizio Stracci
- Medicine and Surgery, Hygiene and Public Health Section, University of Perugia, Perugia 06123, Italy
| | - Pierfrancesco Marconi
- Medicine and Surgery, Biosciences & Medical Embryology Section, University of Perugia, Perugia 06132, Italy
| | - Katia Fettucciari
- Medicine and Surgery, Biosciences & Medical Embryology Section, University of Perugia, Perugia 06132, Italy
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Saravanakumar C, Neethu CS, Purvaja R, Sunantha G, Robin RS, Ramesh R. Networking and co-occurrence of virulent and multidrug resistant environmental bacteria in different aquatic systems: A gap in MDR-virulence transfer? THE SCIENCE OF THE TOTAL ENVIRONMENT 2023; 857:159221. [PMID: 36206910 DOI: 10.1016/j.scitotenv.2022.159221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 09/21/2022] [Accepted: 09/30/2022] [Indexed: 06/16/2023]
Abstract
Co-occurrence of resistance and virulence is often overlooked in aquatic bacteria as environmental reservoirs, while transmission of these characteristics to clinically significant strains present unforeseen problems in future. In this investigation, environmental bacteria identified concurrently from multiple aquatic habitats viz., groundwater, canal, river and coastal waters were profiled for antibiotic resistance, metal tolerance, virulence factors and genes coding for these determinants. Strains from polluted river and canal exhibited higher resistance and virulence, especially Pseudomonas gessardii and P. fluorescens displayed high antibiotic resistance index (ARI > 0.6-0.8) with Alkaline Protease and Phospholipase production. Opportunistic pathogens including Vibrio parahaemolyticus, V. alginolyticus, V. vulnificus, Corynebacterium and Comamonas testosteroni expressed all three virulence factors with relatively low resistance. However, V. vulnificus and V. alginolyticus exhibited multiclass antibiotic resistance (5/6 classes). Metagenomic analysis revealed that genes corresponding to beta-lactam resistance were significantly higher (p < 0.05) in freshwater than seawater, while multidrug resistance gene were higher (p < 0.05) in seawater. In all aquatic bodies, abundant virulence genes belonged to secretion system proteins followed by motility related genes. Culturable bacteria revealed differential distribution of positive and negative correlation between 31 targeted genes with expressed resistance and virulence. Among Acinetobacter, significant positive correlation was found between Phospholipase production, other virulence genes (OVGs) and resistance to DNA Synthesis Inhibitors (DSI). In Pseudomonas, positive correlation was detected between toxin genes (toxA, eta, hlyA and stx) and resistance to cell wall synthesis inhibitors (CSI) as well as with OVGs and adhesion genes (eae, afa, papC and papA). Network analysis displayed unique clustering of genes ncc, arsB, strA, merA and intI dominated by non-pathogens and distinct clustering of genes pho, erm, nfsA, trh, lasB, tdh and invA by Vibrio. This investigation extends insight on co-occurring resistance and virulence in aquatic reservoir bacteria that could pose serious threats to public health in future.
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Affiliation(s)
- C Saravanakumar
- National Centre for Sustainable Coastal Management (NCSCM), Ministry of Environment, Forest and Climate Change (MoEFCC), Chennai 600025, India
| | - C S Neethu
- National Centre for Sustainable Coastal Management (NCSCM), Ministry of Environment, Forest and Climate Change (MoEFCC), Chennai 600025, India
| | - R Purvaja
- National Centre for Sustainable Coastal Management (NCSCM), Ministry of Environment, Forest and Climate Change (MoEFCC), Chennai 600025, India
| | - G Sunantha
- Chulalongkorn University of Engineering, Department of Engineering, Bangkok 10400, Thailand
| | - R S Robin
- National Centre for Sustainable Coastal Management (NCSCM), Ministry of Environment, Forest and Climate Change (MoEFCC), Chennai 600025, India
| | - R Ramesh
- National Centre for Sustainable Coastal Management (NCSCM), Ministry of Environment, Forest and Climate Change (MoEFCC), Chennai 600025, India.
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Antibiotika-assoziierte Diarrhoe. COLOPROCTOLOGY 2022. [DOI: 10.1007/s00053-022-00652-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Characterizing the Contributions of Various Clostridium perfringens Enterotoxin Properties to In Vivo and In Vitro Permeability Effects. mSphere 2022; 7:e0027622. [PMID: 36069435 PMCID: PMC9599344 DOI: 10.1128/msphere.00276-22] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Clostridium perfringens enterotoxin (CPE) is thought to cause lethal enterotoxemia when absorbed from the intestinal lumen into the circulation. CPE action sequentially involves receptor-binding, oligomerization into a prepore, and pore formation. To explore the mechanistic basis by which CPE alters permeability, this study tested the permeability effects of several recombinant CPE (rCPE) species: rCPE and rCPEC186A (which form pores), rC-CPE and rCPED48A (which bind to receptors but cannot oligomerize), rCPEC186A/F91C (which binds and oligomerizes without pore formation), and rCPEY306A/L315A (which has poor receptor-binding ability). On Caco-2 cells, i) only rCPE and rCPEC186A were cytotoxic; ii) rCPE and rCPEC186A affected transepithelial resistance (TEER) and 4 kDa fluorescent dextran (FD4) transit more quickly than binding-capable, but noncytotoxic, rCPE variants; whereas iii) rCPEY306A/L315A did not affect TEER or FD4 transit. Using mouse intestinal loops, rCPE (but not noncytotoxic rC-CPE, rCPED48A or rCPEY306A/L315A) was lethal and caused intestinal histologic damage within 4 h. After 2 h of treatment, rCPE was more strongly absorbed into the serum than those noncytotoxic rCPE species but by 4 h rC-CPE and rCPED48A became absorbed similarly as rCPE, while rCPEY306A/L315A absorption remained low. This increased rC-CPE and rCPED48A absorption from 2 to 4 h did not involve a general intestinal permeability increase because Evans Blue absorption from the intestines did not increase between 2 and 4 h of treatment with rC-CPE or rCPED48A. Collectively, these results indicate that CPE receptor binding is sufficient to slowly affect permeability, but CPE-induced cytotoxicity is necessary for rapid permeability changes and lethality. IMPORTANCE Clostridium perfringens enterotoxin (CPE) causes lethal enterotoxemia when absorbed from the intestines into the bloodstream. Testing recombinant CPE (rCPE) or rCPE variants impaired for various specific steps in CPE action showed that full CPE-induced cytotoxicity causes rapid Caco-2 monolayer permeability alterations, as well as enterotoxemic lethality and rapid CPE absorption in mouse small intestinal loops. However, receptor binding-capable, but noncytotoxic, rCPE variants did cause slow-developing in vitro and in vivo permeability effects. Absorption of binding-capable, noncytotoxic rCPE variants from the intestines did not correlate with general intestinal permeability alterations, suggesting that CPE binding can induce its own uptake. These findings highlight the importance of binding and, especially, cytotoxicity for CPE absorption during enterotoxemia and may assist development of permeability-altering rCPE variants for translational purposes.
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Limosilactobacillus reuteri SLZX19-12 Protects the Colon from Infection by Enhancing Stability of the Gut Microbiota and Barrier Integrity and Reducing Inflammation. Microbiol Spectr 2022; 10:e0212421. [PMID: 35658572 PMCID: PMC9241593 DOI: 10.1128/spectrum.02124-21] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Limosilactobacillus reuteri plays an important role in regulating intestinal functions and maintaining barrier integrity in animals. In this study, Limosilactobacillus reuteri strain SLZX19-12 was isolated from the fecal microbiota of Tibetan pigs, and it was found that this strain is sensitive to common antibiotics and has strong resistance to stress. Upon being administered by gavage at different doses, including low, medium, and high doses, for 14 days, Limosilactobacillus reuteri SLZX19-12 may enhance the intestinal barrier. After administration of a high dose of SLZX19-12, mice were challenged with Salmonella enterica serovar Typhimurium SL1344. Infection with Salmonella Typhimurium SL1344 led to disordered colonic microbiotas, colonic inflammation through the S100A8/S100A9-NF-κB pathway and potential apoptosis, and translocation of pathogens to parenteral visceral organs in mice. However, the mice pretreated with Limosilactobacillus reuteri SLZX19-12 showed lower loads of Salmonella in visceral organs, less colonic inflammation, and higher barrier integrity. More importantly, the administration of strain SLZX19-12 resulted in a more stable microbiota structure of the colon, in which the abundance of Alloprevotella was greatly enhanced. Therefore, this study suggests that Limosilactobacillus reuteri SLZX19-12 can protect the colon from infection by enhancing the stability of gut microbiota and barrier integrity and reducing inflammation. IMPORTANCE The use of antibiotics to treat bacterial infections leads to a series of side effects. As an alternative method, the biocontrol strategy, which uses probiotics to suppress pathogens, is considered a potential way to deal with bacterial infections in gut. However, there are few probiotics that are currently safe and can protect against infection. In this study, Limosilactobacillus reuteri strain SLZX19-12 was obtained from Tibetan pigs, which have higher resistance to infection. This strain is sensitive to conventional antibiotics, secretes a wide spectrum of enzymes, and also promotes the intestinal barrier function in mice. In addition, Limosilactobacillus reuteri SLZX19-12 can promote the stability of the gut microbiota to avoid or alleviate the occurrence or development of foodborne infections.
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Effects of Lacidophilin Tablets, Yogurt, and Bifid Triple Viable Capsules on the Gut Microbiota of Mice with Antibiotic-Associated Diarrhea. THE CANADIAN JOURNAL OF INFECTIOUS DISEASES & MEDICAL MICROBIOLOGY = JOURNAL CANADIEN DES MALADIES INFECTIEUSES ET DE LA MICROBIOLOGIE MEDICALE 2022; 2022:6521793. [PMID: 35360462 PMCID: PMC8964159 DOI: 10.1155/2022/6521793] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 02/08/2022] [Accepted: 02/23/2022] [Indexed: 12/14/2022]
Abstract
Antibiotic-associated diarrhea (AAD) is a common morbidity caused by antibiotic use and is characterized by the dysbiosis of the gut microbiota. Several clinical trials have shown that probiotics can prevent AAD. This study aimed at investigating the effects of Lacidophilin tablets (LB), yogurt (YG), and bifid triple viable capsules (BT) on the gut microbiota of mice with AAD. Mice with diarrhea were randomly allocated to treatment groups or the control group and were treated with either LB, YG, BT, or vehicle control. The body weight, diarrhea scores, cecum index, and cecal length were determined. Fecal samples of all mice were analyzed using 16S rRNA high-throughput sequencing. The results showed that LB, YG, and BT significantly decreased the diarrhea scores and inhibited increases in the cecum index and cecal length induced by AAD. In addition, they significantly changed the composition and richness of the gut microbiota. Specifically, they increased the abundance of the phylum Firmicutes and decreased the abundance of the phyla Bacteroidetes and the family Bacteroidaceae. Treatment with LB and YG also decreased the abundance of the phylum Proteobacteria and only LB could mediate the reduced levels of Lactobacillaceae in AAD mice. At the genus level, YG and BT treatment decreased the abundance of Bacteroides or Parasutterella. To our surprise, only LB treatment dramatically increased the abundance of Lactobacillus and decreased that of potential pathogens, such as Bacteroides, Parabacteroides, and Parasutterella, to almost normal values. Our findings indicate that LB, YG, and BT ameliorated diarrhea by regulating the composition and structure of the gut microbiota and that LB plays an important role in regulating the gut microbiota.
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Supplementation of Bacillus sp. DU-106 Alleviates Antibiotic-Associated Diarrhea in Association with the Regulation of Intestinal Microbiota in Mice. Probiotics Antimicrob Proteins 2022; 14:372-383. [DOI: 10.1007/s12602-022-09906-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/07/2022] [Indexed: 02/08/2023]
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Gu X, Sim JX, Lee WL, Cui L, Chan YF, Chang ED, Teh YE, Zhang AN, Armas F, Chandra F, Chen H, Zhao S, Lee Z, Thompson JR, Ooi EE, Low JG, Alm EJ, Kalimuddin S. Gut Ruminococcaceae levels at baseline correlate with risk of antibiotic-associated diarrhea. iScience 2022; 25:103644. [PMID: 35005566 PMCID: PMC8718891 DOI: 10.1016/j.isci.2021.103644] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/19/2021] [Accepted: 12/13/2021] [Indexed: 12/11/2022] Open
Abstract
Antibiotic-associated diarrhea (AAD) affects a significant proportion of patients receiving antibiotics. We sought to understand if differences in the gut microbiome would influence the development of AAD. We administered a 3-day course of amoxicillin-clavulanate to 30 healthy adult volunteers, and analyzed their stool microbiome, using 16S rRNA gene sequencing, at baseline and up to 4 weeks post antibiotic administration. Lower levels of gut Ruminococcaceae were significantly and consistently observed from baseline until day 7 in participants who developed AAD. Overall, participants who developed AAD experienced a greater decrease in microbial diversity. The probability of AAD could be predicted based on qPCR-derived levels of Faecalibacterium prausnitzii at baseline. Our findings suggest that a lack of gut Ruminococcaceae influences development of AAD. Quantification of F. prausnitzii in stool prior to antibiotic administration may help identify patients at risk of AAD, and aid clinicians in devising individualized treatment regimens to minimize such adverse effects.
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Affiliation(s)
- Xiaoqiong Gu
- Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, 1 Create Way, Singapore 138602, Singapore
- Campus for Research Excellence and Technological Enterprise (CREATE), Singapore 138602, Singapore
| | - Jean X.Y. Sim
- Department of Infectious Diseases, Singapore General Hospital, Academia Level 3, 20 College Road, Singapore 169856, Singapore
| | - Wei Lin Lee
- Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, 1 Create Way, Singapore 138602, Singapore
- Campus for Research Excellence and Technological Enterprise (CREATE), Singapore 138602, Singapore
| | - Liang Cui
- Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, 1 Create Way, Singapore 138602, Singapore
- Campus for Research Excellence and Technological Enterprise (CREATE), Singapore 138602, Singapore
| | - Yvonne F.Z. Chan
- Department of Infectious Diseases, Singapore General Hospital, Academia Level 3, 20 College Road, Singapore 169856, Singapore
| | - Ega Danu Chang
- Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, 1 Create Way, Singapore 138602, Singapore
- Campus for Research Excellence and Technological Enterprise (CREATE), Singapore 138602, Singapore
| | - Yii Ean Teh
- Department of Infectious Diseases, Singapore General Hospital, Academia Level 3, 20 College Road, Singapore 169856, Singapore
| | - An-Ni Zhang
- Department of Biological Engineering, Massachusetts Institute of Technology, 21 Ames Street, Cambridge, MA 02142, USA
| | - Federica Armas
- Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, 1 Create Way, Singapore 138602, Singapore
- Campus for Research Excellence and Technological Enterprise (CREATE), Singapore 138602, Singapore
| | - Franciscus Chandra
- Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, 1 Create Way, Singapore 138602, Singapore
- Campus for Research Excellence and Technological Enterprise (CREATE), Singapore 138602, Singapore
| | - Hongjie Chen
- Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, 1 Create Way, Singapore 138602, Singapore
- Campus for Research Excellence and Technological Enterprise (CREATE), Singapore 138602, Singapore
| | - Shijie Zhao
- Department of Biological Engineering, Massachusetts Institute of Technology, 21 Ames Street, Cambridge, MA 02142, USA
| | - Zhanyi Lee
- Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, 1 Create Way, Singapore 138602, Singapore
- Campus for Research Excellence and Technological Enterprise (CREATE), Singapore 138602, Singapore
| | - Janelle R. Thompson
- Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore
- Asian School of the Environment, Nanyang Technological University, 62 Nanyang Drive, Singapore 637459, Singapore
| | - Eng Eong Ooi
- Program in Emerging Infectious Diseases, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore
- Viral Research and Experimental Medicine Center, SingHealth Duke-NUS Academic Medical Centre (ViREMiCS), 20 College Road, Singapore 169856, Singapore
- Saw Swee Hock School of Public Health, National University of Singapore, 12 Science Drive 2, Singapore 117549, Singapore
| | - Jenny G. Low
- Department of Infectious Diseases, Singapore General Hospital, Academia Level 3, 20 College Road, Singapore 169856, Singapore
- Program in Emerging Infectious Diseases, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore
- Viral Research and Experimental Medicine Center, SingHealth Duke-NUS Academic Medical Centre (ViREMiCS), 20 College Road, Singapore 169856, Singapore
| | - Eric J. Alm
- Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, 1 Create Way, Singapore 138602, Singapore
- Campus for Research Excellence and Technological Enterprise (CREATE), Singapore 138602, Singapore
- Department of Biological Engineering, Massachusetts Institute of Technology, 21 Ames Street, Cambridge, MA 02142, USA
- Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Building E25-321, Cambridge, MA 02139, USA
- Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA
| | - Shirin Kalimuddin
- Department of Infectious Diseases, Singapore General Hospital, Academia Level 3, 20 College Road, Singapore 169856, Singapore
- Program in Emerging Infectious Diseases, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore
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Navarro MA, Li J, Beingesser J, McClane BA, Uzal FA. NanI Sialidase Enhances the Action of Clostridium perfringens Enterotoxin in the Presence of Mucus. mSphere 2021; 6:e0084821. [PMID: 34908460 PMCID: PMC8673254 DOI: 10.1128/msphere.00848-21] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 11/29/2021] [Indexed: 11/29/2022] Open
Abstract
Clostridium perfringens enterotoxin (CPE) is the main virulence factor for C. perfringens type F strains to cause human gastrointestinal diseases, which can involve lethal enterotoxemia. During type F disease, CPE encounters an adherent mucus layer overlying the intestines, so the current study evaluated if NanI potentiates CPE activity in the presence of adherent mucus. CPE alone caused more cytotoxicity transepithelial electrical resistance (TEER) and permeability to fluorescent dextran (FD) for minimal mucus-producing HT29 cells versus that in their derivative HT29-MTX-E12 cells, which produce abundant adherent mucus. However, for HT29-MTX-E12 cells, the presence of NanI significantly increased CPE binding and pore formation, which enhanced their sensitivity to CPE effects on cytotoxicity, TEER, and FD permeability. When the ability of NanI to potentiate CPE-induced enterotoxemia was then tested in a mouse small intestinal loop enterotoxemia model, a pathophysiologically relevant 50 μg/mL dose of CPE did not kill mice. However, the copresence of purified NanI resulted in significant CPE-induced lethality. More CPE was detected in the sera of mice challenged with 50 μg/mL of CPE when NanI was copresent during challenge. The copresence of NanI and CPE during challenge also significantly increased intestinal histologic damage compared to that after challenge with CPE alone, suggesting that NanI enhancement of CPE-induced intestinal damage may increase CPE absorption into blood. Overall, these results indicate that (i) mucus inhibits CPE action and (ii) NanI can potentiate CPE action in the presence of mucus, which may help explain why type F strains that produce relatively low levels of CPE are still pathogenic. IMPORTANCE NanI is a sialidase produced by some Clostridium perfringens type F strains. Here, we found that NanI can significantly increase the action of C. perfringens enterotoxin (CPE), which is the main toxin responsible for severe human enteric disease caused by type F strains. This effect likely helps to explain why even some type F strains that produce small amounts of CPE are pathogenic.
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Affiliation(s)
- Mauricio A. Navarro
- California Animal Health and Food Safety Laboratory System, School of Veterinary Medicine, University of California, Davis, San Bernardino, California, USA
- Instituto de Patología Animal, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile
| | - Jihong Li
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Juliann Beingesser
- California Animal Health and Food Safety Laboratory System, School of Veterinary Medicine, University of California, Davis, San Bernardino, California, USA
| | - Bruce A. McClane
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Francisco A. Uzal
- California Animal Health and Food Safety Laboratory System, School of Veterinary Medicine, University of California, Davis, San Bernardino, California, USA
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Motamedi H, Fathollahi M, Abiri R, Kadivarian S, Rostamian M, Alvandi A. A worldwide systematic review and meta-analysis of bacteria related to antibiotic-associated diarrhea in hospitalized patients. PLoS One 2021; 16:e0260667. [PMID: 34879104 PMCID: PMC8654158 DOI: 10.1371/journal.pone.0260667] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 11/12/2021] [Indexed: 01/05/2023] Open
Abstract
INTRODUCTION Antibiotic-associated diarrhea (AAD) is a major hospital problem and a common adverse effect of antibiotic treatment. The aim of this study was to investigate the prevalence of the most important bacteria that cause AAD in hospitalized patients. MATERIALS AND METHODS PubMed, Web of Science and Scopus databases were searched using multiple relevant keywords and screening carried out based on inclusion/exclusion criteria from March 2001 to October 2021. The random-effects model was used to conduct the meta-analysis. RESULTS Of the 7,377 identified articles, 56 met the inclusion criteria. Pooling all studies, the prevalence of Clostridioides (Clostridium) difficile, Clostridium perfringens, Klebsiella oxytoca, and Staphylococcus aureus as AAD-related bacteria among hospitalized patients were 19.6%, 14.9%, 27%, and 5.2%, respectively. The prevalence of all four bacteria was higher in Europe compared to other continents. The highest resistance of C. difficile was estimated to ciprofloxacin and the lowest resistances were reported to chloramphenicol, vancomycin, and metronidazole. There was no or little data on antibiotic resistance of other bacteria. CONCLUSIONS The results of this study emphasize the need for a surveillance program, as well as timely public and hospital health measures in order to control and treat AAD infections.
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Affiliation(s)
- Hamid Motamedi
- Department of Microbiology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Student Research Committee, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Matin Fathollahi
- Department of Microbiology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Student Research Committee, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ramin Abiri
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sepide Kadivarian
- Department of Microbiology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Student Research Committee, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mosayeb Rostamian
- Infectious Diseases Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Amirhooshang Alvandi
- Medical Technology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Li J, Navarro MA, Uzal FA, McClane BA. NanI Sialidase Contributes to the Growth and Adherence of Clostridium perfringens Type F Strain F4969 in the Presence of Adherent Mucus. Infect Immun 2021; 89:e0025621. [PMID: 34424746 PMCID: PMC8519267 DOI: 10.1128/iai.00256-21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 07/30/2021] [Indexed: 12/13/2022] Open
Abstract
Clostridium perfringens type F strains causing nonfoodborne human gastrointestinal diseases (NFD) typically produce NanI sialidase as their major secreted sialidase. Type F NFDs can persist for several weeks, indicating their pathogenesis involves intestinal colonization, including vegetative cell growth and adherence, with subsequent sporulation that fosters enterotoxin production and release. We previously reported that NanI contributes to type F NFD strain adherence and growth using Caco-2 cells. However, Caco-2 cells make minimal amounts of mucus, which is significant because the intestines are coated with adherent mucus. Therefore, it was important to assess if NanI contributes to the growth and adherence of type F NFD strains in the presence of adherent mucus. Consequently, the current study first demonstrated greater growth of nanI-carrying versus non-nanI-carrying type F strains in the presence of HT29-MTX-E12 cells, which produce an adherent mucus layer, versus their parental HT29 cells, which make minimal mucus. Demonstrating the specific importance of NanI for this effect, type F NFD strain F4969 or a complementing strain grew and adhered better than an isogenic nanI null mutant in the presence of HT29-MTX-E12 cells versus HT29 cells. Those effects involved mucus production by HT29-MTX-E12 cells since mucus reduction using N-acetyl cysteine reduced F4969 growth and adherence. Consistent with those in vitro results, NanI contributed to growth of F4969 in the mouse small intestine. By demonstrating a growth and adherence role for NanI in the presence of adherent mucus, these results further support NanI as a potential virulence factor during type F NFDs.
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Affiliation(s)
- Jihong Li
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Mauricio A. Navarro
- California Animal Health and Food Safety Laboratory, School of Veterinary Medicine, University of California Davis, San Bernardino, California, USA
| | - Francisco A. Uzal
- California Animal Health and Food Safety Laboratory, School of Veterinary Medicine, University of California Davis, San Bernardino, California, USA
| | - Bruce A. McClane
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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Ozturk CN, Ozturk C, Sigurdson SL, Magner WJ, Sheedy B, Lohman R, Moon W. Broad-Spectrum Antibiotics for Breast Expander/Implant Infection: Treatment-Related Adverse Events and Outcomes. Ann Plast Surg 2021; 87:396-401. [PMID: 34559710 DOI: 10.1097/sap.0000000000002720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Despite best practices, infection remains the most common complication after breast reconstruction with expanders and implants, ranging from 2% to 29%. Empiric broad-spectrum antibiotics are frequently used in nonsurgical treatment of implant-associated infections in an effort to salvage the reconstruction. Pitfalls of antibiotherapy include adverse events, vascular access site complications, and drug resistance. Our goals were to describe management of implant infections with broad-spectrum antibiotics, review treatment related adverse events, and report on outcomes of therapy. PATIENTS AND METHODS A retrospective review was carried out to identify patients who were treated with intravenous (IV) antibiotics for periprosthetic infection. Patient characteristics, surgical details, and antibiotic therapy-related adverse events were collected. Eventual outcome related to expander/implant salvage was noted. RESULTS A total of 101 patients (111 treatment episodes) were identified. Mean duration of antibiotic treatment was 18 days (range, 1-40 days). The most commonly used parenteral treatment was a combination of daptomycin with piperacillin-tazobactam (65%) or an alternative agent (16%). Fifty-nine percent of treatment episodes resulted in salvage of the expander or implant. Thirty-five percent treatment episodes were associated with 1 or more adverse events: diarrhea (12.6%), rash (10%), vaginal candidiasis (3.6%), agranulocytosis/neutropenic fever (3.6%), nausea (3.6%), urinary complaint (0.9%), myositis (0.9%), headache (0.9%), vascular line occlusion (1.8%), deep vein thrombosis (1.8%), and finger numbness (0.9%). No patients developed Clostridium difficile colitis. Five episodes (4%) needed discontinuation of antibiotics because of severe adverse events. The prosthesis was explanted in 3 of the cases of discontinued treatment. CONCLUSIONS Our findings show favorable outcomes and well-tolerated adverse effects with broad-spectrum parenteral antibiotherapy for periprosthetic infection. However, every effort should be made to deescalate therapy by narrowing the spectrum or limiting the duration, to minimize adverse events and development of bacterial resistance. Treating surgeons need to carefully weigh benefits of therapy and be aware of potential complications that might necessitate discontinuation of treatment.
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Affiliation(s)
- Cemile Nurdan Ozturk
- From the Department of Head, Neck, Plastic and Reconstructive Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY
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Fettucciari K, Marconi P, Marchegiani A, Fruganti A, Spaterna A, Bassotti G. Invisible steps for a global endemy: molecular strategies adopted by Clostridioides difficile. Therap Adv Gastroenterol 2021; 14:17562848211032797. [PMID: 34413901 PMCID: PMC8369858 DOI: 10.1177/17562848211032797] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 06/26/2021] [Indexed: 02/06/2023] Open
Abstract
Clostridioides difficile infection (CDI) is on the rise worldwide and is associated with an increase in deaths and socio-health burden. C. difficile has become ubiquitous in anthropized environments because of the extreme resistance of its spores. Based on the epidemiological data and knowledge of molecular pathogenesis of C. difficile, it is possible to predict its progressive colonization of the human population for the following reasons: first, its global spread is unstoppable; second, the toxins (Tcds) produced by C. difficile, TcdA and TcdB, mainly cause cell death by apoptosis, but the surviving cells acquire a senescence state that favours persistence of C. difficile in the intestine; third, proinflammatory cytokines, tumour necrosis factor-α and interferon-γ, induced during CDI, enhance the cytotoxicity of Tcds and can increase the survival of senescent cells; fourth, Tcds block mobility and induce apoptosis in immune cells recruited at the infection site; and finally, after remission from primary infection or relapse, C. difficile causes functional abnormalities in the enteric glial cell (EGC) network that can result in irritable bowel syndrome, characterized by a latent inflammatory response that contributes to C. difficile survival and enhances the cytotoxic activity of low doses of TcdB, thus favouring further relapses. Since a 'global endemy' of C. difficile seems inevitable, it is necessary to develop an effective vaccine against Tcds for at-risk individuals, and to perform a prophylaxis/selective therapy with bacteriophages highly specific for C. difficile. We must be aware that CDI will become a global health problem in the forthcoming years, and we must be prepared to face this menace.
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Affiliation(s)
- Katia Fettucciari
- Biosciences & Medical Embryology Section, Department of Medicine and Surgery, University of Perugia, Medical School -Piazza Lucio Severi 1, Edificio B - IV piano; Sant’Andrea delle Fratte, Perugia, 06132, Italy
| | - Pierfrancesco Marconi
- Biosciences & Medical Embryology Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Andrea Marchegiani
- School of Biosciences and Veterinary Medicine, University of Camerino, Macerata, Italy
| | - Alessandro Fruganti
- School of Biosciences and Veterinary Medicine, University of Camerino, Macerata, Italy
| | - Andrea Spaterna
- School of Biosciences and Veterinary Medicine, University of Camerino, Macerata, Italy
| | - Gabrio Bassotti
- Gastroenterology, Hepatology & Digestive Endoscopy Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
- Gastroenterology & Hepatology Unit, Santa Maria della Misericordia Hospital, Perugia, Italy
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Influence of Fluconazole Administration on Gut Microbiome, Intestinal Barrier, and Immune Response in Mice. Antimicrob Agents Chemother 2021; 65:AAC.02552-20. [PMID: 33722893 DOI: 10.1128/aac.02552-20] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 03/06/2021] [Indexed: 12/26/2022] Open
Abstract
Antibiotics that can treat or prevent infectious diseases play an important role in medical therapy. However, the use of antibiotics has potentially negative effects on the health of the host. For example, antibiotics use may affect the host's immune system by altering the gut microbiota. Therefore, the aim of the study was to investigate the influence of antifungal (fluconazole) treatment on the gut microbiota and immune system of mice. Results showed that the gut microbial composition of mice receiving fluconazole treatment was significantly changed after the trial. Fluconazole did not affect the relative abundance of bacteria but significantly reduced the diversity of bacterial flora. In the bacteriome, Firmicutes and Proteobacteria significantly increased, while Bacteroidetes, Deferribacteres, Patescibacteria, and Tenericutes showed a remarkable reduction in the fluconazole-treated group compared with the control group. In the mycobiome, the relative abundance of Ascomycota was significantly decreased and Mucoromycota was significantly increased in the intestine of mice treated with fluconazole compared to the control group. Reverse transcription-quantitative PCR (RT-qPCR) results showed that the relative gene expression of ZO-1, occludin, MyD88, interleukin-1β (IL-1β), and IL-6 was decreased in the fluconazole-treated group compared to the control. Serum levels of IL-2, LZM, and IgM were significantly increased, while the IgG level was considerably downregulated in the fluconazole-treated compared to the control group. These results suggest that the administration of fluconazole can influence the gut microbiota and that a healthy gut microbiome is important for the regulation of the host immune responses.
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Healthcare associated diarrhea, not Clostridioides difficile. Curr Opin Infect Dis 2021; 33:319-326. [PMID: 32657969 DOI: 10.1097/qco.0000000000000653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
PURPOSE OF REVIEW The aim of this article is to review the epidemiology, cause, diagnostic evaluation, and management of healthcare-associated diarrhea (HCAD) with particular attention to current epidemiology and recent developments in diagnostics. RECENT FINDINGS Multiplex polymerase chain reaction gastrointestinal panels allow rapid detection of a wide array of potential enteropathogens but the role, yield, and utility of these tests have not been systematically assessed in patients with HCAD. Recent epidemiologic studies reaffirm that HCAD is predominantly a noninfectious condition most often caused by medications or underlying medical conditions, sometimes Clostridioides difficile, and occasionally viruses. Other infections are rare. SUMMARY Clinical assessment remains fundamental to the evaluation of HCAD and targeted testing for C. difficile is sufficient in most patients. Multiplex gastrointestinal panels may have a role in immunocompromised patients but more study is needed. Medication-induced diarrhea is common and underappreciated and not limited to antibiotics, laxatives, and enemas.
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Verburg I, van Veelen HPJ, Waar K, Rossen JWA, Friedrich AW, Hernández Leal L, García-Cobos S, Schmitt H. Effects of Clinical Wastewater on the Bacterial Community Structure from Sewage to the Environment. Microorganisms 2021; 9:718. [PMID: 33807193 PMCID: PMC8065902 DOI: 10.3390/microorganisms9040718] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 03/21/2021] [Accepted: 03/26/2021] [Indexed: 12/30/2022] Open
Abstract
This study pertains to measure differences in bacterial communities along the wastewater pathway, from sewage sources through the environment. Our main focus was on taxa which include pathogenic genera, and genera harboring antibiotic resistance (henceforth referred to as "target taxa"). Our objective was to measure the relative abundance of these taxa in clinical wastewaters compared to non-clinical wastewaters, and to investigate what changes can be detected along the wastewater pathway. The study entailed a monthly sampling campaign along a wastewater pathway, and taxa identification through 16S rRNA amplicon sequencing. Results indicated that clinical and non-clinical wastewaters differed in their overall bacterial composition, but that target taxa were not enriched in clinical wastewater. This suggests that treatment of clinical wastewater before release into the wastewater system would only remove a minor part of the potential total pathogen load in wastewater treatment plants. Additional findings were that the relative abundance of most target taxa was decreased after wastewater treatment, yet all investigated taxa were detected in 68% of the treated effluent samples-meaning that these bacteria are continuously released into the receiving surface water. Temporal variation was only observed for specific taxa in surface water, but not in wastewater samples.
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Affiliation(s)
- Ilse Verburg
- Wetsus, European Centre of Excellence for Sustainable Water Technology, 8900 CC Leeuwarden, The Netherlands; (I.V.); (H.P.J.v.V.); (L.H.L.)
- Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (J.W.A.R.); (A.W.F.); (S.G.-C.)
| | - H. Pieter J. van Veelen
- Wetsus, European Centre of Excellence for Sustainable Water Technology, 8900 CC Leeuwarden, The Netherlands; (I.V.); (H.P.J.v.V.); (L.H.L.)
| | - Karola Waar
- Izore, Centrum Infectieziekten Friesland, 8900 JA Leeuwarden, The Netherlands;
| | - John W. A. Rossen
- Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (J.W.A.R.); (A.W.F.); (S.G.-C.)
| | - Alex W. Friedrich
- Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (J.W.A.R.); (A.W.F.); (S.G.-C.)
| | - Lucia Hernández Leal
- Wetsus, European Centre of Excellence for Sustainable Water Technology, 8900 CC Leeuwarden, The Netherlands; (I.V.); (H.P.J.v.V.); (L.H.L.)
| | - Silvia García-Cobos
- Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (J.W.A.R.); (A.W.F.); (S.G.-C.)
| | - Heike Schmitt
- Wetsus, European Centre of Excellence for Sustainable Water Technology, 8900 CC Leeuwarden, The Netherlands; (I.V.); (H.P.J.v.V.); (L.H.L.)
- Institute for Risk Assessment Sciences, Utrecht University, 3508 TD Utrecht, The Netherlands
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), 3721 MA Bilthoven, The Netherlands
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Household food sources and diarrhoea incidence in poor urban communities, Accra Ghana. PLoS One 2021; 16:e0245466. [PMID: 33508014 PMCID: PMC7842991 DOI: 10.1371/journal.pone.0245466] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 01/02/2021] [Indexed: 01/05/2023] Open
Abstract
Diarrhoeal diseases remain a significant cause of morbidity and mortality, particularly in poor urban communities in the Global South. Studies on food access and safety have however not considered the sources of discrete food categories and their propensity to harbour and transmit diarrhoeal disease pathogens in poor urban settings. We sought to contribute to knowledge on urban food environment and enteric infections by interrogating the sources and categories of common foods and their tendency to transmit diarrhoea in low-income communities in Accra. We modelled the likelihood of diarrhoea transmission through specific food categories sourced from home or out of home after controlling for alternate transmission pathways and barriers. We used structured interviews where households that participated in the study were selected through a multi-stage systematic sampling approach. We utilized data on 506 households from 3 low-income settlements in Accra. These settlements have socio-economic characteristics mimicking typical low-income communities in the Global South. The results showed that the incidence of diarrhoea in a household is explained by type and source of food, source of drinking water, wealth and the presence of children below five years in the household. Rice-based staples which were consumed by 94.5% of respondents in the week preceding the survey had a higher likelihood of transmitting diarrhoeal diseases when consumed out of home than when eaten at home. Sources of hand-served dumpling-type foods categorized as "staple balls" had a nuanced relationship with incidence of diarrhoea. These findings reinforce the need for due diligence in addressing peculiar needs of people in vulnerable conditions of food environment in poor urban settlements in order to reap a co-benefit of reduced incidence of diarrhoea while striving to achieve the global development goal on ending hunger.
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Duan H, Yu L, Tian F, Zhai Q, Fan L, Chen W. Antibiotic-induced gut dysbiosis and barrier disruption and the potential protective strategies. Crit Rev Food Sci Nutr 2020; 62:1427-1452. [PMID: 33198506 DOI: 10.1080/10408398.2020.1843396] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The oral antibiotic therapies administered widely to people and animals can cause gut dysbiosis and barrier disruption inevitably. Increasing attention has been directed toward antibiotic-induced gut dysbiosis, which involves a loss of diversity, changes in the abundances of certain taxa and consequent effects on their metabolic capacity, and the spread of antibiotic-resistant bacterial strains. Treatment with beta-lactam, glycopeptide, and macrolide antibiotics is associated with the depletion of beneficial commensal bacteria in the genera Bifidobacterium and Lactobacillus. The gut microbiota is a reservoir for antibiotic resistance genes, the prevalence of which increases sharply after antibiotic ingestion. The intestinal barrier, which comprises secretory, physical, and immunological barriers, is also a target of antibiotics. Antibiotic induced changes in the gut microbiota composition could induce weakening of the gut barrier through changes in mucin, cytokine, and antimicrobial peptide production by intestinal epithelial cells. Reports have indicated that dietary interventions involving prebiotics, probiotics, omega-3 fatty acids, and butyrate supplementation, as well as fecal microbiota transplantation, can alleviate antibiotic-induced gut dysbiosis and barrier injuries. This review summarizes the characteristics of antibiotic-associated gut dysbiosis and barrier disruption, as well as the strategies for alleviating this condition. This information is intended to provide a foundation for the exploration of safer, more efficient, and affordable strategies to prevent or relieve antibiotic-induced gut injuries.
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Affiliation(s)
- Hui Duan
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, Jiangsu, China
| | - Leilei Yu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Research Laboratory for Probiotics at, Jiangnan University, Wuxi, Jiangsu, China
| | - Fengwei Tian
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Research Laboratory for Probiotics at, Jiangnan University, Wuxi, Jiangsu, China
| | - Qixiao Zhai
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Research Laboratory for Probiotics at, Jiangnan University, Wuxi, Jiangsu, China
| | - Liuping Fan
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Research Laboratory for Probiotics at, Jiangnan University, Wuxi, Jiangsu, China
| | - Wei Chen
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Research Laboratory for Probiotics at, Jiangnan University, Wuxi, Jiangsu, China
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Shao H, Zhang C, Xiao N, Tan Z. Gut microbiota characteristics in mice with antibiotic-associated diarrhea. BMC Microbiol 2020; 20:313. [PMID: 33059603 PMCID: PMC7559773 DOI: 10.1186/s12866-020-01999-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 10/07/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Antibiotic-associated diarrhea (AAD), defined as diarrhea that occurs in association with the administration of antibiotics and without another clear etiology, is one of the most common adverse drug events of antibiotics therapy. We established a diarrhea model induced by gentamycin and cefradine to investigate the microbiota characteristics in the intestinal lumen of mice with AAD and provide insights into noteworthy bacteria related to gentamicin and cefradine-associated diarrhea. RESULTS The number of OTUs in the model group and the normal group was 983 and 2107, respectively, and 872 identical OTUs were shared between two groups. Species richness and species diversity of intestinal microbe were altered by antibiotics administration. PCoA showed a clear separation between AAD and health control. The dominant phyla of AAD mice were Firmicutes (52.63%) and Proteobacteria (46.37%). Among the genus with top 20 abundance, the relative abundance of 7 genera, Ruminococcus, Blautia, Enterococcus, Eubacterium, Clostridium, Coprococcus, and Aerococcus, were enriched in the model group. Based upon the LEfSe analysis, Enterococcus, Eubacterium, Ruminococcus, and Blautia were identified as potential biomarkers for AAD. CONCLUSIONS The bacterial diversity of the intestinal lumen was diminished after gentamicin and cefradine administration. The alterations in the abundance and composition of gut microbiota further led to the dysfunction of gut microbiota. More specifically, gentamicin and cefradine significantly increased the abundance of the opportunistic pathogens, of which Enterococcus and Clostridium were the most prominent and most worthy of attention.
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Affiliation(s)
- Haoqing Shao
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China.,Hunan Key Laboratory of TCM Prescription and Syndromes Translational Medicine, Changsha, Hunan, China
| | - Chenyang Zhang
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China.,Hunan Key Laboratory of TCM Prescription and Syndromes Translational Medicine, Changsha, Hunan, China
| | - Nenqun Xiao
- School of Pharmaceutical Science, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Zhoujin Tan
- Hunan Key Laboratory of TCM Prescription and Syndromes Translational Medicine, Changsha, Hunan, China. .,School of Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China.
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Li J, Oh J, Kienesberger S, Kim NY, Clarke DJ, Zechner EL, Crawford JM. Making and Breaking Leupeptin Protease Inhibitors in Pathogenic Gammaproteobacteria. Angew Chem Int Ed Engl 2020. [DOI: 10.1002/ange.202005506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Jhe‐Hao Li
- Department of Chemistry Yale University New Haven CT 06520 USA
- Chemical Biology Institute Yale University West Haven CT 06516 USA
| | - Joonseok Oh
- Department of Chemistry Yale University New Haven CT 06520 USA
- Chemical Biology Institute Yale University West Haven CT 06516 USA
| | | | - Nam Yoon Kim
- Department of Chemistry Yale University New Haven CT 06520 USA
- Chemical Biology Institute Yale University West Haven CT 06516 USA
| | - David J. Clarke
- School of Microbiology and APC Microbiome Ireland University College Cork Cork Ireland
| | - Ellen L. Zechner
- Institute of Molecular Biosciences University of Graz 8010 Graz Austria
- BioTechMed-Graz 8010 Graz Austria
| | - Jason M. Crawford
- Department of Chemistry Yale University New Haven CT 06520 USA
- Chemical Biology Institute Yale University West Haven CT 06516 USA
- Department of Microbial Pathogenesis Yale University School of Medicine New Haven CT 06536 USA
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The role of the globular heads of the C1q receptor in TcdA-induced human colonic epithelial cell apoptosis via a mitochondria-dependent pathway. BMC Microbiol 2020; 20:274. [PMID: 32878596 PMCID: PMC7465811 DOI: 10.1186/s12866-020-01958-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 08/25/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Clostridioides (formerly Clostridium) difficile infection is the leading cause of antibiotic-associated colitis. Studies have demonstrated that C. difficile toxin A (TcdA) can cause apoptosis of many human cell types. The purpose of this study was to investigate the relationships among exposure to TcdA, the role of the receptor for the globular heads of C1q (gC1qR) gene and the underlying intracellular apoptotic mechanism in human colonic epithelial cells (NCM 460). In this study, gC1qR expression was examined using real-time polymerase chain reaction (PCR), western blotting and immunohistochemical staining. Cell viability was assessed by the water-soluble tetrazolium salt (WST-1) assay, and cell apoptosis was assessed by flow cytometry and the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay. Mitochondrial function was assessed based on reactive oxygen species (ROS) generation, changes in the mitochondrial membrane potential (ΔΨm) and the content of ATP. RESULTS Our study demonstrated that increasing the concentration of TcdA from 10 ng/ml to 20 ng/ml inhibited cell viability and induced cell apoptosis (p < 0.01). Moreover, the TcdA-induced gC1qR expression and enhanced expression of gC1qR caused mitochondrial dysfunction (including production of ROS and decreases in the ΔΨm and the content of ATP) and cell apoptosis. However, silencing of the gC1qR gene reversed TcdA-induced cell apoptosis and mitochondrial dysfunction. CONCLUSION These data support a mechanism by which gC1qR plays a crucial role in TcdA-induced apoptosis of human colonic epithelial cells in a mitochondria-dependent manner.
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Cheng R, Liang H, Zhang Y, Guo J, Miao Z, Shen X, Chen G, Cheng G, Li M, He F. Contributions of Lactobacillus plantarum PC170 administration on the recovery of gut microbiota after short-term ceftriaxone exposure in mice. Benef Microbes 2020; 11:489-509. [PMID: 32811176 DOI: 10.3920/bm2019.0191] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
This study aimed to determine the impact of Lactobacillus plantarum PC170 concurrent with antibiotic treatment and/or during the recovery phase after antibiotic treatment on the body weight, faecal bacterial composition, short-chain fatty acids (SCFAs) concentration, and splenic cytokine mRNA expression of mice. Orally administrated ceftriaxone quantitatively and significantly decreased body weight, faecal total bacteria, Akkermansia muciniphila, and Lactobacillus plantarum, and faecal SCFAs concentration. Ceftriaxone treatment also dramatically altered the faecal microbiota with an increased Chao1 index, decreased species diversities and Bacteroidetes, and more Firmicutes and Proteobacteria. After ceftriaxone intervention, these changes all gradually started to recover. However, faecal microbiota diversities were still totally different from control by significantly increased α- and β-diversities. Bacteroidetes all flourished and became dominant during the recovery process. However, mice treated with PC170 both in parallel with and after ceftriaxone treatment encouraged more Bacteroidetes, Verrucomicrobia, and Actinobacteria, and the diversity by which to make faecal microbiota was very much closer to control. Furthermore, the expression of splenic pro-inflammatory cytokine tumour necrosis factor-α mRNA in mice supplemented with PC170 during the recovery phase was significantly lower than natural recovery. These results indicated that antibiotics, such as ceftriaxone, even with short-term intervention, could dramatically damage the structure of gut microbiota and their abilities to produce SCFAs with loss of body weight. Although such damages could be partly recovered with the cessation of antibiotics, the implication of antibiotics to gut microbiota might remain even after antibiotic treatment. The selected strain PC170 might be a potential probiotic because of its contributions in helping the host animal to remodel or stabilise its gut microbiome and enhancing the anti-inflammatory response as protection from the side effects of antibiotic therapy when it was administered in parallel with and after antibiotic treatment.
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Affiliation(s)
- R Cheng
- Department of Nutrition, Food Hygiene and Toxicology, West China School of Public Health and West China Fourth Hospital, and Healthy Food Evaluation Research Center, Sichuan University, No. 16, 3rd section, South Renmin Road, Chengdu 610041, Sichuan, China P.R
| | - H Liang
- Department of Nutrition, Food Hygiene and Toxicology, West China School of Public Health and West China Fourth Hospital, and Healthy Food Evaluation Research Center, Sichuan University, No. 16, 3rd section, South Renmin Road, Chengdu 610041, Sichuan, China P.R
| | - Y Zhang
- Department of Nutrition, Food Hygiene and Toxicology, West China School of Public Health and West China Fourth Hospital, and Healthy Food Evaluation Research Center, Sichuan University, No. 16, 3rd section, South Renmin Road, Chengdu 610041, Sichuan, China P.R
| | - J Guo
- Department of Nutrition, Food Hygiene and Toxicology, West China School of Public Health and West China Fourth Hospital, and Healthy Food Evaluation Research Center, Sichuan University, No. 16, 3rd section, South Renmin Road, Chengdu 610041, Sichuan, China P.R
| | - Z Miao
- Department of Nutrition, Food Hygiene and Toxicology, West China School of Public Health and West China Fourth Hospital, and Healthy Food Evaluation Research Center, Sichuan University, No. 16, 3rd section, South Renmin Road, Chengdu 610041, Sichuan, China P.R
| | - X Shen
- Department of Nutrition, Food Hygiene and Toxicology, West China School of Public Health and West China Fourth Hospital, and Healthy Food Evaluation Research Center, Sichuan University, No. 16, 3rd section, South Renmin Road, Chengdu 610041, Sichuan, China P.R
| | - G Chen
- Sichuan Academy of Food and Fermentation Industries, Chengdu 610041, Sichuan, China P.R
| | - G Cheng
- Department of Nutrition, Food Hygiene and Toxicology, West China School of Public Health and West China Fourth Hospital, and Healthy Food Evaluation Research Center, Sichuan University, No. 16, 3rd section, South Renmin Road, Chengdu 610041, Sichuan, China P.R
| | - M Li
- Department of Nutrition, Food Hygiene and Toxicology, West China School of Public Health and West China Fourth Hospital, and Healthy Food Evaluation Research Center, Sichuan University, No. 16, 3rd section, South Renmin Road, Chengdu 610041, Sichuan, China P.R
| | - F He
- Department of Nutrition, Food Hygiene and Toxicology, West China School of Public Health and West China Fourth Hospital, and Healthy Food Evaluation Research Center, Sichuan University, No. 16, 3rd section, South Renmin Road, Chengdu 610041, Sichuan, China P.R
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48
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Li JH, Oh J, Kienesberger S, Kim NY, Clarke DJ, Zechner EL, Crawford JM. Making and Breaking Leupeptin Protease Inhibitors in Pathogenic Gammaproteobacteria. Angew Chem Int Ed Engl 2020; 59:17872-17880. [PMID: 32609431 DOI: 10.1002/anie.202005506] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 06/29/2020] [Indexed: 12/12/2022]
Abstract
Leupeptin is a bacterial small molecule that is used worldwide as a protease inhibitor. However, its biosynthesis and genetic distribution remain unknown. We identified a family of leupeptins in gammaproteobacterial pathogens, including Photorhabdus, Xenorhabdus, and Klebsiella species, amongst others. Through genetic, metabolomic, and heterologous expression analyses, we established their construction by discretely expressed ligases and accessory enzymes. In Photorhabdus species, a hypothetical protein required for colonizing nematode hosts was established as a new class of proteases. This enzyme cleaved the tripeptide aldehyde protease inhibitors, leading to the formation of "pro-pyrazinones" featuring a hetero-tricyclic architecture. In Klebsiella oxytoca, the pathway was enriched in clinical isolates associated with respiratory tract infections. Thus, the bacterial production and proteolytic degradation of leupeptins can be associated with animal colonization phenotypes.
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Affiliation(s)
- Jhe-Hao Li
- Department of Chemistry, Yale University, New Haven, CT, 06520, USA.,Chemical Biology Institute, Yale University, West Haven, CT, 06516, USA
| | - Joonseok Oh
- Department of Chemistry, Yale University, New Haven, CT, 06520, USA.,Chemical Biology Institute, Yale University, West Haven, CT, 06516, USA
| | | | - Nam Yoon Kim
- Department of Chemistry, Yale University, New Haven, CT, 06520, USA.,Chemical Biology Institute, Yale University, West Haven, CT, 06516, USA
| | - David J Clarke
- School of Microbiology and APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Ellen L Zechner
- Institute of Molecular Biosciences, University of Graz, 8010, Graz, Austria.,BioTechMed-Graz, 8010, Graz, Austria
| | - Jason M Crawford
- Department of Chemistry, Yale University, New Haven, CT, 06520, USA.,Chemical Biology Institute, Yale University, West Haven, CT, 06516, USA.,Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, 06536, USA
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49
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Yang J, Yang H. Transcriptome Analysis of the Clostridioides difficile Response to Different Doses of Bifidobacterium breve. Front Microbiol 2020; 11:1863. [PMID: 32849451 PMCID: PMC7411088 DOI: 10.3389/fmicb.2020.01863] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 07/15/2020] [Indexed: 12/17/2022] Open
Abstract
Probiotics are widely used in the prevention of Clostridioides difficile infection (CDI). The precise dosage of probiotics is a challenge. In this study, Clostridioides difficile ATCC 9689 (CD) was exposed to different doses of Bifidobacterium breve (YH68). A transcriptomic analysis was performed on CD cells that were separately exposed to low or high doses of YH68 cell-free culture supernatant (CFCS; CDL; or CDH, respectively). The results showed that the inhibitory effect of YH68 (cell pellets or CFCS) on the growth and the damage to the cell membrane integrity of CD exhibited a dose-response relationship at the physiological level. At the transcriptional level, a large number of differentially expressed genes (DEGs) were concentrated in amino acid, carbohydrate, energy metabolism and membrane transport in CDL and CDH cells, suggesting that both doses of YH68-CFCS triggered a significant change in activities in these metabolic pathways. Importantly, a significant stimulation or suppression was found in the pathogenic pathways (quorum sensing, signal transduction, flagellar assembly, biofilm formation, and drug resistance) of CDL and CDH cells, whereas there were some differences between the two doses. For example, the expression levels of genes related to quorum sensing and signal transduction in CDH cells were suppressed significantly, whereas genes encoding toxin production and sporulation factors were enhanced; in CDL cells, the expression levels of genes associated with flagellar assembly and biofilm formation were suppressed, whereas genes associated with drug resistance were upregulated significantly. These results indicated that the inhibitory effect of YH68-CFCS against CD, especially in pathogenic and metabolic aspects, did not demonstrate a dose-response relationship at the transcriptional level.
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Affiliation(s)
- Jingpeng Yang
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Hong Yang
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
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50
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Mekonnen SA, Merenstein D, Fraser CM, Marco ML. Molecular mechanisms of probiotic prevention of antibiotic-associated diarrhea. Curr Opin Biotechnol 2020; 61:226-234. [PMID: 32087535 DOI: 10.1016/j.copbio.2020.01.005] [Citation(s) in RCA: 105] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 01/10/2020] [Accepted: 01/13/2020] [Indexed: 02/08/2023]
Abstract
Antibiotic-associated diarrhea (AAD) is a common and unintended adverse effect of antibiotic treatment. It is characterized by the disruption of the gut microbiota, decreased intestinal short chain fatty acid (SCFA) concentrations, accumulation of luminal carbohydrates and colonic bile acids, altered water absorption, and ultimately diarrhea. Probiotics were shown to prevent AAD in numerous clinical trials. This review examines what is currently known about how probiotics reduce the risk for AAD via modulating the gut microbiota, altering nutrient and bile acid metabolism, inducing epithelial solute transporter activity, supporting intestinal barrier function, and influencing the immune system. Although probiotics are frequently prescribed with antibiotic use, mechanistic evidence verifying how they confer protection against AAD is extremely limited. This information is urgently needed for improving recommendations for sustaining probiotic development and for implementing probiotics in clinical settings.
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Affiliation(s)
- Solomon A Mekonnen
- Department of Food Science and Technology, University of California, Davis, CA, USA
| | - Daniel Merenstein
- Department of Family Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Claire M Fraser
- Department of Medicine, Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Maria L Marco
- Department of Food Science and Technology, University of California, Davis, CA, USA.
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