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Marsico AL, da Silva-Tomaeli SC, Marques PSB, Feres O, Lopes LS, Sbragia L. Hyperbaric oxygen therapy alleviates intestinal and brain damage in experimental necrotizing enterocolitis. Med Gas Res 2025; 15:471-477. [PMID: 40300882 DOI: 10.4103/mgr.medgasres-d-24-00108] [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: 10/24/2024] [Accepted: 01/17/2025] [Indexed: 05/01/2025] Open
Abstract
Necrotizing enterocolitis is the most common gastrointestinal emergency in newborns. Its etiology involves bacterial colonization, enteral formula feeding, and hypoxic-ischemic injury. The pathology of necrotizing enterocolitis is characterized by coagulation necrosis and bacterial overgrowth, with limited preventative methods available. In addition to affecting the intestine, this disease has long-term neurological consequences for survivors. Hyperbaric oxygen therapy, a well-established treatment for soft tissue infections and injuries caused by hypoperfusion, may serve as an alternative approach for necrotizing enterocolitis. In this study, a necrotizing enterocolitis model was developed in newborn Sprague-Dawley rat pups through the administration of a hyperosmolar formula, combined with exposure to hypothermia and hypoxia. The rat pups received hyperbaric oxygen therapy sessions at 3 absolute atmospheres for 2 hours each, which were administered over 1 or 2 days. The results demonstrated that hyperbaric oxygen therapy significantly reduced mortality in rats with necrotizing enterocolitis and preserved the number of brain cells in the hippocampus. Additionally, hyperbaric oxygen therapy increased the expression of nitric oxide synthase, intestinal fatty acid-binding protein, and superoxide dismutase 3 in the intestine, and elevated superoxide dismutase 3 levels in the hippocampus. These findings suggest that hyperbaric oxygen therapy not only reduces mortality but also mitigates the severity of intestinal and brain lesions in experimental necrotizing enterocolitis, preserving intestinal cell integrity and enhancing antioxidant mechanisms.
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Affiliation(s)
- Ana Laura Marsico
- Division of Pediatric Surgery, Department of Surgery and Anatomy, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirão Preto, SP, Brazil
| | - Stephanya C da Silva-Tomaeli
- Division of Anatomy, Department of Morphology and Pathology, Federal University of Sao Carlos, Sao Carlos, SP, Brazil
| | - Pamella S B Marques
- Division of Neuroanatomy, Department of Surgery and Anatomy, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirão Preto, SP, Brazil
| | - Omar Feres
- Division of Coloproctology, Department of Surgery and Anatomy, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirão Preto, SP, Brazil
| | - Luiza S Lopes
- Division of Neuroanatomy, Department of Surgery and Anatomy, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirão Preto, SP, Brazil
| | - Lourenco Sbragia
- Division of Pediatric Surgery, Department of Surgery and Anatomy, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirão Preto, SP, Brazil
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Zhang D, Xie D, Qu Y, Mu D, Wang S. Digging deeper into necrotizing enterocolitis: bridging clinical, microbial, and molecular perspectives. Gut Microbes 2025; 17:2451071. [PMID: 39826099 DOI: 10.1080/19490976.2025.2451071] [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: 10/04/2024] [Revised: 12/26/2024] [Accepted: 01/02/2025] [Indexed: 01/20/2025] Open
Abstract
Necrotizing Enterocolitis (NEC) is a severe, life-threatening inflammatory condition of the gastrointestinal tract, especially affecting preterm infants. This review consolidates evidence from various biomedical disciplines to elucidate the complex pathogenesis of NEC, integrating insights from clinical, microbial, and molecular perspectives. It emphasizes the modulation of NEC-associated inflammatory pathways by probiotics and novel biologics, highlighting their therapeutic potential. We further critically examine dysbiotic alterations within the gut microbiota, with a particular focus on imbalances in bacterial and viral communities, which may contribute to the onset of NEC. The intricate interactions among toll-like receptor 4 (TLR4), microvascular integrity, immune activation, and the inflammatory milieu are meticulously summarized, offering a sophisticated understanding of NEC pathophysiology. This academic review aims to enhance the etiological comprehension of NEC, promote the development of targeted therapeutic interventions, and impart the significant impact of perinatal factors on the formulation of preventive and curative strategies for the disease.
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Affiliation(s)
- Deshuang Zhang
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, China
- Division of Neonatology/Pediatric Surgery, Department of Pediatrics, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Dongke Xie
- Division of Neonatology/Pediatric Surgery, Department of Pediatrics, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yi Qu
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, China
| | - Dezhi Mu
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, China
| | - Shaopu Wang
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu, China
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Morrissey T, Taverner F, Sawyer A, Strupp K. Common error traps in anesthesia for neonatal surgical emergencies. Paediatr Anaesth 2025; 35:6-16. [PMID: 39503266 DOI: 10.1111/pan.15029] [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: 08/30/2024] [Revised: 10/22/2024] [Accepted: 10/24/2024] [Indexed: 11/08/2024]
Abstract
Neonatal surgical emergencies are challenging, often high-risk procedures for the pediatric anesthesiologist. Though each emergency presents different anesthetic challenges, several error traps exist that are common to all procedures in this patient population. These error traps include errors in surgical timing, airway management, maintenance of normothermia and normoglycemia, and recognition of pharmacologic and physiologic differences. In this narrative review, we will discuss each error trap to aid the clinician in recognizing, planning for, and mitigating adverse events.
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Affiliation(s)
- Tyler Morrissey
- Department of Anesthesiology, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado, USA
| | - Fiona Taverner
- College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
- Department of Anaesthesia and Pain Medicine, Flinders Medical Centre, Adelaide, South Australia, Australia
| | - Anthony Sawyer
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, California, USA
| | - Kim Strupp
- Department of Anesthesiology, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado, USA
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Sbragia L, Gualberto IJN, Xia J, Gadde R, Saulsbery A, Hameedi S, Mársico Dalto ALF, Olutoye OO. Intestinal Fatty Acid-binding Protein as a Marker of Necrotizing Enterocolitis Incidence and Severity: a Scoping Review. J Surg Res 2024; 303:613-627. [PMID: 39437600 DOI: 10.1016/j.jss.2024.09.059] [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: 07/11/2024] [Revised: 08/26/2024] [Accepted: 09/16/2024] [Indexed: 10/25/2024]
Abstract
INTRODUCTION Necrotizing enterocolitis (NEC) is a severe inflammatory disease of the gastrointestinal tract and one of the most common life-threatening emergencies affecting newborns. Intestinal fatty acid-binding protein (I-FABP) has been used as a possible marker of intestinal damage in NEC. We aimed to carry out a scoping review of all publications that explore the role of I-FABP in NEC to inspire new research into the potential utility of I-FABP as a marker of NEC. METHODS We searched for relevant publications using the keywords "necrotizing enterocolitis," "intestinal fatty acid binding protein," "NEC," and "I-FABP" in the National Library of Medicine (PubMed/MEDLINE), Embase, SCOPUS, and Web of Science. Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews was used for reporting findings. RESULTS We identified 61 relevant articles, which we divided into clinical (n = 47) and experimental (n = 14) groups. CONCLUSIONS I-FABP is a promising marker of NEC, especially for NEC stage 2 and 3. Urinary I-FABP follows the same patterns as serum and plasma I-FABP. The definitive roles of I-FABP in early diagnosis of NEC, differential diagnosis in breast feeding, alimentary intolerance, and screening of surgical NEC need clarification and remain a challenge to investigators.
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Affiliation(s)
- Lourenço Sbragia
- Division of Pediatric Surgery, Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Sao Paulo, Brazil; Center for Regenerative Medicine, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio, Division of Pediatric Surgery, Department of Surgery, The Ohio State University College of Medicine, Columbus, Ohio
| | - Igor José Nogueira Gualberto
- Division of Pediatric Surgery, Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Sao Paulo, Brazil
| | - Jason Xia
- Center for Regenerative Medicine, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio, Division of Pediatric Surgery, Department of Surgery, The Ohio State University College of Medicine, Columbus, Ohio
| | - Rahul Gadde
- Center for Regenerative Medicine, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio, Division of Pediatric Surgery, Department of Surgery, The Ohio State University College of Medicine, Columbus, Ohio
| | - Angela Saulsbery
- Center for Regenerative Medicine, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio, Division of Pediatric Surgery, Department of Surgery, The Ohio State University College of Medicine, Columbus, Ohio
| | - Sophia Hameedi
- Center for Regenerative Medicine, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio, Division of Pediatric Surgery, Department of Surgery, The Ohio State University College of Medicine, Columbus, Ohio
| | - Ana Laura Ferreira Mársico Dalto
- Division of Pediatric Surgery, Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Sao Paulo, Brazil
| | - Oluyinka O Olutoye
- Center for Regenerative Medicine, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio, Division of Pediatric Surgery, Department of Surgery, The Ohio State University College of Medicine, Columbus, Ohio.
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Wang Y, Cheng T, Cui Y, Qu D, Peng X, Yang L, Xiao X. Associations between gut microbiota and adverse neurodevelopmental outcomes in preterm infants: a two-sample Mendelian randomization study. Front Neurosci 2024; 18:1344125. [PMID: 38419663 PMCID: PMC10899413 DOI: 10.3389/fnins.2024.1344125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Accepted: 02/05/2024] [Indexed: 03/02/2024] Open
Abstract
Gut microbiota are associated with adverse neurodevelopmental outcomes in preterm infants; however, the precise causal relationship remains unclear. In this study, we conducted a two-sample Mendelian randomization (MR) analysis to comprehensively study the relationship between gut microbiota and adverse neurodevelopmental outcomes in preterm infants and identify specific causal bacteria that may be associated with the occurrence and development of adverse neurodevelopmental outcomes in preterm infants. The genome-wide association analysis (GWAS) of the MiBioGen biogroup was used as the exposure data. The GWAS of six common adverse neurodevelopmental outcomes in premature infants from the FinnGen consortium R9 was used as the outcome data. Genetic variations, namely, single nucleotide polymorphisms (SNPs) below the locus-wide significance level (1 × 10-5) and genome-wide statistical significance threshold (5 × 10-8) were selected as instrumental variables (IVs). MR studies use inverse variance weighting (IVW) as the main method. To supplement this, we also applied three additional MR methods: MR-Egger, weighted median, and weighted mode. In addition, the Cochrane's Q test, MR-Egger intercept test, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO), and leave-one-out methods were used for sensitivity analysis. Our study shows a causal relationship between specific gut microbiota and neurodevelopmental outcomes in preterm infants. These findings provide new insights into the mechanism by which gut microbiota may mediate adverse neurodevelopmental outcomes in preterm infants.
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Affiliation(s)
- Yuqian Wang
- Department of Graduate, Dalian Medical University, Dalian, Liaoning, China
- Department of Pediatrics, The Second Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Tongfei Cheng
- Department of Pediatrics, The Affiliated Women’s and Children’s Hospital of Qingdao University, Qingdao, Shandong, China
| | - Yifan Cui
- Department of Pediatrics, Dalian Women and Children’s Medical Group, Dalian, Liaoning, China
| | - Danyang Qu
- Department of Pediatrics, The Second Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Xin Peng
- Department of Pediatrics, The Second Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Liu Yang
- Department of Pediatrics, The Second Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Xuwu Xiao
- Department of Graduate, Dalian Medical University, Dalian, Liaoning, China
- Department of Pediatrics, Dalian Women and Children’s Medical Group, Dalian, Liaoning, China
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Hung CC, Chao YP, Lee Y, Huang CW, Huang SH, Chang CC, Cheng CH. Cingulate white matter mediates the effects of fecal Ruminococcus on neuropsychiatric symptoms in patients with amyloid-positive amnestic mild cognitive impairment. BMC Geriatr 2023; 23:720. [PMID: 37936084 PMCID: PMC10631051 DOI: 10.1186/s12877-023-04417-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 10/18/2023] [Indexed: 11/09/2023] Open
Abstract
BACKGROUND Microbiota-gut-brain axis interacts with one another to regulate brain functions. However, whether the impacts of gut dysbiosis on limbic white matter (WM) tracts contribute to the neuropsychiatric symptoms (NPS) in patients with amyloid-positive amnestic mild cognitive impairment (aMCI+), have not been explored yet. This study aimed to investigate the mediation effects of limbic WM integrity on the association between gut microbiota and NPS in patients with aMCI+. METHODS Twenty patients with aMCI + and 20 healthy controls (HCs) were enrolled. All subjects underwent neuropsychological assessments and their microbial compositions were characterized using 16S rRNA Miseq sequencing technique. Amyloid deposition inspected by positron emission tomography imaging and limbic WM tracts (i.e., fornix, cingulum, and uncinate fasciculus) detected by diffusion tensor imaging were additionally measured in patients with aMCI+. We employed a regression-based mediation analysis using Hayes's PROCESS macro in this study. RESULTS The relative abundance of genera Ruminococcus and Lactococcus was significantly decreased in patients with aMCI + versus HCs. The relative abundance of Ruminococcus was negatively correlated with affective symptom cluster in the aMCI + group. Notably, this association was mediated by WM integrity of the left cingulate gyrus. CONCLUSIONS Our findings suggest Ruminococcus as a potential target for the management of affective impairments in patients with aMCI+.
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Affiliation(s)
- Chun-Che Hung
- Department of Occupational Therapy and Graduate Institute of Behavioral Sciences, Chang Gung University, No. 259, Wenhua 1st Road, 333, Taoyuan, Taiwan
- Laboratory of Brain Imaging and Neural Dynamics (BIND Lab), Chang Gung University, Taoyuan, Taiwan
| | - Yi-Ping Chao
- Department of Computer Science and Information Engineering, Chang Gung University, Taoyuan, Taiwan
- Department of Otorhinolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Yejin Lee
- Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, USA
| | - Chi-Wei Huang
- Department of Neurology, Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung university College of Medicine, No. 123 Ta-Pei Rd., Niau-Sung Dist, 833, Kaohsiung, Taiwan
| | - Shu-Hua Huang
- Department of Nuclear Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chiung-Chih Chang
- Department of Neurology, Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung university College of Medicine, No. 123 Ta-Pei Rd., Niau-Sung Dist, 833, Kaohsiung, Taiwan.
| | - Chia-Hsiung Cheng
- Department of Occupational Therapy and Graduate Institute of Behavioral Sciences, Chang Gung University, No. 259, Wenhua 1st Road, 333, Taoyuan, Taiwan.
- Laboratory of Brain Imaging and Neural Dynamics (BIND Lab), Chang Gung University, Taoyuan, Taiwan.
- Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan.
- Department of Psychiatry, Chang Gung Memorial Hospital, Linkou, Taiwan.
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Mesfin FM, Manohar K, Shelley WC, Brokaw JP, Liu J, Ma M, Markel TA. Stem cells as a therapeutic avenue for active and long-term complications of Necrotizing Enterocolitis. Semin Pediatr Surg 2023; 32:151311. [PMID: 37276782 PMCID: PMC10330659 DOI: 10.1016/j.sempedsurg.2023.151311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Necrotizing enterocolitis (NEC) is a devastating neonatal intestinal disease associated with significant morbidity and mortality. Although decades of research have been dedicated to understanding the pathogenesis of NEC and developing therapies, it remains the leading cause of death among neonatal gastrointestinal diseases. Mesenchymal stem cells (MSCs) have garnered significant interest recently as potential therapeutic agents for the treatment of NEC. They have been shown to rescue intestinal injury and reduce the incidence and severity of NEC in various preclinical animal studies. MSCs and MSC-derived organoids and tissue engineered small intestine (TESI) have shown potential for the treatment of long-term sequela of NEC such as short bowel syndrome, neurodevelopmental delay, and chronic lung disease. Although the advances made in the use of MSCs are promising, further research is needed prior to the widespread use of these cells for the treatment of NEC.
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Affiliation(s)
- Fikir M Mesfin
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Krishna Manohar
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - W Christopher Shelley
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - John P Brokaw
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jianyun Liu
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Minglin Ma
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY, USA
| | - Troy A Markel
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, USA; Riley Hospital for Children at Indiana University Health, Indianapolis, IN, USA.
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Satti S, Palepu MSK, Singh AA, Jaiswal Y, Dash SP, Gajula SNR, Chaganti S, Samanthula G, Sonti R, Dandekar MP. Anxiolytic- and antidepressant-like effects of Bacillus coagulans Unique IS-2 mediate via reshaping of microbiome gut-brain axis in rats. Neurochem Int 2023; 163:105483. [PMID: 36641109 DOI: 10.1016/j.neuint.2023.105483] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 12/14/2022] [Accepted: 01/05/2023] [Indexed: 01/13/2023]
Abstract
BACKGROUND Due to the rising cases of treatment-refractory affective disorders, the discovery of newer therapeutic approaches is needed. In recent times, probiotics have garnered notable attention in managing stress-related disorders. Herein, we examined the effect of Bacillus coagulans Unique IS-2® probiotic on anxiety- and depression-like phenotypes employing maternal separation (MS) and chronic-unpredictable mild stress (CUMS) model in rats. METHODS Both male and female Sprague-Dawley rats were subjected to MS + CUMS. Probiotic treatment was provided for 6 weeks via drinking water. Anxiety- and depression-like phenotypes were assessed using sucrose-preference test (SPT), forced-swimming test (FST), elevated-plus maze test (EPM), and open-field test (OFT). Blood, brain, intestine, and fecal samples were obtained for biochemical and molecular studies. RESULTS Stress-exposed rats drank less sucrose solution, showed increased passivity, and explored less in open-arms in SPT, FST, and EPM, respectively. These stress-generated neurobehavioral aberrations were alleviated by 6-week of Bacillus coagulans Unique IS-2 treatment. The overall locomotor activity in OFT remained unchanged. The decreased levels of BDNF and serotonin and increased levels of C-reactive protein, TNF-α, IL-1β, and dopamine, in the hippocampus and/or frontal cortex of stress-exposed rats were reversed following probiotic treatment. Administration of probiotic also restored the systemic levels of L-tryptophan, L-kynurenine, kynurenic-acid, and 3-hydroxyanthranilic acid, villi/crypt ratio, goblet-cell count, Firmicutes to Bacteroides ratio, and levels of acetate, propionate, and butyrate in fecal samples. These results indicate remodeling of the microbiome gut-brain axis in Bacillus coagulans Unique IS-2 recipient rats. However, protein levels of doublecortin, GFAP, and zona occludens in the hippocampus and occludin-immunoreactivity in the intestine remained unchanged. No prominent sex-specific changes were noted. CONCLUSION Anxiolytic- and antidepressant-like effects of Bacillus coagulans Unique IS-2 in MS + CUMS rat model may be mediated via reshaping the microbiome gut-brain axis.
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Affiliation(s)
- Srilakshmi Satti
- Department of Biological Sciences, Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research NIPER, Hyderabad, India
| | - Mani Surya Kumar Palepu
- Department of Biological Sciences, Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research NIPER, Hyderabad, India
| | - Aditya A Singh
- Department of Biological Sciences, Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research NIPER, Hyderabad, India
| | - Yash Jaiswal
- Department of Biological Sciences, Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research NIPER, Hyderabad, India
| | - Surya Prakash Dash
- Department of Biological Sciences, Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research NIPER, Hyderabad, India
| | - Siva Nageswara Rao Gajula
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research NIPER, Hyderabad, India
| | - Sowmya Chaganti
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research NIPER, Hyderabad, India
| | - Gananadhamu Samanthula
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research NIPER, Hyderabad, India
| | - Rajesh Sonti
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research NIPER, Hyderabad, India
| | - Manoj P Dandekar
- Department of Biological Sciences, Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research NIPER, Hyderabad, India.
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Wang Y, Hang C, Hu J, Li C, Zhan C, Pan J, Yuan T. Role of gut-brain axis in neurodevelopmental impairment of necrotizing enterocolitis. Front Neurosci 2023; 17:1059552. [PMID: 36743802 PMCID: PMC9894661 DOI: 10.3389/fnins.2023.1059552] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 01/02/2023] [Indexed: 01/20/2023] Open
Abstract
Necrotizing enterocolitis (NEC) is a common gastrointestinal disease of preterm infants with high morbidity and mortality. In survivors of NEC, one of the leading causes of long-term morbidity is the development of severe neurocognitive injury. The exact pathogenesis of neurodevelopmental delay in NEC remains unknown, but microbiota is considered to have dramatic effects on the development and function of the host brain via the gut-brain axis. In this review, we discuss the characteristics of microbiota of NEC, the impaired neurological outcomes, and the role of the complex interplay between the intestinal microbiota and brain to influence neurodevelopment in NEC. The increasing knowledge of microbial-host interactions has the potential to generate novel therapies for manipulating brain development in the future.
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Affiliation(s)
- Yu Wang
- Department of Neonatology, Children’s Hospital of Zhejiang University, Hangzhou, China
| | - Chengcheng Hang
- Department of Neonatology, Children’s Hospital of Zhejiang University, Hangzhou, China
| | - Jun Hu
- Department of Surgical Intensive Care Unit, Second Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Chen Li
- Department of Neonatology, Children’s Hospital of Zhejiang University, Hangzhou, China
| | - Canyang Zhan
- Department of Neonatology, Children’s Hospital of Zhejiang University, Hangzhou, China
| | - Jiarong Pan
- Department of Neonatology, Children’s Hospital of Zhejiang University, Hangzhou, China
| | - Tianming Yuan
- Department of Neonatology, Children’s Hospital of Zhejiang University, Hangzhou, China,*Correspondence: Tianming Yuan,
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Tseng WL, Chen CH, Chang JH, Peng CC, Jim WT, Lin CY, Hsu CH, Liu TY, Chang HY. Risk Factors of Language Delay at Two Years of Corrected Age among Very-Low-Birth-Weight Preterm Infants: A Population-Based Study. CHILDREN (BASEL, SWITZERLAND) 2023; 10:children10020189. [PMID: 36832318 PMCID: PMC9955016 DOI: 10.3390/children10020189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/13/2023] [Accepted: 01/18/2023] [Indexed: 01/21/2023]
Abstract
Language delays are often underestimated in very-low-birth-weight (VLBW) preterm infants. We aimed to identify the risk factors of language delay at two years of corrected age in this vulnerable population. VLBW infants, who were assessed at two years of corrected age using the Bayley Scale of Infant Development, third edition, were included using a population-based cohort database. Language delay was defined as mild to moderate if the composite score was between 70 and 85 and severe if the score was < 70. Multivariable logistic regression analysis was used to identify the perinatal risk factors associated with language delay. The study comprised 3797 VLBW preterm infants; 678 (18%) had a mild to moderate delay and 235 (6%) had a severe delay. After adjusting for confounding factors, low maternal education level, low maternal socioeconomic status, extremely low birth weight, male sex, and severe intraventricular hemorrhage (IVH) and/or cystic periventricular leukomalacia (PVL) were found to be significantly associated with both mild to moderate and severe delays. Resuscitation at delivery, necrotizing enterocolitis, and patent ductus arteriosus requiring ligation showed significant associations with severe delay. The strongest factors predicting both mild to moderate and severe language delays were the male sex and severe IVH and/or cystic PVL; thus, early targeted intervention is warranted in these populations.
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Affiliation(s)
- Wei-Lun Tseng
- Department of Pediatrics, MacKay Children’s Hospital, Taipei 104217, Taiwan
| | - Chia-Huei Chen
- Department of Pediatrics, MacKay Children’s Hospital, Taipei 104217, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City 251020, Taiwan
| | - Jui-Hsing Chang
- Department of Pediatrics, MacKay Children’s Hospital, Taipei 104217, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City 251020, Taiwan
| | - Chun-Chih Peng
- Department of Pediatrics, MacKay Children’s Hospital, Taipei 104217, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City 251020, Taiwan
| | - Wai-Tim Jim
- Department of Pediatrics, MacKay Children’s Hospital, Taipei 104217, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City 251020, Taiwan
| | - Chia-Ying Lin
- Department of Pediatrics, MacKay Children’s Hospital, Taipei 104217, Taiwan
| | - Chyong-Hsin Hsu
- Department of Pediatrics, MacKay Children’s Hospital, Taipei 104217, Taiwan
| | - Tzu-Yu Liu
- Department of Pediatrics, Hsinchu MacKay Memorial Hospital, Hsinchu City 30046, Taiwan
| | - Hung-Yang Chang
- Department of Pediatrics, MacKay Children’s Hospital, Taipei 104217, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City 251020, Taiwan
- Correspondence: ; Tel.: +886-2543-3535; Fax: +886-2523-2448
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11
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Manohar K, Mesfin FM, Liu J, Shelley WC, Brokaw JP, Markel TA. Gut-Brain cross talk: The pathogenesis of neurodevelopmental impairment in necrotizing enterocolitis. Front Pediatr 2023; 11:1104682. [PMID: 36873645 PMCID: PMC9975605 DOI: 10.3389/fped.2023.1104682] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 01/23/2023] [Indexed: 02/17/2023] Open
Abstract
Necrotizing enterocolitis (NEC) is a devastating condition of multi-factorial origin that affects the intestine of premature infants and results in high morbidity and mortality. Infants that survive contend with several long-term sequelae including neurodevelopmental impairment (NDI)-which encompasses cognitive and psychosocial deficits as well as motor, vision, and hearing impairment. Alterations in the gut-brain axis (GBA) homeostasis have been implicated in the pathogenesis of NEC and the development of NDI. The crosstalk along the GBA suggests that microbial dysbiosis and subsequent bowel injury can initiate systemic inflammation which is followed by pathogenic signaling cascades with multiple pathways that ultimately lead to the brain. These signals reach the brain and activate an inflammatory cascade in the brain resulting in white matter injury, impaired myelination, delayed head growth, and eventual downstream NDI. The purpose of this review is to summarize the NDI seen in NEC, discuss what is known about the GBA, explore the relationship between the GBA and perinatal brain injury in the setting of NEC, and finally, highlight the existing research into possible therapies to help prevent these deleterious outcomes.
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Affiliation(s)
- Krishna Manohar
- Department of Surgery, Indiana University School of Medicine (IUSM), Indianapolis, IN, United States
| | - Fikir M Mesfin
- Department of Surgery, Indiana University School of Medicine (IUSM), Indianapolis, IN, United States
| | - Jianyun Liu
- Department of Surgery, Indiana University School of Medicine (IUSM), Indianapolis, IN, United States
| | - W Christopher Shelley
- Department of Surgery, Indiana University School of Medicine (IUSM), Indianapolis, IN, United States
| | - John P Brokaw
- Department of Surgery, Indiana University School of Medicine (IUSM), Indianapolis, IN, United States
| | - Troy A Markel
- Department of Surgery, Indiana University School of Medicine (IUSM), Indianapolis, IN, United States.,Riley Hospital for Children, Indiana University Health, Indianapolis, IN, United States
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12
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Li W, Tang J, Zhu Z, Tang W. Initial surgical treatment of necrotizing enterocolitis: a meta-analysis of peritoneal drainage versus laparotomy. Eur J Pediatr 2022; 181:2593-2601. [PMID: 35451633 DOI: 10.1007/s00431-022-04454-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 03/17/2022] [Accepted: 03/21/2022] [Indexed: 11/29/2022]
Abstract
Necrotizing enterocolitis (NEC) in premature infants is associated with high morbidity and mortality, and the optimal intervention remains uncertain. To compare the mortality of primary peritoneal drainage versus primary peritoneal laparotomy as initial surgical intervention for NEC. All data were extracted from PubMed, Embase, and the Cochrane Library. Studies published up to December 2021. Patients with NEC. Studies centered on primary peritoneal drainage and primary peritoneal laparotomy as the initial surgical treatment. Mortality outcomes were available for both interventions. Randomized controlled trials, retrospective cohort studies, and case series in peer-reviewed journals. Language limited to English. Odds ratio (OR) with 95% confidence intervals (CIs) was used to evaluate mortality outcome. Subgroup analyses and linear regression were performed to ascertain the association between mortality pre-specified factors. Data of 1062 patients received peritoneal drainage and 2185 patients received peritoneal laparotomy from five case series, five retrospective cohort studies, and three randomized controlled trials. Peritoneal drainage caused similar mortality (OR 1.49, 95% CI 0.99-2.26) compared with peritoneal laparotomy as initial surgical management for NEC infants. The subgroup analysis of study design, sample size, birth weight, and sex showed similar findings, but inconsistent results were found for country (USA: 1.47, 95% CI 0.90-2.41; Canada: 2.53, 95% CI 0.30-21.48; Australia: 10.29, 95% CI 1.03-102.75; Turkey: 0.09, 95% CI 0.01-0.63) and gestational age (age mean difference < 3: 1.23, 95% CI 0.72-2.11; age mean difference ≥ 3: 2.29, 95% CI 1.04-5.05). No statistically significance was found for the linear regression between mortality and sample size (P = 0.842), gestational age (P = 0.287), birth weight (P = 0.257), sex (P = 0.6). Small sample size, high heterogeneity, NEC, and spontaneous intestinal perforation (SIP) had to be analyzed together, lack of selection criteria for the future selection of an intervention, and no clear, standardized procedures. Conclusion: There was no significant difference in mortality between peritoneal drainage and laparotomy as initial surgical intervention. The results suggest that either intervention could be used in selected patients. What is Known: • Necrotizing enterocolitis (NEC) in premature infants is associated with high morbidity and mortality, and the optimal intervention remains uncertain. What is New: • No significant difference of mortality between peritoneal drainage and laparotomy as initial surgical intervention.
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Affiliation(s)
- Wei Li
- Department of Neonatal Surgery, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Jie Tang
- Department of Neonatal Surgery, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Zhongxian Zhu
- Department of Neonatal Surgery, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Weibing Tang
- Department of Neonatal Surgery, Children's Hospital of Nanjing Medical University, Nanjing, China.
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13
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Cai N, Liao W, Chen Z, Tao M, Chen S. The Mean Platelet Volume Combined with Procalcitonin as an Early Accessible Marker Helps to Predict the Severity of Necrotizing Enterocolitis in Preterm Infants. Int J Gen Med 2022; 15:3789-3795. [PMID: 35422655 PMCID: PMC9004728 DOI: 10.2147/ijgm.s346665] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 01/10/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose Methods Results Conclusion
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Affiliation(s)
- Na Cai
- Department of Pediatrics, The First Hospital Affiliated to Army Medical University, Chongqing, 400038, People’s Republic of China
| | - Wei Liao
- Department of Pediatrics, The First Hospital Affiliated to Army Medical University, Chongqing, 400038, People’s Republic of China
| | - Zhiqiang Chen
- Department of Pediatrics, The First Hospital Affiliated to Army Medical University, Chongqing, 400038, People’s Republic of China
| | - Min Tao
- Department of Pediatrics, The First Hospital Affiliated to Army Medical University, Chongqing, 400038, People’s Republic of China
- Correspondence: Min Tao; Sheng Chen, Department of Pediatrics, The First Hospital Affiliated to Army Medical University, No. 30, Gaotanyan Street, Chongqing, 400038, People’s Republic of China, Tel +86-23-68766215; +86-23-68766213, Email ;
| | - Sheng Chen
- Department of Pediatrics, The First Hospital Affiliated to Army Medical University, Chongqing, 400038, People’s Republic of China
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14
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Vlug LE, Verloop MW, Dierckx B, Bosman L, de Graaff JC, Rings EH, Wijnen RM, de Koning BA, Legerstee JS. Cognitive Outcomes in Children With Conditions Affecting the Small Intestine: A Systematic Review and Meta-analysis. J Pediatr Gastroenterol Nutr 2022; 74:368-376. [PMID: 35226646 PMCID: PMC8860224 DOI: 10.1097/mpg.0000000000003368] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/09/2021] [Indexed: 12/13/2022]
Abstract
OBJECTIVES The aim of the study was to assess cognitive outcomes in children with intestinal failure (IF) and children at high risk of IF with conditions affecting the small intestine requiring parenteral nutrition. METHODS EMBASE, Cochrane, Web of Science, Google Scholar, MEDLINE, and PsycINFO were searched from inception to October 2020. Studies were included constituting original data on developmental quotient (DQ), intelligence quotient (IQ) and/or severe developmental delay/disability (SDD) rates assessed with standardized tests. We used appropriate standardized tools to extract data and assess study quality. We performed random effects meta-analyses to estimate pooled means of DQ/IQ and pooled SDD rates (general population mean for DQ/IQ: 100, for percentage with SDD: 1.8%) for 4 groups: IF, surgical necrotizing enterocolitis (NEC), abdominal wall defects (AWD), and midgut malformations (MM). Associations of patient characteristics with DQ/IQ were evaluated with meta-regressions. RESULTS Thirty studies met the inclusion criteria. The pooled mean DQ/IQ for IF, NEC, AWD, and MM were 86.8, 83.3, 96.6, and 99.5, respectively. The pooled SDD rates for IF, NEC, AWD and MM were 28.6%, 32.8%, 8.5%, and 3.7%, respectively. Meta-regressions indicated that lower gestational age, longer hospital stay, and higher number of surgeries but not parenteral nutrition duration, were associated with lower DQ/IQ. CONCLUSIONS Adverse developmental outcomes are common in children with IF and NEC, and to a much lesser extent in children with AWD and MM. It is important to monitor cognitive development in children with conditions affecting the small intestine and to explore avenues for prevention and remediation.
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Affiliation(s)
- Lotte E. Vlug
- Division of Gastroenterology, Department of Pediatrics
| | | | - Bram Dierckx
- Department of Child and Adolescent Psychiatry/Psychology
| | - Lotte Bosman
- Department of Child and Adolescent Psychiatry/Psychology
| | - Jurgen C. de Graaff
- Department of Anesthesiology, Erasmus MC Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam
| | - Edmond H.H.M. Rings
- Division of Gastroenterology, Department of Pediatrics
- Division of Gastroenterology, Department of Pediatrics, Willem Alexander Children's Hospital, Leiden University Medical Center, Leiden
| | - René M.H. Wijnen
- Department of Pediatric Surgery, Erasmus MC Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands
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15
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The Microbiota-Gut Axis in Premature Infants: Physio-Pathological Implications. Cells 2022; 11:cells11030379. [PMID: 35159189 PMCID: PMC8834399 DOI: 10.3390/cells11030379] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 12/22/2021] [Accepted: 01/17/2022] [Indexed: 11/16/2022] Open
Abstract
Intriguing evidence is emerging in regard to the influence of gut microbiota composition and function on host health from the very early stages of life. The development of the saprophytic microflora is conditioned by several factors in infants, and peculiarities have been found for babies born prematurely. This population is particularly exposed to a high risk of infection, postnatal antibiotic treatment, feeding difficulties and neurodevelopmental disabilities. To date, there is still a wide gap in understanding all the determinants and the mechanism behind microbiota disruption and its influence in the development of the most common complications of premature infants. A large body of evidence has emerged during the last decades showing the existence of a bidirectional communication axis involving the gut microbiota, the gut and the brain, defined as the microbiota–gut–brain axis. In this context, given that very few data are available to demonstrate the correlation between microbiota dysbiosis and neurodevelopmental disorders in preterm infants, increasing interest has arisen to better understand the impact of the microbiota–gut–brain axis on the clinical outcomes of premature infants and to clarify how this may lead to alternative preventive, diagnostic and therapeutic strategies. In this review, we explored the current evidence regarding microbiota development in premature infants, focusing on the effects of delivery mode, type of feeding, environmental factors and possible influence of the microbiota–gut–brain axis on preterm clinical outcomes during their hospital stay and on their health status later in life.
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16
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Angelika D, Etika R, Fitriah M, Kusumawardani NN, Vita AD, Irawan R, Liem KD, Ugrasena IDG. Association between glial fibrillary acidic protein, glial-derived neurotrophic factor, and fatty acid-binding protein-2 at birth in the incidence of necrotizing enterocolitis in preterm infants. Front Pediatr 2022; 10:1010013. [PMID: 36340713 PMCID: PMC9630751 DOI: 10.3389/fped.2022.1010013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 09/30/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND This study aimed to analyze the relationship between glial fibrillary acidic protein (GFAP), glial-derived neurotrophic factor (GDNF), and fatty acid-binding protein-2 (FABP-2) in preterm infants on the incidence of NEC. METHODS Preterm infants with a birth weight <1,500 g and gestational age <34 weeks were included in this study. Biomarker examination was performed using the umbilical vein blood at birth (first sample). Biomarker examination was repeated if the infant developed symptoms of NEC using peripheral vein blood (second sample). Infants were observed for 14 days. If NEC did not exist, a biomarker examination was performed at 14 days. RESULTS This study included 30 preterm infants, nine infants experienced NEC. The values of GFAP, GDNF, and FABP-2 (median and range) in the group with NEC were higher than those in the group without NEC in both the first samples {GFAP [1.40 (0.20-6.50) vs. 0.30 (0.10-1.30) P = 0.014], GDNF [2.84 (1.05-14.11) vs. 1.56 (1.07-3.48) P = 0.050], and FABP-2 [621.70 (278.40-2,207.00) vs. 294.20 (211.40-597.50) P = 0.002]} and second samples {GFAP [2.40 (0.30-3.10) vs. 0.30 (0.10-0.60) P = 0.003], GDNF [2.99 (0.56-10.30) vs. 1.46 (0.85-2.24) P = 0.019], and FABP-2 [646.8 (179.20-1,571.00) vs. 314.90 (184.70-521.60) P = 0.040]}. In infants with NEC, the median values of GFAP [2.40 (0.30-3.10) vs. 1.40 (0.20-6.50) P = 0.767], GDNF [2.99 (0.56-10.30) vs. 2.84 (1.05-14.11) P = 0.859], and FABP-2 [646.80 (179.20-1,571.00) vs. 621.70 (278.40-2,207.00) P = 0.953] in the second sample were higher than those in the first sample. Logistic regression demonstrated that GFAP at birth (Odds Ratio [OR] = 15.629, 95% Confidence Interval [CI] = 1.697-143.906, P = 0.015) and FABP-2 levels at birth (OR = 1.008, 95% CI = 1.001-1.015, P = 0.033) were significantly associated with an increased risk of NEC. CONCLUSION Increased GFAP, GDNF, and FABP-2 at birth are associated with NEC occurrence within two weeks of birth. These findings suggest that early-onset NEC is associated with intestinal injury that occurs during the perinatal or even prenatal period.
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Affiliation(s)
- Dina Angelika
- Doctoral Program of Medical Science, Faculty of Medicine Universitas Airlangga, Surabaya, Indonesia
| | - Risa Etika
- Department of Child Health, Faculty of Medicine Universitas Airlangga, Surabaya, Indonesia
| | - Munawaroh Fitriah
- Department of Clinical Pathology, Faculty of Medicine Universitas Airlangga, Surabaya, Indonesia
| | | | - Angelica Diana Vita
- Medical Program, Faculty of Medicine Universitas Airlangga, Surabaya, Indonesia
| | - Roedi Irawan
- Department of Child Health, Faculty of Medicine Universitas Airlangga, Surabaya, Indonesia
| | - Kian Djien Liem
- Department of Neonatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - I Dewa Gede Ugrasena
- Department of Child Health, Faculty of Medicine Universitas Airlangga, Surabaya, Indonesia
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Uniyal A, Tiwari V, Rani M, Tiwari V. Immune-microbiome interplay and its implications in neurodegenerative disorders. Metab Brain Dis 2022; 37:17-37. [PMID: 34357554 DOI: 10.1007/s11011-021-00807-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 07/22/2021] [Indexed: 12/28/2022]
Abstract
The neurodegeneration and its related CNS pathologies need an urgent toolbox to minimize the global mental health burden. The neuroimmune system critically regulates the brain maturation and survival of neurons across the nervous system. The chronic manipulated immunological drive can accelerate the neuronal pathology hence promoting the burden of neurodegenerative disorders. The gut is home for trillions of microorganisms having a mutual relationship with the host system. The gut-brain axis is a unique biochemical pathway through which the gut residing microbes connects with the brain cells and regulates various physiological and pathological cascades. The gut microbiota and CNS communicate using a common language that synchronizes the tuning of immune cells. The intestinal gut microbial community has a profound role in the maturation of the immune system as well as the development of the nervous system. We have critically summarised the clinical and preclinical reports from the past a decade emphasising that the significant changes in gut microbiota can enhance the host susceptibility towards neurodegenerative disorders. In this review, we have discussed how the gut microbiota-mediated immune response inclines the host physiology towards neurodegeneration and indicated the gut microbiota as a potential future candidate for the management of neurodegenerative disorders.
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Affiliation(s)
- Ankit Uniyal
- Department of Pharmaceutical Engineering and Technology, Neuroscience and Pain Research Laboratory, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, 221005, India
| | - Vineeta Tiwari
- Department of Pharmaceutical Engineering and Technology, Neuroscience and Pain Research Laboratory, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, 221005, India
| | - Mousmi Rani
- Department of Pharmaceutical Engineering and Technology, Neuroscience and Pain Research Laboratory, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, 221005, India
| | - Vinod Tiwari
- Department of Pharmaceutical Engineering and Technology, Neuroscience and Pain Research Laboratory, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, 221005, India.
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18
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Chi C, Fan Y, Li C, Li Y, Guo S, Li T, Buys N, Clifton VL, Colditz PB, Yin C, Sun J. Early Gut Microbiota Colonisation of Premature Infants Fed with Breastmilk or Formula with or without Probiotics: A Cohort Study. Nutrients 2021; 13:4068. [PMID: 34836323 PMCID: PMC8624512 DOI: 10.3390/nu13114068] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 11/06/2021] [Accepted: 11/09/2021] [Indexed: 12/18/2022] Open
Abstract
Premature infants have a fragile ecology of the gut microbiota, which is associated with many health problems and may be influenced by formula versus breast feeding. The present study investigated differences in the process of gut microbiota colonisation in preterm infants fed with breastmilk or formula with or without probiotics before 12 weeks. This cohort study recruited 138 premature infants; 31 in the breastmilk (BM) group, 59 in the probiotics formula (PF) group and 48 in the non-probiotics formula (NPF) group, according to the feeding practice they received at birth. Gut bacterial composition was identified with 16S rRNA gene sequencing in faecal samples collected at 1 week, 6 weeks and 12 weeks after birth. The alpha diversity was higher in the PF group compared to the other groups at week 1 and 6 (both p < 0.01) but showed no difference at week 12. The beta diversity of the three groups showed a trend towards similarity at the first two stages (p < 0.001 and p = 0.009, respectively) and finally showed no difference at week 12. Canonical redundancy analysis showed that feeding type could explain the difference in gut microbiota composition at week one and six (both p < 0.01). At genus level, Bifidobacterium was enriched in the PF group, while the Enterococcus and Streptococcus was enriched in the NPF group. In summary, formula with probiotics feeding after birth can affect gut microbiota colonisation and lead to a bacterial community with less potential pathogens.
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Affiliation(s)
- Cheng Chi
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China; (C.C.); (Y.F.); (S.G.); (T.L.)
- Menzies Health Institute Queensland, School of Medicine and Dentistry, Griffith University, Gold Coast, QLD 4215, Australia;
- School of Nursing, Jining Medical University, Jining 272067, China;
| | - Yali Fan
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China; (C.C.); (Y.F.); (S.G.); (T.L.)
| | - Cheng Li
- School of Nursing, Jining Medical University, Jining 272067, China;
| | - Yu Li
- School of Nursing, Weifang Medical University, Weifang 261042, China;
| | - Shan Guo
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China; (C.C.); (Y.F.); (S.G.); (T.L.)
| | - Tianhe Li
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China; (C.C.); (Y.F.); (S.G.); (T.L.)
| | - Nicholas Buys
- Menzies Health Institute Queensland, School of Medicine and Dentistry, Griffith University, Gold Coast, QLD 4215, Australia;
| | - Vicki L. Clifton
- Faculty of Medicine, Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD 4072, Australia;
| | - Paul B. Colditz
- Perinatal Research Centre, UQCCR, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4072, Australia;
| | - Chenghong Yin
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China; (C.C.); (Y.F.); (S.G.); (T.L.)
| | - Jing Sun
- Menzies Health Institute Queensland, School of Medicine and Dentistry, Griffith University, Gold Coast, QLD 4215, Australia;
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19
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Lure AC, Du X, Black EW, Irons R, Lemas DJ, Taylor JA, Lavilla O, de la Cruz D, Neu J. Using machine learning analysis to assist in differentiating between necrotizing enterocolitis and spontaneous intestinal perforation: A novel predictive analytic tool. J Pediatr Surg 2021; 56:1703-1710. [PMID: 33342603 DOI: 10.1016/j.jpedsurg.2020.11.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 10/27/2020] [Accepted: 11/07/2020] [Indexed: 02/06/2023]
Abstract
PURPOSE Necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) are devastating diseases in preterm neonates, often requiring surgical treatment. Previous studies evaluated outcomes in peritoneal drain placement versus laparotomy, but the accuracy of the presumptive diagnosis remains unknown without bowel visualization. Predictive analytics provide the opportunity to determine the etiology of perforation and guide surgical decision making. The purpose of this investigation was to build and evaluate machine learning models to differentiate NEC and SIP. METHODS Neonates who underwent drain placement or laparotomy NEC or SIP were identified and grouped definitively via bowel visualization. Patient characteristics were analyzed using machine learning methodologies, which were optimized through areas under the receiver operating characteristic curve (AUROC). The model was further evaluated using a validation cohort. RESULTS 40 patients were identified. A random forest model achieved 98% AUROC while a ridge logistic regression model reached 92% AUROC in differentiating diseases. When applying the trained random forest model to the validation cohort, outcomes were correctly predicted. CONCLUSIONS This study supports the feasibility of using a novel machine learning model to differentiate between NEC and SIP prior to any intended surgical interventions. LEVEL OF EVIDENCE level II TYPE OF STUDY: Clinical Research Paper.
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Affiliation(s)
- Allison C Lure
- University of Florida College of Medicine, Department of Pediatrics, 1600 SW Archer Rd, Gainesville, FL 32610, United States.
| | - Xinsong Du
- University of Florida College of Medicine, Department of Health Outcomes & Biomedical Informatics, 2004 Mowry Rd, Gainesville, FL 32610, United States
| | - Erik W Black
- University of Florida College of Medicine, Department of Pediatrics, 1600 SW Archer Rd, Gainesville, FL 32610, United States; University of Florida College of Education, 1221 SW 5th Ave, Gainesville, FL 32601, United States
| | - Raechel Irons
- University of Florida College of Medicine, Department of Pediatrics, 1600 SW Archer Rd, Gainesville, FL 32610, United States
| | - Dominick J Lemas
- University of Florida College of Medicine, Department of Health Outcomes & Biomedical Informatics, 2004 Mowry Rd, Gainesville, FL 32610, United States
| | - Janice A Taylor
- University of Florida College of Medicine, Department of Surgery, 1600 SW Archer Rd, Gainesville, FL 32610, United States
| | - Orlyn Lavilla
- University of Florida College of Medicine, Department of Pediatrics, 1600 SW Archer Rd, Gainesville, FL 32610, United States
| | - Diomel de la Cruz
- University of Florida College of Medicine, Department of Pediatrics, 1600 SW Archer Rd, Gainesville, FL 32610, United States
| | - Josef Neu
- University of Florida College of Medicine, Department of Pediatrics, 1600 SW Archer Rd, Gainesville, FL 32610, United States
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20
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The microbiome, guard or threat to infant health. Trends Mol Med 2021; 27:1175-1186. [PMID: 34518093 DOI: 10.1016/j.molmed.2021.08.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/29/2021] [Accepted: 08/11/2021] [Indexed: 11/23/2022]
Abstract
Despite improvements in survival for very low birthweight (VLBW) premature infants, there continues to be significant morbidity for these infants at remarkable cost to the healthcare system. Concurrent development of the preterm infant intestine alongside the gut microbiome in the clinical setting rather than in the protected in utero environment where it would usually occur creates significant vulnerabilities for the infant's immature intestine and immune system, resulting in devastating illness and neurological injury. However, the microbiome also has the capacity to promote healthy development. Studies of parallel gut microbiome and preterm infant development have given key insight into the impact of the microbiome on intestinal as well as neural development and may provide potential therapeutic targets to prevent preterm infant morbidities.
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21
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Abstract
Necrotizing enterocolitis (NEC) is an inflammatory disease affecting premature infants. Intestinal microbial composition may play a key role in determining which infants are predisposed to NEC and when infants are at highest risk of developing NEC. It is unclear how to optimize antibiotic therapy in preterm infants to prevent NEC and how to optimize antibiotic regimens to treat neonates with NEC. This article discusses risk factors for NEC, how dysbiosis in preterm infants plays a role in the pathogenesis of NEC, and how probiotic and antibiotic therapy may be used to prevent and/or treat NEC and its sequelae.
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Affiliation(s)
- Jennifer Duchon
- Division of Newborn Medicine, Jack and Lucy Department of Pediatrics, Icahn School of Medicine at Mount Sinai, 1000 10th Avenue, New York, NY 10019, USA
| | - Maria E Barbian
- Division of Neonatal-Perinatal Medicine, Emory University School of Medicine and Children's Healthcare of Atlanta, 2015 Uppergate Drive Northeast, 3rd Floor, Atlanta, GA 30322, USA
| | - Patricia W Denning
- Division of Neonatal-Perinatal Medicine, Emory University School of Medicine, Children's Healthcare of Atlanta, Emory University Hospital Midtown, 550 Peachtree Street, 3rd Floor MOT, Atlanta, GA 30308, USA.
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22
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Wang Y, Jaggers RM, Mar P, Galley JD, Shaffer T, Rajab A, Deshpande S, Mashburn-Warren L, Buzzo JR, Goodman SD, Bailey MT, Besner GE. Lactobacillus reuteri in its biofilm state promotes neurodevelopment after experimental necrotizing enterocolitis in rats. Brain Behav Immun Health 2021; 14. [PMID: 34296201 PMCID: PMC8294173 DOI: 10.1016/j.bbih.2021.100256] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Necrotizing enterocolitis (NEC) is a devastating disease affecting premature newborns with no known cure. Up to half of survivors subsequently exhibit cognitive impairment and neurodevelopmental defects. We created a novel probiotics delivery system in which the probiotic Lactobacillus reuteri (Lr) was induced to form a biofilm [Lr (biofilm)] by incubation with dextranomer microspheres loaded with maltose (Lr-DM-maltose). We have previously demonstrated that a single dose of the probiotic Lr administered in its biofilm state significantly reduces the incidence of NEC and decreases inflammatory cytokine production in an animal model of the disease. The aim of our current study was to determine whether a single dose of the probiotic Lr administered in its biofilm state protects the brain after experimental NEC. We found that rat pups exposed to NEC reached developmental milestones significantly slower than breast fed pups, with mild improvement with Lr (biofilm) treatment. Exposure to NEC had a negative effect on cognitive behavior, which was prevented by Lr (biofilm) treatment. Lr administration also reduced anxiety-like behavior in NEC-exposed rats. The behavioral effects of NEC were associated with increased numbers of activated microglia, decreased myelin basic protein (MBP), and decreased neurotrophic gene expression, which were prevented by administration of Lr (biofilm). Our data indicate early enteral treatment with Lr in its biofilm state prevented the deleterious effects of NEC on developmental impairments.
Early treatment with Lr in its biofilm state improves cognitive function in pups that survive experimental NEC. Lr in its biofilm state reduces microglia activation and MBP loss, and maintains memory and learning-related gene expression. Administration of Lr in its biofilm state protects the brain, as well as intestines, during experimental NEC.
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Affiliation(s)
- Yijie Wang
- Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Department of Pediatric Surgery, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA
| | - Robert M Jaggers
- Center for Microbial Pathogenesis, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA
| | - Pamela Mar
- Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Department of Pediatric Surgery, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA
| | - Jeffrey D Galley
- Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Department of Pediatric Surgery, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA
| | - Terri Shaffer
- Preclinical Imaging and Behavior Core/Animal Resources Core, The Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA
| | - Adrian Rajab
- Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Department of Pediatric Surgery, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA
| | - Shivani Deshpande
- Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Department of Pediatric Surgery, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA
| | - Lauren Mashburn-Warren
- Center for Microbial Pathogenesis, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA
| | - John R Buzzo
- Center for Microbial Pathogenesis, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA
| | - Steven D Goodman
- Center for Microbial Pathogenesis, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA
| | - Michael T Bailey
- Center for Microbial Pathogenesis, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA
| | - Gail E Besner
- Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Department of Pediatric Surgery, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA
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23
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Al-Hadidi A, Navarro J, Goodman SD, Bailey MT, Besner GE. Lactobacillus reuteri in Its Biofilm State Improves Protection from Experimental Necrotizing Enterocolitis. Nutrients 2021; 13:nu13030918. [PMID: 33809097 PMCID: PMC8000340 DOI: 10.3390/nu13030918] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/09/2021] [Accepted: 03/10/2021] [Indexed: 12/11/2022] Open
Abstract
Necrotizing enterocolitis (NEC) is a devastating disease predominately found in premature infants that is associated with significant morbidity and mortality. Despite decades of research, medical management with broad spectrum antibiotics and bowel rest has remained relatively unchanged, with no significant improvement in patient outcomes. The etiology of NEC is multi-factorial; however, gastrointestinal dysbiosis plays a prominent role in a neonate's vulnerability to and development of NEC. Probiotics have recently emerged as a new avenue for NEC therapy. However, current delivery methods are associated with potential limitations, including the need for at least daily administration in order to obtain any improvement in outcomes. We present a novel formulation of enterally delivered probiotics that addresses the current limitations. A single enteral dose of Lactobacillus reuteri delivered in a biofilm formulation increases probiotic survival in acidic gastric conditions, increases probiotic adherence to gastrointestinal epithelial cells, and reduces the incidence, severity, and neurocognitive sequelae of NEC in experimental models.
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Affiliation(s)
- Ameer Al-Hadidi
- Department of Pediatric Surgery, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Center for Perinatal Research, The Research Institute at Nationwide Children’s Hospital, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA;
| | - Jason Navarro
- Center for Microbial Pathogenesis, The Research Institute at Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA; (J.N.); (S.D.G.); (M.T.B.)
| | - Steven D. Goodman
- Center for Microbial Pathogenesis, The Research Institute at Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA; (J.N.); (S.D.G.); (M.T.B.)
| | - Michael T. Bailey
- Center for Microbial Pathogenesis, The Research Institute at Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA; (J.N.); (S.D.G.); (M.T.B.)
| | - Gail E. Besner
- Department of Pediatric Surgery, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Center for Perinatal Research, The Research Institute at Nationwide Children’s Hospital, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA;
- Correspondence: ; Tel.: +1-614-722-3914
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24
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Chi C, Li C, Buys N, Wang W, Yin C, Sun J. Effects of Probiotics in Preterm Infants: A Network Meta-analysis. Pediatrics 2021; 147:e20200706. [PMID: 33323491 DOI: 10.1542/peds.2020-0706] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/09/2020] [Indexed: 11/24/2022] Open
Abstract
CONTEXT Probiotics have proven to be effective in promoting premature infants' health, but the optimal usage is unknown. OBJECTIVE To compare probiotic supplements for premature infants. DATA SOURCES We searched PubMed, Embase, Cochrane, and ProQuest from inception of these databases to June 1, 2020. STUDY SELECTION Randomized trials of probiotic supplement intervention for preterm infants were screened by 2 reviewers independently. The primary outcomes were mortality and the morbidity of necrotizing enterocolitis (NEC). Secondary outcomes were morbidity of sepsis, time to achieve full enteral feeding, and length of hospital stay. DATA EXTRACTION The data of primary and secondary outcomes were extracted by 2 reviewers and pooled with a random-effects model. RESULTS The meta-analysis included 45 trials with 12 320 participants. Bifidobacterium plus Lactobacillus was associated with lower rates of mortality (risk ratio 0.56; 95% credible interval 0.34-0.84) and NEC morbidity (0.47; 0.27-0.79) in comparison to the placebo; Lactobacillus plus prebiotic was associated with lower rates of NEC morbidity (0.06; 0.01-0.41) in comparison to the placebo; Bifidobacterium plus prebiotic had the highest probability of having the lowest rate of mortality (surface under the cumulative ranking curve 83.94%); and Lactobacillus plus prebiotic had the highest probability of having the lowest rate of NEC (surface under the cumulative ranking curve 95.62%). LIMITATIONS In few studies did authors report the data of infants with a lower birth weight or gestational age. CONCLUSIONS The efficacy of single probiotic supplements is limited, compared to combined use of probiotics. To achieve optimal effect on premature infant health, combined use of prebiotic and probiotic, especially Lactobacillus or Bifidobacterium, is recommended.
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Affiliation(s)
- Cheng Chi
- School of Nursing, Jining Medical University, Jining, China
- Department of Internal Medicine, Beijing Obstetrics and Gynecology Hospital and Capital Medical University, Beijing, China; and
- School of Medicine and
| | - Cheng Li
- School of Nursing, Jining Medical University, Jining, China;
- Department of Internal Medicine, Beijing Obstetrics and Gynecology Hospital and Capital Medical University, Beijing, China; and
| | - Nicholas Buys
- Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia
| | - Wenjun Wang
- School of Nursing, Jining Medical University, Jining, China
| | - Chenghong Yin
- Department of Internal Medicine, Beijing Obstetrics and Gynecology Hospital and Capital Medical University, Beijing, China; and
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25
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Matei A, Montalva L, Goodbaum A, Lauriti G, Zani A. Neurodevelopmental impairment in necrotising enterocolitis survivors: systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 2020; 105:432-439. [PMID: 31801792 DOI: 10.1136/archdischild-2019-317830] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 11/08/2019] [Accepted: 11/12/2019] [Indexed: 02/06/2023]
Abstract
AIM To determine (1) the incidence of neurodevelopmental impairment (NDI) in necrotising enterocolitis (NEC), (2) the impact of NEC severity on NDI in these babies and (3) the cerebral lesions found in babies with NEC. METHODS Systematic review: three independent investigators searched for studies reporting infants with NDI and a history of NEC (PubMed, Medline, Cochrane Collaboration, Scopus). Meta-analysis: using RevMan V.5.3, we compared NDI incidence and type of cerebral lesions between NEC infants versus preterm infants and infants with medical vs surgical NEC. RESULTS Of 10 674 abstracts screened, 203 full-text articles were examined. In 31 studies (n=2403 infants with NEC), NDI incidence was 40% (IQR 28%-64%) and was higher in infants with surgically treated NEC (43%) compared with medically managed NEC (27%, p<0.00001). The most common NDI in NEC was cerebral palsy (18%). Cerebral lesions: intraventricular haemorrhage (IVH) was more common in NEC babies (26%) compared with preterm infants (18%; p<0.0001). There was no difference in IVH incidence between infants with surgical NEC (25%) and those treated medically (20%; p=0.4). The incidence of periventricular leukomalacia (PVL) was significantly increased in infants with NEC (11%) compared with preterm infants (5%; p<0.00001). CONCLUSIONS This study shows that a large proportion of NEC survivors has NDI. NEC babies are at higher risk of developing IVH and/or PVL than babies with prematurity alone. The degree of NDI seems to correlate to the severity of gut damage, with a worse status in infants with surgical NEC compared with those with medical NEC. TRIAL REGISTRATION NUMBER CRD42019120522.
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Affiliation(s)
- Andreea Matei
- Division of General and Thoracic Surgery, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Louise Montalva
- Division of General and Thoracic Surgery, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Alexa Goodbaum
- Division of General and Thoracic Surgery, Department of Surgery, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Giuseppe Lauriti
- Department of Pediatric Surgery, Spirito Santo Hospital, Pescara, Italy.,G. d'Annunzio University, Chieti-Pescara, Italy
| | - Augusto Zani
- Division of General and Thoracic Surgery, The Hospital for Sick Children, Toronto, Ontario, Canada
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26
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Chi C, Xue Y, Liu R, Wang Y, Lv N, Zeng H, Buys N, Zhu B, Sun J, Yin C. Effects of a formula with a probiotic Bifidobacterium lactis Supplement on the gut microbiota of low birth weight infants. Eur J Nutr 2020; 59:1493-1503. [PMID: 31197506 DOI: 10.1007/s00394-019-02006-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 05/16/2019] [Indexed: 12/17/2022]
Abstract
PURPOSE Low birth weight (LBW) infants have a less diverse gut microbiota, enriched in potential pathogens, which places them at high risk of systemic inflammation diseases. This study aimed to identify the differences in gut bacterial community structure between LBW infants who received probiotics and LBW infants who did not receive probiotics. METHODS Forty-one infants were allocated to the non-probiotic group (N group) and 56 infants to the probiotic group (P group), according to whether the formula they received contained a probiotic Bifidobacterium lactis. Gut bacterial composition was identified with sequencing of the 16S rRNA gene in fecal samples collected at 14 days after birth. RESULTS There was no significant difference between the alpha diversity of the two groups, while the beta diversity was significantly different (p < 0.05). Our results showed that Bifidobacterium and Lactobacillus (both p < 0.05) were enriched in the P group, while Veillonella, Dolosigranulum and Clostridium sensu stricto 1 (all p < 0.05) were enriched in the N group. Predicted metagenome function analysis revealed enhancement of fatty acids, peroxisome, starch, alanine, tyrosine and peroxisome pathways in the P group, and enhancement of plant pathogen, Salmonella and Helicobacter pylori infection pathways in the N group. CONCLUSIONS Probiotic supplement in formula may affect the composition, stability and function of LBW infants' gut microbiota. LBW infants who receive probiotic intervention may benefit from gut microbiota that contains more beneficial bacteria.
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Affiliation(s)
- Cheng Chi
- Department of Internal Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, China
| | - Yong Xue
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China
| | - Ruixia Liu
- Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, China
| | - Yanxin Wang
- Department of Internal Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, China
| | - Na Lv
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Science, Beijing, 100101, China
| | - Huihui Zeng
- Department of Neonatology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, China
| | - Nicholas Buys
- Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, 4222, Australia
| | - Baoli Zhu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Science, Beijing, 100101, China.
| | - Jing Sun
- School of Medicine, Griffith University, Gold Coast, QLD, 4222, Australia.
| | - Chenghong Yin
- Department of Internal Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, China.
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27
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Romani L, Del Chierico F, Chiriaco M, Foligno S, Reddel S, Salvatori G, Cifaldi C, Faraci S, Finocchi A, Rossi P, Bagolan P, D'Argenio P, Putignani L, Fusaro F. Gut Mucosal and Fecal Microbiota Profiling Combined to Intestinal Immune System in Neonates Affected by Intestinal Ischemic Injuries. Front Cell Infect Microbiol 2020; 10:59. [PMID: 32158700 PMCID: PMC7052114 DOI: 10.3389/fcimb.2020.00059] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 02/06/2020] [Indexed: 02/06/2023] Open
Abstract
Background and Purpose: Early life microbiota plays a crucial role in human health by acting as a barrier from pathogens' invasion and maintaining the intestinal immune homoeostasis. Altered fecal microbiota (FM) ecology was reported in newborns affected by intestinal ischemia. Our purpose was to describe, in these patients, the FM, the mucosal microbiota (MM) and the mucosal immunity. Methods: Fourteen newborns underwent intestinal resection because of intestinal ischemia. FM and MM were determined through targeted-metagenomics, diversity assignment and Kruskal-Wallis analyses of Operational taxonomic units (OTUs). The mucosal immune cells were analyzed through cytofluorimetry. Results and Conclusion: Based on the severity intestinal injueris we identified two groups: extensive (EII) and focal intestinal ischemia (FII). FM and MM varied in EII and FII groups, showing in the EII group the predominance of Proteobacteria and Enterobacteriaceae and the reduction of Bacteroidetes and Verrucomicrobia for both microbiota. The MM was characterized by a statistically significant reduction of Bacteroides, Lachnospiraceae and Ruminococcaceae and by a higher diversity in the EII compared to FII group. FM showed a prevalence of Proteobacteria, while the Shannon index was lower in the EII compared to FII group. An overall increment in B- and T-lymphocytes and Natural killer (NK) T-like cells was found for EII mucosal samples associated to an increment of TNF-α and INF-γ expressing cells, compared to FII group. FM and MM carry specific signatures of intestinal ischemic lesions. Further research may be crucial to address the role of specific taxa in EII, expecially with reference to inflammation grade and ischemia extension.
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Affiliation(s)
- Lorenza Romani
- Division of Immunology and Infectious Diseases, University-Hospital Pediatric Department (DPUO), Bambino Gesù Children's Hospital, IRCSS, Rome, Italy
| | | | - Maria Chiriaco
- Division of Immunology and Infectious Diseases, University-Hospital Pediatric Department (DPUO), Bambino Gesù Children's Hospital, IRCSS, Rome, Italy
| | - Silvia Foligno
- Neonatal Intensive Care Unit, Department of Medical and Surgical Neonatology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Sofia Reddel
- Unit of Human Microbiome, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Guglielmo Salvatori
- Neonatal Intensive Care Unit, Department of Medical and Surgical Neonatology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Cristina Cifaldi
- Division of Immunology and Infectious Diseases, University-Hospital Pediatric Department (DPUO), Bambino Gesù Children's Hospital, IRCSS, Rome, Italy
| | - Simona Faraci
- Digestive Endoscopy and Surgery Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Andrea Finocchi
- Division of Immunology and Infectious Diseases, University-Hospital Pediatric Department (DPUO), Bambino Gesù Children's Hospital, IRCSS, Rome, Italy
| | - Paolo Rossi
- Division of Immunology and Infectious Diseases, University-Hospital Pediatric Department (DPUO), Bambino Gesù Children's Hospital, IRCSS, Rome, Italy
| | - Pietro Bagolan
- Department of Medical and Surgical Neonatology, Neonatal Surgery Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Patrizia D'Argenio
- Division of Immunology and Infectious Diseases, University-Hospital Pediatric Department (DPUO), Bambino Gesù Children's Hospital, IRCSS, Rome, Italy
| | - Lorenza Putignani
- Unit of Parasitology and Unit of Human Microbiome, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Fabio Fusaro
- Department of Medical and Surgical Neonatology, Neonatal Surgery Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
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28
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Surgical necrotizing enterocolitis but not spontaneous intestinal perforation is associated with adverse neurological outcome at school age. Sci Rep 2020; 10:2373. [PMID: 32047169 PMCID: PMC7012917 DOI: 10.1038/s41598-020-58761-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 12/30/2019] [Indexed: 11/08/2022] Open
Abstract
Gastrointestinal complications during the neonatal period, i.e. necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP), are associated with adverse short-term outcome in very-low-birthweight infants (VLBWI, <1500 g birth weight). However, little is known about the neurological outcome of survivors at school age. We analysed data of 2241 infants followed-up at the age of 6 years. To determine the effect of NEC and SIP on cognitive outcome in consideration of other important confounding factors, we used multivariable logistic regression models. In addition, infants with surgical diagnosis of NEC (n = 43) or SIP (n = 41) were compared to NEC (n = 43) or SIP (n = 41) negative controls using Mahalanobis distance matching. Infants with a history for NEC had a three times increased risk (RR 3.0 [1.8-4.2], p < 0.001) to develop IQ scores <85 while history of surgical SIP did not increase the relative risk for lower IQs at school age (RR 1.0 [0.4-2.1], p = 1.000). In a matched-cohort analysis, we confirmed that infants with surgical NEC had lower mean IQ results than unaffected controls (±SD) (85±17 vs. 94±14, p = 0.023) while no differences were found for history of SIP. Our results reflect that the different aetiology and inflammatory extent of NEC and SIP may lead to disparate neurodevelopment trajectories. Hence, our data suggest a potential role of early gut-brain axis distortion in infants with NEC which needs to be further explored.
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29
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Xiang L, Lou Y, Liu L, Liu Y, Zhang W, Deng J, Guan Y, She M, You X, Liu M, Li H, Xu X, Liu F, Cai X. Gut Microbiotic Features Aiding the Diagnosis of Acute Ischemic Stroke. Front Cell Infect Microbiol 2020; 10:587284. [PMID: 33409158 PMCID: PMC7779606 DOI: 10.3389/fcimb.2020.587284] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 11/18/2020] [Indexed: 12/14/2022] Open
Abstract
Increasing evidence suggests that features of the gut microbiota correlate with ischemic stroke. However, the specific characteristics of the gut microbiota in patients suffering different types of ischemic stroke, or recovering from such strokes, have rarely been studied, and potential microbiotic predictors of different types of stroke have seldom been analyzed. We subjected fecal specimens from patients with lacunar or non-lacunar acute ischemic infarctions, and those recovering from such strokes, to bacterial 16S rRNA sequencing and compared the results to those of healthy volunteers. We identified microbial markers of different types of ischemic stroke and verified that these were of diagnostic utility. Patients with two types of ischemic stroke, and those recovering from ischemic stroke, exhibited significant shifts in microbiotic diversities compared to healthy subjects. Cluster of Orthologous Groups of Proteins (COG) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed reduced metabolic and transport-related pathway activities in ischemic stroke patients. We performed fivefold cross-validation using a Random Forest model to identify two optimal bacterial species (operational taxonomic units; OTUs) serving as markers of lacunar infarction; these were Lachnospiraceae (OTU_45) and Bacteroides (OTU_4), and the areas under the receiver operating characteristic curves (AUCs under the ROCs) were 0.881 and 0.872 respectively. In terms of non-lacunar acute ischemic infarction detection, the two optimal species were Bilophila (OTU_330) and Lachnospiraceae (OTU_338); the AUCs under the ROCs were 0.985 and 0.929 respectively. In post-ischemic stroke patients, the three optimal species were Pseudomonas (OTU_35), Sphingomonadaceae (OTU_303), and Akkermansia (OTU_9); the AUCs under the ROCs were 1, 0.897, and 0.846 respectively. Notably, the gut microbial markers were of considerable value for utility when diagnosing lacunar infarction, non-lacunar acute ischemic infarction, and post-ischemic stroke. This study is the first to characterize the gut microbiotic profiles of patients with lacunar or non-lacunar, acute ischemic strokes, and those recovering from stroke, and to identify microbiotic predictors of such strokes.
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Affiliation(s)
- Lei Xiang
- Department of Integrative Chinese and Western Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Yanfeng Lou
- Department of Dermatology, Jinling Hospital, Southern Medical University, Nanjing, China
| | - Lingyu Liu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Yuanling Liu
- Administrative Department, Guangdong Province Hospital for Women and Children Healthcare, Guangzhou, China
| | - Weizheng Zhang
- Clinical Laboratory, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jianxin Deng
- Department of Endocrinology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center of Shenzhen University, Shenzhen, China
| | - Yubin Guan
- Clinical Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Miaoqin She
- Research Section, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Xinchao You
- Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Minqi Liu
- Clinical Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Hongwei Li
- Institute of Biotherapy, Southern Medical University, Guangzhou, China
| | - Xiaosong Xu
- Clinical Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- *Correspondence: Xiangsheng Cai, ; Fang Liu, ; Xiaosong Xu,
| | - Fang Liu
- Department of Dermatology, Jinling Hospital, Southern Medical University, Nanjing, China
- *Correspondence: Xiangsheng Cai, ; Fang Liu, ; Xiaosong Xu,
| | - Xiangsheng Cai
- Clinical Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Center for Medical Experiments, University of Chinese Academy of Science-Shenzhen Hospital, Shenzhen, China
- *Correspondence: Xiangsheng Cai, ; Fang Liu, ; Xiaosong Xu,
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30
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Meister AL, Doheny KK, Travagli RA. Necrotizing enterocolitis: It's not all in the gut. Exp Biol Med (Maywood) 2019; 245:85-95. [PMID: 31810384 DOI: 10.1177/1535370219891971] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Necrotizing enterocolitis is the leading cause of death due to gastrointestinal disease in preterm neonates, affecting 5–12% of neonates born at a very-low birth weight. Necrotizing enterocolitis can present with a slow and insidious onset, with some neonates displaying early symptoms such as feeding intolerance. Treatment during the early stages includes bowel rest and careful use of antibiotics, but surgery is required if pneumoperitoneum and intestinal perforation occur. Mortality rates among neonates requiring surgery are estimated to be 20–30%, mandating the development of non-invasive and reliable biomarkers to predict necrotizing enterocolitis before the onset of clinical signs. Such biomarkers would allow at-risk neonates to receive maximal preventative therapies such as careful nutritional consideration, probiotics, and increased skin-to-skin care.Impact statementNecrotizing enterocolitis (NEC) is a devastating gastrointestinal disease; its high mortality rate mandates the development of non-invasive biomarkers to predict NEC before its onset. This review summarizes the pathogenesis, prevention, unresolved issues, and long-term outcomes of NEC.
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Affiliation(s)
- Alissa L Meister
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA, USA
| | - Kim K Doheny
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA, USA.,Neonatal-Perinatal Medicine, Penn State College of Medicine, Hershey, PA, USA
| | - R Alberto Travagli
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA, USA
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31
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Gauda EB, McLemore GL. Premature birth, homeostatic plasticity and respiratory consequences of inflammation. Respir Physiol Neurobiol 2019; 274:103337. [PMID: 31733340 DOI: 10.1016/j.resp.2019.103337] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 10/11/2019] [Accepted: 11/10/2019] [Indexed: 12/23/2022]
Abstract
Infants who are born premature can have persistent apnea beyond term gestation, reemergence of apnea associated with inflammation during infancy, increased risk of sudden unexplained death, and sleep disorder breathing during infancy and childhood. The autonomic nervous system, particularly the central neural networks that control breathing and peripheral and central chemoreceptors and mechanoreceptors that modulate the activity of the central respiratory network, are rapidly developing during the last trimester (22-37 weeks gestation) of fetal life. With advances in neonatology, in well-resourced, developed countries, infants born as young as 23 weeks gestation can survive. Thus, a substantial part of maturation of central and peripheral systems that control breathing occurs ex-utero in infants born at the limit of viability. The balance of excitatory and inhibitory influences dictates the ultimate output from the central respiratory network. We propose in this review that simply being born early in the last trimester can trigger homeostatic plasticity within the respiratory network tipping the balance toward inhibition that persists in infancy. We discuss the intersection of premature birth, homeostatic plasticity and biological mechanisms leading to respiratory depression during inflammation in former premature infants.
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Affiliation(s)
- Estelle B Gauda
- The Hospital for Sick Children, Division of Neonatology, Department of Pediatrics, University of Toronto, Toronto, Ontario, M5G 1X8, Canada.
| | - Gabrielle L McLemore
- Department of Biology, School of Computer, Mathematics and Natural Sciences (SCMNS), Morgan State University, Baltimore, MD, 21251, United States
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Elgin TG, Fricke EM, Gong H, Reese J, Mills DA, Kalantera KM, Underwood MA, McElroy SJ. Fetal exposure to maternal inflammation interrupts murine intestinal development and increases susceptibility to neonatal intestinal injury. Dis Model Mech 2019; 12:dmm.040808. [PMID: 31537532 PMCID: PMC6826024 DOI: 10.1242/dmm.040808] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 09/12/2019] [Indexed: 02/06/2023] Open
Abstract
Fetal exposure to chorioamnionitis can impact the outcomes of the developing fetus both at the time of birth and in the subsequent neonatal period. Infants exposed to chorioamnionitis have a higher incidence of gastrointestinal (GI) pathology, including necrotizing enterocolitis (NEC); however, the mechanism remains undefined. To simulate the fetal exposure to maternal inflammation (FEMI) induced by chorioamnionitis, pregnant mice (C57BL/6J, IL-6 -/-, RAG -/- or TNFR1 -/-) were injected intraperitoneally on embryonic day (E)15.5 with lipopolysaccharide (LPS; 100 µg/kg body weight). Pups were delivered at term, and reared to postnatal day (P)0, P7, P14, P28 or P56. Serum and intestinal tissue samples were collected to quantify growth, inflammatory markers, histological intestinal injury, and goblet and Paneth cells. To determine whether FEMI increased subsequent susceptibility to intestinal injury, a secondary dose of LPS (100 µg/kg body weight) was given on P5, prior to tissue harvesting on P7. FEMI had no effect on growth of the offspring or their small intestine. FEMI significantly decreased both goblet and Paneth cell numbers while simultaneously increasing serum levels of IL-1β, IL-10, KC/GRO (CXCL1 and CXCL2), TNF and IL-6. These alterations were IL-6 dependent and, importantly, increased susceptibility to LPS-induced intestinal injury later in life. Our data show that FEMI impairs normal intestinal development by decreasing components of innate immunity and simultaneously increasing markers of inflammation. These changes increase susceptibility to intestinal injury later in life and provide novel mechanistic data to potentially explain why preterm infants exposed to chorioamnionitis prior to birth have a higher incidence of NEC and other GI disorders.
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Affiliation(s)
- Timothy G Elgin
- Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA
| | - Erin M Fricke
- Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA
| | - Huiyu Gong
- Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA
| | - Jeffrey Reese
- Department of Pediatrics, Vanderbilt University, Nashville, TN 37232, USA
| | - David A Mills
- Department of Food Science and Technology, University of California Davis, Davis, CA 95616, USA
| | - Karen M Kalantera
- Department of Food Science and Technology, University of California Davis, Davis, CA 95616, USA
| | - Mark A Underwood
- Department of Pediatrics, University of California Davis, Sacramento, CA 95817, USA
| | - Steven J McElroy
- Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA .,Department of Microbiology and Immunology, University of Iowa, Iowa City, IA 52242, USA
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Gan X, Mao J, Li J. [Clinical features and outcomes of neonatal necrotizing enterocolitis]. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2019; 21. [PMID: 31642439 PMCID: PMC7389726 DOI: 10.7499/j.issn.1008-8830.2019.10.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 03/07/2023]
Abstract
OBJECTIVE To study the clinical features of neonatal necrotizing enterocolitis (NEC) and risk factors for poor outcomes. METHODS A retrospective analysis was performed for the clinical data of 121 preterm infants diagnosed with NEC. According to the treatment method, they were divided into a non-surgical group (n=66) and a surgical group (n=55). According to the outcome, they were divided into a survival group (n=76) and a death group (n=45). Clinical features were compared between these groups. Risk factors for poor outcomes were analyzed by multivariate logistic regression analysis. RESULTS Compared with the non-surgical group, the surgical group had significantly lower corrected gestational age, minimum platelet count, and incidence rate of bloody stool at the onset of NEC (P<0.05). The maximum C-reactive protein (CRP) and mortality rate in the surgical group were significantly higher than those in the non-surgical group (P<0.05). Compared with the survival group, the death group had significantly lower gestational age at birth, birth weight, proportion of small-for-gestational-age infants, and corrected gestational age, body weight and minimum platelet count at the onset of NEC (P<0.05). The incidence of patent ductus arteriosus, rate of use of ibuprofen, maximum CRP and rate of surgical treatment in the death group were significantly higher than those in the survival group (P<0.05). The multivariate logistic regression analysis showed that ibuprofen treatment was a risk factor for death in infants with NEC (OR=9.149, P<0.05). CONCLUSIONS Ibuprofen treatment increases the risk for death in preterm infants with NEC.
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Affiliation(s)
- Xin Gan
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, China.
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Chi C, Xue Y, Lv N, Hao Y, Liu R, Wang Y, Ding X, Zeng H, Li G, Shen Q, Hu X, Chen L, Jiang T, Zhao J, Buys N, Sun J, Yin C, Zhu B. Longitudinal Gut Bacterial Colonization and Its Influencing Factors of Low Birth Weight Infants During the First 3 Months of Life. Front Microbiol 2019; 10:1105. [PMID: 31156608 PMCID: PMC6529567 DOI: 10.3389/fmicb.2019.01105] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 04/30/2019] [Indexed: 12/03/2022] Open
Abstract
Establishment of low birth weight (LBW) infant gut microbiota may have lifelong implications for the health of individuals. However, no longitudinal cohort studies have been conducted to characterize the gut microbial profiles of LBW infants and their influencing factors. Our objective was to understand how the gut bacterial community structure of LBW and normal birth weight (NBW) infants varies across the first 3 months of life and assess the influencing factors. In this observational cohort study, gut bacterial composition was identified with sequencing of the 16S rRNA gene in fecal samples of 69 LBW infants and 65 NBW controls at 0 day, 3 days, 2 weeks, 6 weeks, and 3 months (defined as stages 1-5) after birth. Alpha-diversity of both groups displayed a decreasing trend followed by slight variations. There were significant differences on the Shannon index of the two groups at stages 1 to 3 (P = 0.041, P = 0.032, and P = 0.014, respectively). The microbiota community structure of LBW infants were significantly different from NBW infants throughout the 3 months (all P < 0.05) but not at stage 2 (P = 0.054). There was a significant increase in abundance in Firmicutes while a decrease in Proteobacteria, and at genus level the abundance of Enterococcus, Klebsiella, and Streptococcus increased while it decreased for Haemophilus in LBW group. Birth weight was the main factor explaining the observed variation at all stages, except at stage 2. Delivery mode (4.78%) and antibiotic usage (3.50%) contributed to explain the observed variation at stage 3, and pregestational BMI (4.61%) partially explained the observed variation at stage 4. In conclusion, gut microbial communities differed in NBW and LBW infants from birth to 3 months of life, and were affected by birth weight, delivery mode, antibiotic treatment, and pregestational BMI.
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Affiliation(s)
- Cheng Chi
- Department of Internal Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Yong Xue
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
| | - Na Lv
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
| | - Yanan Hao
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
| | - Ruixia Liu
- Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Yanxin Wang
- Department of Internal Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Xin Ding
- Department of Obstetrics, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Huihui Zeng
- Department of Neonatology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Geng Li
- Department of Neonatology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Qun Shen
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Xiaosong Hu
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Lijun Chen
- National Engineering Center of Dairy for Early Life Health, Beijing Sanyuan Foods Co., Ltd., Beijing, China
| | - Tiemin Jiang
- National Engineering Center of Dairy for Early Life Health, Beijing Sanyuan Foods Co., Ltd., Beijing, China
| | - Junying Zhao
- National Engineering Center of Dairy for Early Life Health, Beijing Sanyuan Foods Co., Ltd., Beijing, China
| | - Nicholas Buys
- School of Medicine, Griffith University, Brisbane, QLD, Australia
| | - Jing Sun
- School of Medicine, Griffith University, Brisbane, QLD, Australia
| | - Chenghong Yin
- Department of Internal Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Baoli Zhu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
- Beijing Key Laboratory of Microbial Drug Resistance and Resistome, Beijing, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Department of Pathogenic Biology, School of Basic Medical Sciences, Southwest Medical University, Chengdu, China
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Biouss G, Antounians L, Li B, O'Connell JS, Seo S, Catania VD, Guadagno J, Rahman A, Zani-Ruttenstock E, Svergun N, Pierro A, Zani A. Experimental necrotizing enterocolitis induces neuroinflammation in the neonatal brain. J Neuroinflammation 2019; 16:97. [PMID: 31077225 PMCID: PMC6511222 DOI: 10.1186/s12974-019-1481-9] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 04/16/2019] [Indexed: 01/15/2023] Open
Abstract
Background Necrotizing enterocolitis (NEC) is an inflammatory gastrointestinal disease primarily affecting preterm neonates. Neonates with NEC suffer from a degree of neurodevelopmental delay that is not explained by prematurity alone. There is a need to understand the pathogenesis of neurodevelopmental delay in NEC. In this study, we assessed the macroscopic and microscopic changes that occur to brain cell populations in specific brain regions in a neonatal mouse model of NEC. Moreover, we investigated the role of intestinal inflammation as part of the mechanism responsible for the changes observed in the brain of pups with NEC. Methods Brains of mice were assessed for gross morphology and cerebral cortex thickness (using histology). Markers for mature neurons, oligodendrocytes, neural progenitor cells, microglia, and astrocytes were used to quantify their cell populations in different regions of the brain. Levels of cell apoptosis in the brain were measured by Western blotting and immunohistochemistry. Endoplasmic reticulum (ER) stress markers and levels of pro-inflammatory cytokines (in the ileum and brain) were measured by RT-qPCR and Western blotting. A Pearson test was used to correlate the levels of cytokines (ELISA) in the brain and ileum and to correlate activated microglia and astrocyte populations to the severity of NEC. Results NEC pups had smaller brain weights, higher brain-to-body weight ratios, and thinner cortices compared to control pups. NEC pups had increased levels of apoptosis and ER stress. In addition, NEC was associated with a reduction in the number of neurons, oligodendrocytes, and neural progenitors in specific regions of the brain. Levels of pro-inflammatory cytokines and the density of activated microglia and astrocytes were increased in the brain and positively correlated with the increase in the levels pro-inflammatory cytokines in the gut and the severity of NEC damage respectively. Conclusions NEC is associated with severe changes in brain morphology, a pro-inflammatory response in the brain that alters cell homeostasis and density of brain cell populations in specific cerebral regions. We show that the severity of neuroinflammation is associated with the severity of NEC. Our findings suggest that early intervention during NEC may reduce the chance of acute neuroinflammation and cerebral damage. Electronic supplementary material The online version of this article (10.1186/s12974-019-1481-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- George Biouss
- Developmental and Stem Cell Biology Program, PGCRL, The Hospital for Sick Children, 686 Bay Street, Toronto, Ontario, M5G 0A4, Canada.,Division of General and Thoracic Surgery, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada.,Translational Medicine Program, PGCRL, The Hospital for Sick Children, 686 Bay Street, Toronto, Ontario, M5G 0A4, Canada
| | - Lina Antounians
- Developmental and Stem Cell Biology Program, PGCRL, The Hospital for Sick Children, 686 Bay Street, Toronto, Ontario, M5G 0A4, Canada.,Division of General and Thoracic Surgery, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada
| | - Bo Li
- Division of General and Thoracic Surgery, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada.,Translational Medicine Program, PGCRL, The Hospital for Sick Children, 686 Bay Street, Toronto, Ontario, M5G 0A4, Canada
| | - Joshua S O'Connell
- Division of General and Thoracic Surgery, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada.,Translational Medicine Program, PGCRL, The Hospital for Sick Children, 686 Bay Street, Toronto, Ontario, M5G 0A4, Canada
| | - Shogo Seo
- Division of General and Thoracic Surgery, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada.,Translational Medicine Program, PGCRL, The Hospital for Sick Children, 686 Bay Street, Toronto, Ontario, M5G 0A4, Canada
| | - Vincenzo D Catania
- Developmental and Stem Cell Biology Program, PGCRL, The Hospital for Sick Children, 686 Bay Street, Toronto, Ontario, M5G 0A4, Canada.,Division of General and Thoracic Surgery, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada
| | - Jennifer Guadagno
- Developmental and Stem Cell Biology Program, PGCRL, The Hospital for Sick Children, 686 Bay Street, Toronto, Ontario, M5G 0A4, Canada.,Division of General and Thoracic Surgery, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada
| | - Abidur Rahman
- Developmental and Stem Cell Biology Program, PGCRL, The Hospital for Sick Children, 686 Bay Street, Toronto, Ontario, M5G 0A4, Canada
| | - Elke Zani-Ruttenstock
- Division of General and Thoracic Surgery, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada.,Translational Medicine Program, PGCRL, The Hospital for Sick Children, 686 Bay Street, Toronto, Ontario, M5G 0A4, Canada.,Department of Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Nataliia Svergun
- Developmental and Stem Cell Biology Program, PGCRL, The Hospital for Sick Children, 686 Bay Street, Toronto, Ontario, M5G 0A4, Canada
| | - Agostino Pierro
- Division of General and Thoracic Surgery, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada.,Translational Medicine Program, PGCRL, The Hospital for Sick Children, 686 Bay Street, Toronto, Ontario, M5G 0A4, Canada.,Department of Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Augusto Zani
- Developmental and Stem Cell Biology Program, PGCRL, The Hospital for Sick Children, 686 Bay Street, Toronto, Ontario, M5G 0A4, Canada. .,Division of General and Thoracic Surgery, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada. .,Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
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Bellodas Sanchez J, Kadrofske M. Necrotizing enterocolitis. Neurogastroenterol Motil 2019; 31:e13569. [PMID: 30793842 DOI: 10.1111/nmo.13569] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2018] [Revised: 01/15/2019] [Accepted: 01/17/2019] [Indexed: 12/12/2022]
Abstract
Necrotizing enterocolitis (NEC) is an acute inflammatory disease of the intestine which primarily affects preterm infants and is a leading cause of morbidity and mortality in the neonatal intensive care unit. From a clinical standpoint, and during the early course of the disease, NEC can be difficult to distinguish from other diseases and conditions common to the preterm infant, and this warrants the need for specific disease biomarkers. The pathogenesis of NEC is only partly understood but likely involves an altered intestinal barrier immune response to feeding and the developing microbiome. Recent evidence points toward a role of the enteric nervous system in NEC pathogenesis. In this issue, Meister and colleagues use a rodent model of NEC to demonstrate that NEC is associated with diminished vagal tone, as determined by decreased high-frequency heart rate variability (HF-HRV), and altered myenteric nitrergic inhibitory neurotransmission. These results augment their previous findings that describe decreased HF-HRV in human preterm infants with NEC. This mini-review provides a brief summary of clinical and pathophysiologic aspects of NEC with focus on certain aspects of neurogastroenterology.
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Affiliation(s)
- Jenny Bellodas Sanchez
- Neonatal-Perinatal Medicine Fellowship Program, Michigan State University and Sparrow Hospital, Lansing, Michigan
| | - Mark Kadrofske
- Department of Pediatrics and Human Development, Division of Neonatology, Michigan State University, East Lansing, Michigan
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Niemarkt HJ, De Meij TG, van Ganzewinkel CJ, de Boer NKH, Andriessen P, Hütten MC, Kramer BW. Necrotizing Enterocolitis, Gut Microbiota, and Brain Development: Role of the Brain-Gut Axis. Neonatology 2019; 115:423-431. [PMID: 30974443 PMCID: PMC6604259 DOI: 10.1159/000497420] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 01/21/2019] [Indexed: 12/17/2022]
Abstract
Necrotizing enterocolitis (NEC) is a relatively common disease in very-low-birth-weight infants and is associated with high mortality and morbidity. In survivors, neurodevelopmental impairment is frequently seen. The exact etiology remains largely to be elucidated, but microbiota are considered to play a major role in the development of NEC. Furthermore, emerging evidence exists that the microbiota is also of importance in brain function and development. Therefore, microbiota characterization has not only potential as a diagnostic or even preventive tool to predict NEC, but may also serve as a biomarker to monitor and possibly even as a target to manipulate brain development. Analysis of fecal volatile organic compounds, which shape the volatile metabolome and reflect microbiota function and host interaction, has been shown to be of interest in the diagnosis of NEC and late-onset sepsis. In this review, we discuss evidence of the role of the complex interplay between microbiota, NEC, and brain development, including the brain-gut axis in preterm infants.
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Affiliation(s)
- Hendrik J Niemarkt
- Department of Neonatology, Máxima Medical Centre, Veldhoven, The Netherlands
| | - Tim G De Meij
- Department of Pediatric Gastroenterology, Amsterdam University Medical Centre, Amsterdam, The Netherlands
| | | | - Nanne K H de Boer
- Department of Gastroenterology and Hepatology, AG&M Research Institute, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Peter Andriessen
- Department of Neonatology, Máxima Medical Centre, Veldhoven, The Netherlands
| | - Matthias C Hütten
- Department of Pediatrics, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Boris W Kramer
- Department of Pediatrics, Maastricht University Medical Centre, Maastricht, The Netherlands,
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Majeed M, Nagabhushanam K, Arumugam S, Majeed S, Ali F. Bacillus coagulans MTCC 5856 for the management of major depression with irritable bowel syndrome: a randomised, double-blind, placebo controlled, multi-centre, pilot clinical study. Food Nutr Res 2018; 62:1218. [PMID: 29997457 PMCID: PMC6034030 DOI: 10.29219/fnr.v62.1218] [Citation(s) in RCA: 113] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 06/04/2018] [Accepted: 06/13/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The modification of microbial ecology in human gut by supplementing probiotics may be an alternative strategy to ameliorate or prevent depression. OBJECTIVE The current study was conducted to assess the safety and efficacy of the probiotic strain Bacillus coagulans MTCC 5856 for major depressive disorder (MDD) in IBS patients. METHOD Patients (n = 40) diagnosed for MDD with IBS were randomized (1:1) to receive placebo or B. coagulans MTCC 5856 at a daily dose of 2 × 109 cfu (2 billion spores) and were maintained to the end of double-blind treatment (90 days). Changes from baseline in clinical symptoms of MDD and IBS were evaluated through questionnaires. RESULTS Significant change (p = 0.01) in favour of the B. coagulans MTCC 5856 was observed for the primary efficacy measure Hamilton Rating Scale for Depression (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), Center for Epidemiological Studies Depression Scale (CES-D) and Irritable bowel syndrome quality of life questionnaire (IBS-QOL). Secondary efficacy measures i.e. Clinical Global Impression-Improvement rating Scale (CGI-I), Clinical Global Impression Severity rating Scale (CGI-S), Gastrointestinal Discomfort Questionnaire (GI-DQ) and Modified Epworth Sleepiness Scale (mESS) also showed significant results (p = 0.01) in B. coagulans MTCC 5856 group compared to placebo group except dementia total reaction scoring. Serum myeloperoxidase, an inflammatory biomarker was also significantly reduced (p < 0.01) when compared with the baseline and end of the study. All the safety parameters remained well within the normal clinical range and had no clinically significant difference between the screening and at the end of the study. CONCLUSION B. coagulans MTCC 5856 showed robust efficacy for the treatment of patients experiencing IBS symptoms with major depressive disorder. The improvement in depression and IBS symptoms was statistically significant and clinically meaningful. These findings support B. coagulans MTCC 5856 as an important new treatment option for major depressive disorder in IBS patients.
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Affiliation(s)
- Muhammed Majeed
- Sami Labs Limited, Bangalore, Karnataka, India
- Sabinsa Corporation, East Windsor, NJ, USA
- Sabinsa Corporation, Payson, UT, USA
- ClinWorld Private Limited, Bangalore, Karnataka, India
| | | | | | - Shaheen Majeed
- Sabinsa Corporation, East Windsor, NJ, USA
- Sabinsa Corporation, Payson, UT, USA
| | - Furqan Ali
- Sami Labs Limited, Bangalore, Karnataka, India
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