|
1
|
Martí JM, Kok CR, Thissen JB, Mulakken NJ, Avila-Herrera A, Jaing CJ, Allen JE, Be NA. Addressing the dynamic nature of reference data: a new nucleotide database for robust metagenomic classification. mSystems 2025; 10:e0123924. [PMID: 40111052 PMCID: PMC12013259 DOI: 10.1128/msystems.01239-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 02/14/2025] [Indexed: 03/22/2025] Open
Abstract
Accurate metagenomic classification relies on comprehensive, up-to-date, and validated reference databases. While the NCBI BLAST Nucleotide (nt) database, encompassing a vast collection of sequences from all domains of life, represents an invaluable resource, its massive size-currently exceeding 1012 nucleotides-and exponential growth pose significant challenges for researchers seeking to maintain current nt-based indices for metagenomic classification. Recognizing that no current nt-based indices exist for the widely used Centrifuge classifier, and the last public version currently available was released in 2018, we addressed this critical gap by leveraging advanced high-performance computing resources. We present new Centrifuge-compatible nt databases, meticulously constructed using a novel pipeline incorporating different quality control measures, including reference decontamination and filtering. These measures demonstrably reduce spurious classifications, as shown through our reanalysis of published metagenomic data where Plasmodium annotations were dramatically reduced using our decontaminated database, highlighting how database quality can significantly impact research conclusions. Through temporal comparisons, we also reveal how our approach minimizes inconsistencies in taxonomic assignments stemming from asynchronous updates between public sequence and taxonomy databases. These discrepancies are particularly evident in taxa such as Listeria monocytogenes and Naegleria fowleri, where classification accuracy varied significantly across database versions. These new databases, made available as pre-built Centrifuge indexes, respond to the need for an open, robust, nt-based pipeline for taxonomic classification in metagenomics. Applications such as environmental metagenomics, forensics, and clinical metagenomics, which require comprehensive taxonomic coverage, will benefit from this resource. Our work highlights the importance of treating reference databases as dynamic entities, subject to ongoing quality control and validation akin to software development best practices. This approach is crucial for ensuring accuracy and reliability of metagenomic analysis, especially as databases continue to expand in size and complexity. IMPORTANCE Accurately identifying the diverse microbes present in a sample, whether from the human gut, a soil sample, or a crime scene, is crucial for fields ranging from medicine to environmental science. Researchers rely on comprehensive DNA databases to match sequenced DNA fragments to known microbial species. However, the widely used NCBI nt database, while vast, poses significant challenges. Its massive size makes it difficult for many researchers to use effectively with taxonomic classifiers, and inconsistencies and contamination within the database can impact the accuracy of microbial identification. This work addresses these challenges by providing cleaned, updated, and validated nt-based databases specifically optimized for the widely used Centrifuge classification tool. This new resource demonstrably reduces errors and improves the reliability of microbial identification across diverse taxonomic groups. Moreover, by providing readily usable indexes, we overcome the size barrier, enabling researchers to leverage the full potential of the nt database for metagenomic analysis. Our findings underscore the need to treat reference databases as dynamic entities, emphasizing continuous quality control and versioning as essential practices for robust and reproducible metagenomics research.
Collapse
Affiliation(s)
- Jose Manuel Martí
- Global Security Computing Applications Division, Lawrence Livermore National Laboratory, Livermore, California, USA
| | - Car Reen Kok
- Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California, USA
| | - James B. Thissen
- Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California, USA
| | - Nisha J. Mulakken
- Global Security Computing Applications Division, Lawrence Livermore National Laboratory, Livermore, California, USA
| | - Aram Avila-Herrera
- Global Security Computing Applications Division, Lawrence Livermore National Laboratory, Livermore, California, USA
| | - Crystal J. Jaing
- Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California, USA
| | - Jonathan E. Allen
- Global Security Computing Applications Division, Lawrence Livermore National Laboratory, Livermore, California, USA
| | - Nicholas A. Be
- Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California, USA
| |
Collapse
|
|
2
|
Birg A, Lin HC. The Role of Bacteria-Derived Hydrogen Sulfide in Multiple Axes of Disease. Int J Mol Sci 2025; 26:3340. [PMID: 40244174 PMCID: PMC11990059 DOI: 10.3390/ijms26073340] [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: 12/15/2024] [Revised: 03/27/2025] [Accepted: 03/27/2025] [Indexed: 04/18/2025] Open
Abstract
In this review article, we discuss and explore the role of bacteria-derived hydrogen sulfide. Hydrogen sulfide is a signaling molecule produced endogenously that plays an important role in health and disease. It is also produced by the gut microbiome. In the setting of microbial disturbances leading to disruption of intestinal homeostasis (dysbiosis), the concentration of available hydrogen sulfide can also vary leading to pathologic sequelae. The brain-gut axis is the original studied paradigm of gut microbiome and host interaction. In recent years, our understanding of microbial and host interaction has expanded greatly to include specific pathways that have branched into their own axes. These axes share a principal concept of microbiota changes, intestinal permeability, and an inflammatory response, some of which are modulated by hydrogen sulfide (H2S). In this review, we will discuss multiple axes including the gut-immune, gut-heart, and gut-endocrine axes. We will evaluate the role of H2S in modulation of intestinal barrier, mucosal healing in intestinal inflammation and tumor genesis. We will also explore the role of H2S in alpha-synuclein aggregation and ischemic injury. Finally, we will discuss H2S in the setting of metabolic syndrome as int pertains to hypertension, atherosclerosis and glucose-like peptide-1 activity. Majority of studies that evaluate hydrogen sulfide focus on endogenous production; the role of this review is to examine the lesser-known bacteria-derived source of hydrogen sulfide in the progression of diseases as it relates to these axes.
Collapse
Affiliation(s)
- Aleksandr Birg
- Medicine Service, New Mexico VA Health Care System, Albuquerque, NM 87108, USA;
- Division of Gastroenterology and Hepatology, University of New Mexico, Albuquerque, NM 87106, USA
| | - Henry C. Lin
- Medicine Service, New Mexico VA Health Care System, Albuquerque, NM 87108, USA;
- Division of Gastroenterology and Hepatology, University of New Mexico, Albuquerque, NM 87106, USA
| |
Collapse
|
|
3
|
Zhou W, Zhou Y, Zhang S, Li B, Li Z, Bai Z, Sun D, Huangfu C, Wang N, Xia T, Huang C, Guan L, Yang X, Hu Y, Zhang P, Shen P, Wang R, Ni Z, Gao Y. Gut microbiota's role in high-altitude cognitive impairment: the therapeutic potential of Clostridium sp. supplementation. SCIENCE CHINA. LIFE SCIENCES 2025; 68:1132-1148. [PMID: 39704932 DOI: 10.1007/s11427-024-2779-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 11/13/2024] [Indexed: 12/21/2024]
Abstract
Prolonged exposure to high-altitude environments may increase the risk of cognitive decline in young migrants. Recent studies suggest that hypobaric hypoxia-induced alterations in gut microbial composition could partly contribute to this risk. However, the absence of direct evidence from cohort studies and an unclear mechanism hinder intervention development based on this hypothesis. This study recruited 109 young male migrants living in Xizang to investigate the microbial mechanisms underlying cognitive impairment associated with high-altitude migration. Multi-omic analysis revealed distinct microbiome and metabolome features in migrants with cognitive decline, notably a reduced abundance of Clostridium species and disrupted fecal absorption of L-valine. Mechanistic studies showed that hypobaric hypoxia significantly damaged the intestinal barrier, leading to lipopolysaccharide (LPS) leakage and an influx of inflammatory factors into the peripheral blood, which activated microglia and caused neuronal injury in the hippocampus of mice. Additionally, compromised L-valine absorption due to intestinal barrier damage correlated with lower hippocampal glutamate levels and neurotrophic factors. Intervention with Clostridium sp. effectively restored the intestinal barrier and enhanced L-valine absorption, which mitigated hypobaric hypoxia-induced inflammation and hippocampal neural damage in mice. In conclusion, cognitive impairment among young migrants at high altitude may be attributed to hypobaric hypoxia-induced gut microbiota disruption and subsequent intestinal barrier dysfunction. This study may provide a promising approach for preventing and treating high-altitude-associated cognitive impairment.
Collapse
Affiliation(s)
- Wei Zhou
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Yongqiang Zhou
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Shikun Zhang
- Department of Stem Cell and Regenerative Medicine, Institute of Health Service and Transfusion Medicine, Beijing, 100850, China
| | - Bin Li
- Mountain Sickness Research Institute, No.950 Hospital, Yecheng, 844900, China
| | - Zhong Li
- Department of Stomatology, the First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Zhijie Bai
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Dezhi Sun
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Chaoji Huangfu
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Ningning Wang
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Tiantian Xia
- Medical School of Qinghai University, Xining, 810016, China
| | - Congshu Huang
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Lina Guan
- General Hospital of Xinjiang Military Command, Urumqi, 830000, China
| | - Xi Yang
- General Hospital of Xinjiang Military Command, Urumqi, 830000, China
| | - Yangyi Hu
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Pengfei Zhang
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Pan Shen
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China.
| | - Rui Wang
- General Hospital of Xinjiang Military Command, Urumqi, 830000, China.
| | - Zhexin Ni
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China.
| | - Yue Gao
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China.
- State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, 100853, China.
| |
Collapse
|
|
4
|
Nikpour M, Morrisroe K, Calderone A, Yates D, Silman A. Occupational dust and chemical exposures and the development of autoimmune rheumatic diseases. Nat Rev Rheumatol 2025; 21:137-156. [PMID: 39910253 DOI: 10.1038/s41584-024-01216-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/20/2024] [Indexed: 02/07/2025]
Abstract
Although the association between certain occupational exposures and the development of autoimmune rheumatic disease was first described over a century ago, this association has only become more widely recognized in the past 10 years because of the use of high-silica-content engineered stone in construction and home renovation. There is now a substantial and growing body of evidence that occupational dust and chemical exposure, be it through mining, stonemasonry, building or other trades, increases the risk of various systemic autoimmune rheumatic diseases (SARDs) including rheumatoid arthritis and systemic sclerosis. Although the pathogenic mechanisms of silica-induced autoimmunity are not fully elucidated, it is thought that alveolar macrophage ingestion of silica and the ensuing phagosomal damage is an initiating event that ultimately leads to production of autoantibodies and immune-mediated tissue injury. The purportedly causal association between occupational exposure to chemicals, such as organic solvents, and an increased risk of SARDs is less frequently recognized compared with silica dust, and its immunopathogenesis is less well understood. An appreciation of the importance of occupational dust and chemical exposures in the development of SARDs has implications for workplace health and safety regulations and offers a unique opportunity to better understand autoimmune disease pathogenesis and implement preventative strategies.
Collapse
Affiliation(s)
- Mandana Nikpour
- University of Sydney Musculoskeletal Research Flagship Centre and School of Public Health, Camperdown, Sydney, New South Wales, Australia.
- Department of Rheumatology, Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales, Australia.
| | - Kathleen Morrisroe
- Department of Medicine, The University of Melbourne at St Vincent's Hospital (Melbourne), Fitzroy, Victoria, Australia
- Department of Rheumatology, St Vincent's Hospital (Melbourne), Fitzroy, Victoria, Australia
| | - Alicia Calderone
- Department of Rheumatology, St Vincent's Hospital (Melbourne), Fitzroy, Victoria, Australia
| | - Deborah Yates
- Asbestos & Dust Diseases Research Institute, Concord, New South Wales, Australia
- Respiratory & Sleep Medicine, Macquarie University Hospital, Macquarie University, New South Wales, Australia
| | - Alan Silman
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK
| |
Collapse
|
|
5
|
Ayyanar MP, Vijayan M. A review on gut microbiota and miRNA crosstalk: implications for Alzheimer's disease. GeroScience 2025; 47:339-385. [PMID: 39562408 PMCID: PMC11872870 DOI: 10.1007/s11357-024-01432-5] [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: 09/23/2024] [Accepted: 11/07/2024] [Indexed: 11/21/2024] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and progressive neuronal damage. Recent research has highlighted the significant roles of the gut microbiota and microRNAs (miRNAs) in the pathogenesis of AD. This review explores the intricate interaction between gut microbiota and miRNAs, emphasizing their combined impact on Alzheimer's progression. First, we discuss the bidirectional communication within the gut-brain axis and how gut dysbiosis contributes to neuroinflammation and neurodegeneration in AD. Changes in gut microbiota composition in Alzheimer's patients have been linked to inflammation, which exacerbates disease progression. Next, we delve into the biology of miRNAs, focusing on their roles in gene regulation, neurodevelopment, and neurodegeneration. Dysregulated miRNAs are implicated in AD pathogenesis, influencing key processes like inflammation, tau pathology, and amyloid deposition. We then examine how the gut microbiota modulates miRNA expression, particularly in the brain, potentially altering neuroinflammatory responses and synaptic plasticity. The interplay between gut microbiota and miRNAs also affects blood-brain barrier integrity, further contributing to Alzheimer's pathology. Lastly, we explore therapeutic strategies targeting this gut microbiota-miRNA axis, including probiotics, prebiotics, and dietary interventions, aiming to modulate miRNA expression and improve AD outcomes. While promising, challenges remain in fully elucidating these interactions and translating them into effective therapies. This review highlights the importance of understanding the gut microbiota-miRNA relationship in AD, offering potential pathways for novel therapeutic approaches aimed at mitigating the disease's progression.
Collapse
Affiliation(s)
- Maruthu Pandian Ayyanar
- Department of Biology, The Gandhigram Rural Institute (Deemed to be University), Gandhigram, 624302, Tamil Nadu, India
| | - Murali Vijayan
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA.
| |
Collapse
|
|
6
|
Sampson TR, Tansey MG, West AB, Liddle RA. Lewy body diseases and the gut. Mol Neurodegener 2025; 20:14. [PMID: 39885558 PMCID: PMC11783828 DOI: 10.1186/s13024-025-00804-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 01/21/2025] [Indexed: 02/01/2025] Open
Abstract
Gastrointestinal (GI) involvement in Lewy body diseases (LBDs) has been observed since the initial descriptions of patients by James Parkinson. Recent experimental and human observational studies raise the possibility that pathogenic alpha-synuclein (⍺-syn) might develop in the GI tract and subsequently spread to susceptible brain regions. The cellular and mechanistic origins of ⍺-syn propagation in disease are under intense investigation. Experimental LBD models have implicated important contributions from the intrinsic gut microbiome, the intestinal immune system, and environmental toxicants, acting as triggers and modifiers to GI pathologies. Here, we review the primary clinical observations that link GI dysfunctions to LBDs. We first provide an overview of GI anatomy and the cellular repertoire relevant for disease, with a focus on luminal-sensing cells of the intestinal epithelium including enteroendocrine cells that express ⍺-syn and make direct contact with nerves. We describe interactions within the GI tract with resident microbes and exogenous toxicants, and how these may directly contribute to ⍺-syn pathology along with related metabolic and immunological responses. Finally, critical knowledge gaps in the field are highlighted, focusing on pivotal questions that remain some 200 years after the first descriptions of GI tract dysfunction in LBDs. We predict that a better understanding of how pathophysiologies in the gut influence disease risk and progression will accelerate discoveries that will lead to a deeper overall mechanistic understanding of disease and potential therapeutic strategies targeting the gut-brain axis to delay, arrest, or prevent disease progression.
Collapse
Affiliation(s)
- Timothy R Sampson
- Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, 30329, USA
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA
| | - Malú Gámez Tansey
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA
- Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL, 32610, USA
- McKnight Brain Institute, University of Florida, Gainesville, FL, 32610, USA
- Normal Fixel Institute of Neurological Diseases, Gainesville, FL, 32608, USA
| | - Andrew B West
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.
- Duke Center for Neurodegeneration and Neurotherapeutic Research, Department of Pharmacology and Cancer Biology, Durham, NC, 27710, USA.
| | - Rodger A Liddle
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.
- Duke Institute for Brain Sciences, Duke University, Durham, NC, 27710, USA.
- Department of Medicine, Duke University and Department of Veterans Affairs Health Care System, Durham, NC, 27710, USA.
| |
Collapse
|
|
7
|
Chaudhari DS, Francescutti DM, Winters AD, Koka O, Kracht DJ, Greenberg JM, Theis KR, Angoa-Perez M. Contributions of the gut microbiota to Gulf War Illness susceptibility: Findings from a mouse model. Life Sci 2024; 359:123244. [PMID: 39551360 DOI: 10.1016/j.lfs.2024.123244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 11/01/2024] [Accepted: 11/11/2024] [Indexed: 11/19/2024]
Abstract
AIMS In light of the evidence supporting a significant role of the gut microbiome in Gulf War Illness (GWI) pathology, we sought to examine its contribution to GWI susceptibility in a mouse model. We also aimed to identify bacterial taxa and microbially-derived metabolites associated with disease susceptibility. MAIN METHODS Male mice receiving pyridostigmine bromide (PB) orally, and controls were evaluated for symptoms of GWI at 8 weeks post-treatment. The Kansas criteria were adapted to assess behaviors associated with the following domains: gastrointestinal alterations, pain, mood, cognitive function, skin and respiratory disturbances. PB-treated subjects were classified into susceptible (GWI-S) or resilient (GWI-R). The status of the gut microbiome was assessed via analyses of the 16S rRNA gene and microbial-derived metabolites were evaluated with metabolomics tools. KEY FINDINGS Our results indicate that application of the Kansas criteria to behavioral outcomes in PB-treated mice resulted in a GWI susceptibility rate of ~35 %, similar to the one reported in humans. The composition and structure of the gut microbiome was different in GWI-S subjects compared to both control and GWI-R mice at 8 weeks but differences in microbial community structure were observed prior to PB treatment between GWI-R and GWI-S mice. GWI-S subjects exhibited a pattern of differentially abundant bacterial taxa and microbial metabolites. SIGNIFICANCE To our knowledge, this is the first preclinical report in which a stratification by susceptibility to GWI and its association with the gut microbiome is described. In light of the research conundrum that vulnerability to GWI represents, the use of tools that could provide further insight into this complex factor should be considered.
Collapse
Affiliation(s)
- Diptaraj S Chaudhari
- Research and Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA; Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Dina M Francescutti
- Research and Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA; Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Andrew D Winters
- Research and Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA; Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Orena Koka
- Research and Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA; Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA
| | - David J Kracht
- Research and Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA
| | - Jonathan M Greenberg
- Research and Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA; Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Kevin R Theis
- Department of Biochemistry, Microbiology and Immunology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Mariana Angoa-Perez
- Research and Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA; Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA.
| |
Collapse
|
|
8
|
Rahangdale S, Deshmukh P, Sammeta S, Aglawe M, Kale M, Umekar M, Kotagale N, Taksande B. Agmatine modulation of gut-brain axis alleviates dysbiosis-induced depression-like behavior in rats. Eur J Pharmacol 2024; 981:176884. [PMID: 39134294 DOI: 10.1016/j.ejphar.2024.176884] [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: 01/16/2024] [Revised: 07/20/2024] [Accepted: 08/09/2024] [Indexed: 08/19/2024]
Abstract
Depression is a global health concern affecting nearly 280 million individuals. It not only imposes a significant burden on economies and healthcare systems but also manifests complex physiological connections and consequences. Agmatine, a putative neuromodulator derived primarily from beneficial gut microbes specially Lactobacillus, has emerged as a potential therapeutic agent for mental health. The microbiota-gut-brain axis is involved in the development of depression through the peripheral nervous system, endocrine system, and immune system and may be a key factor in the effect of agmatine. Therefore, this study aimed to investigate the potential mechanism of agmatine in antibiotic-induced dysbiosis and depression-like behavior in rats, focusing on its modulation of the gut-brain axis. Depression-like behavior associated with dysbiosis was induced through a seven-day regimen of the broad-spectrum antibiotic, comprising ampicillin and metronidazole and validated through microbial, biochemical, and behavioral alterations. On day 8, antibiotic-treated rats exhibited loose fecal consistency, altered fecal microbiota, and depression-like behavior in forced swim test. Pro-inflammatory cytokines were elevated, while agmatine and monoamine levels decreased in the hippocampus and prefrontal cortex. Antibiotic administration disrupted tight junction proteins in the ileum, affecting gut architecture. Oral administration of agmatine alone or combined with probiotics significantly reversed antibiotic-induced dysbiosis, restoring gut microbiota and mitigating depression-like behaviors. This intervention also restored neuro-inflammatory markers, increased agmatine and monoamine levels, and preserved gut integrity. The study highlights the regulatory role of endogenous agmatine in the gut-brain axis in broad-spectrum antibiotic induced dysbiosis and associated depression-like behavior.
Collapse
Affiliation(s)
- Sandip Rahangdale
- Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur, M.S., 441 002, India
| | - Pankaj Deshmukh
- Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur, M.S., 441 002, India
| | - Shivkumar Sammeta
- Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur, M.S., 441 002, India
| | - Manish Aglawe
- Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur, M.S., 441 002, India
| | - Mayur Kale
- Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur, M.S., 441 002, India
| | - Milind Umekar
- Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur, M.S., 441 002, India
| | - Nandkishor Kotagale
- Government College of Pharmacy, Kathora Naka, VMV Road, Amravati, M.S., 44604, India
| | - Brijesh Taksande
- Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur, M.S., 441 002, India.
| |
Collapse
|
|
9
|
Yang W, Cui H, Wang C, Wang X, Yan C, Cheng W. A review of the pathogenesis of epilepsy based on the microbiota-gut-brain-axis theory. Front Mol Neurosci 2024; 17:1454780. [PMID: 39421261 PMCID: PMC11484502 DOI: 10.3389/fnmol.2024.1454780] [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: 06/25/2024] [Accepted: 09/20/2024] [Indexed: 10/19/2024] Open
Abstract
The pathogenesis of epilepsy is related to the microbiota-gut-brain axis, but the mechanism has not been clarified. The microbiota-gut-brain axis is divided into the microbiota-gut-brain axis (upward pathways) and the brain-gut-microbiota axis (downward pathways) according to the direction of conduction. Gut microorganisms are involved in pathological and physiological processes in the human body and participate in epileptogenesis through neurological, immunological, endocrine, and metabolic pathways, as well as through the gut barrier and blood brain barrier mediated upward pathways. After epilepsy, the downward pathway mediated by the HPA axis and autonomic nerves triggers "leaky brain "and "leaky gut," resulting in the formation of microbial structures and enterobacterial metabolites associated with epileptogenicity, re-initiating seizures via the upward pathway. Characteristic changes in microbial and metabolic pathways in the gut of epileptic patients provide new targets for clinical prevention and treatment of epilepsy through the upward pathway. Based on these changes, this review further redescribes the pathogenesis of epilepsy and provides a new direction for its prevention and treatment.
Collapse
Affiliation(s)
- Wentao Yang
- Department of Fist Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Hua Cui
- Department of Fist Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Chaojie Wang
- Department of Fist Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Xuan Wang
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Ciai Yan
- Department of Fist Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Weiping Cheng
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| |
Collapse
|
|
10
|
Kaul M, Mukherjee D, Weiner HL, Cox LM. Gut microbiota immune cross-talk in amyotrophic lateral sclerosis. Neurotherapeutics 2024; 21:e00469. [PMID: 39510899 PMCID: PMC11585889 DOI: 10.1016/j.neurot.2024.e00469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 09/18/2024] [Accepted: 10/04/2024] [Indexed: 11/15/2024] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons. While there has been significant progress in defining the genetic contributions to ALS, greater than 90 % of cases are sporadic, which suggests an environmental component. The gut microbiota is altered in ALS and is an ecological factor that contributes to disease by modulating immunologic, metabolic, and neuronal signaling. Depleting the microbiome worsens disease in the SOD1 ALS animal model, while it ameliorates disease in the C9orf72 model of ALS, indicating critical subtype-specific interactions. Furthermore, administering beneficial microbiota or microbial metabolites can slow disease progression in animal models. This review discusses the current state of microbiome research in ALS, including interactions with different ALS subtypes, evidence in animal models and human studies, key immunologic and metabolomic mediators, and a path toward microbiome-based therapies for ALS.
Collapse
Affiliation(s)
- Megha Kaul
- Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham & Women's Hospital, Boston, MA, 02115, USA
| | - Debanjan Mukherjee
- Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham & Women's Hospital, Boston, MA, 02115, USA
| | - Howard L Weiner
- Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham & Women's Hospital, Boston, MA, 02115, USA.
| | - Laura M Cox
- Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham & Women's Hospital, Boston, MA, 02115, USA.
| |
Collapse
|
|
11
|
Guo C, Chen L, Xu R, Zhu J. Insecticide-Induced Metabolic Dysregulation in Model Microbe E. coli Discovered by Comprehensive Metabolic Profiling. ACS OMEGA 2024; 9:39817-39826. [PMID: 39346865 PMCID: PMC11425713 DOI: 10.1021/acsomega.4c05103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 07/25/2024] [Accepted: 07/30/2024] [Indexed: 10/01/2024]
Abstract
Fipronil, malathion, and permethrin are widely used insecticides in agriculture, public areas, and residential spaces. The globally abused application of these chemicals results in residues surpassing established maximum residue levels, giving rise to potential toxicity in unintended organisms. Long-term exposure and the persistent accumulation of these insecticides in animals and humans pose threats such as neurotoxicity, liver and kidney damage, and microbiota dysbiosis. Despite the known risks, the specific impact of these insecticides on gut microbiota and their metabolic processes, as well as the subsequent effects on host health, remain largely unknown. This study aimed to address this gap by utilizing nonpathogenic Escherichia coli as a representative of human gut bacteria and examining its growth and metabolic perturbations induced by exposure to fipronil, malathion, and permethrin. Our research showed that exposure of E. coli to fipronil, malathion, and permethrin at physiologically relevant concentrations resulted in significant growth inhibition. Furthermore, we have observed the biodegradation of fipronil and permethrin by E. coli, while no biodegradation was found for malathion. Thus, E. coli is capable of degrading fipronil and permethrin, thereby enabling the removal of those substances. Next, we studied how insecticides affect bacterial metabolism to understand their influence on the functions of the microbes. Our metabolomics analysis revealed chemical-dependent alterations in metabolic profiles and metabolite compositions following insecticide exposure. These changes encompassed shifts in carboxylic acids and derivatives, organooxygen compounds, as well as indoles and their derivatives. To gain a deeper insight into the systematic changes induced by these insecticides, we conducted a metabolic pathway analysis. Our data indicated that fipronil, compared with malathion and permethrin, exhibited opposite regulation in glycine, serine, and threonine metabolism and valine, leucine, and isoleucine biosynthesis. In summary, our study demonstrates the capability of E. coli to degrade fipronil and permethrin, leading to their removal, while malathion remains unaffected. Additionally, we reveal chemical-dependent alterations in bacterial metabolism induced by insecticide exposure, with specific impacts on metabolic pathways, particularly in pathways related to amino acid metabolism.
Collapse
Affiliation(s)
- Chao Guo
- Human Nutrition Program, Department of Human Sciences, The Ohio State University, Columbus, Ohio 43210, United States
| | - Li Chen
- Human Nutrition Program, Department of Human Sciences, The Ohio State University, Columbus, Ohio 43210, United States
- James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, United States
| | - Rui Xu
- Human Nutrition Program, Department of Human Sciences, The Ohio State University, Columbus, Ohio 43210, United States
| | - Jiangjiang Zhu
- Human Nutrition Program, Department of Human Sciences, The Ohio State University, Columbus, Ohio 43210, United States
- James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, United States
| |
Collapse
|
|
12
|
Trivedi A, Bose D, Moffat K, Pearson E, Walsh D, Cohen D, Skupsky J, Chao L, Golier J, Janulewicz P, Sullivan K, Krengel M, Tuteja A, Klimas N, Chatterjee S. Gulf War Illness Is Associated with Host Gut Microbiome Dysbiosis and Is Linked to Altered Species Abundance in Veterans from the BBRAIN Cohort. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2024; 21:1102. [PMID: 39200711 PMCID: PMC11354743 DOI: 10.3390/ijerph21081102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 08/09/2024] [Accepted: 08/13/2024] [Indexed: 09/02/2024]
Abstract
Gulf War Illness (GWI) is a debilitating condition marked by chronic fatigue, cognitive problems, pain, and gastrointestinal (GI) complaints in veterans who were deployed to the 1990-1991 Gulf War. Fatigue, GI complaints, and other chronic symptoms continue to persist more than 30 years post-deployment. Several potential mechanisms for the persistent illness have been identified and our prior pilot study linked an altered gut microbiome with the disorder. This study further validates and builds on our prior preliminary findings of host gut microbiome dysbiosis in veterans with GWI. Using stool samples and Multidimensional Fatigue Inventory (MFI) data from 89 GW veteran participants (63 GWI cases and 26 controls) from the Boston biorepository, recruitment, and integrative network (BBRAIN) for Gulf War Illness, we found that the host gut bacterial signature of veterans with GWI showed significantly different Bray-Curtis beta diversity than control veterans. Specifically, a higher Firmicutes to Bacteroidetes ratio, decrease in Akkermansia sp., Bacteroides thetaiotamicron, Bacteroides fragilis, and Lachnospiraceae genera and increase in Blautia, Streptococcus, Klebsiella, and Clostridium genera, that are associated with gut, immune, and brain health, were shown. Further, using MaAsLin and Boruta algorithms, Coprococcus and Eisenbergiella were identified as important predictors of GWI with an area under the curve ROC predictive value of 74.8%. Higher self-reported MFI scores in veterans with GWI were also significantly associated with an altered gut bacterial diversity and species abundance of Lachnospiraceae and Blautia. These results suggest potential therapeutic targets for veterans with GWI that target the gut microbiome and specific symptoms of the illness.
Collapse
Affiliation(s)
- Ayushi Trivedi
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (A.T.); (D.B.)
| | - Dipro Bose
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (A.T.); (D.B.)
| | - Kelly Moffat
- CosmosID, Germantown, MD 20874, USA; (K.M.); (D.W.)
| | | | - Dana Walsh
- CosmosID, Germantown, MD 20874, USA; (K.M.); (D.W.)
| | - Devra Cohen
- Miami VA Healthcare System, Miami, FL 33125, USA;
- Institute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA;
| | - Jonathan Skupsky
- VA Research and Development, VA Long Beach Health Care, Long Beach, CA 90822, USA;
| | - Linda Chao
- San Francisco Veterans Affairs Health Care System, San Francisco, CA 94121, USA
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143, USA
- Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, CA 94143, USA
| | - Julia Golier
- J. Peters VA Medical Center, Bronx, NY 10468, USA;
- Psychiatry Department, Icahn School of Medicine at Mount Sinai, 1428 Madison Ave, New York, NY 10029, USA
| | - Patricia Janulewicz
- Department of Environmental Health, Boston University School of Public Health, 715 Albany St. T4W, Boston, MA 02130, USA; (P.J.)
| | - Kimberly Sullivan
- Department of Environmental Health, Boston University School of Public Health, 715 Albany St. T4W, Boston, MA 02130, USA; (P.J.)
| | - Maxine Krengel
- Department of Neurology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02130, USA;
| | - Ashok Tuteja
- Division of Gastroenterology, School of Medicine, University of Utah, Salt Lake City, UT 84132, USA;
| | - Nancy Klimas
- Institute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA;
- Geriatric Research and Education Clinical Center, Miami VA Heathcare System, Miami, FL 33125, USA
| | - Saurabh Chatterjee
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (A.T.); (D.B.)
- Institute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA;
- Department of Medicine, Infectious Disease, UCI School of Medicine, Irvine, CA 92697, USA
| |
Collapse
|
|
13
|
Peer A, Samuelson DR. The Role of the Microbiome in Allergy, Asthma, and Occupational Lung Disease. Curr Allergy Asthma Rep 2024; 24:415-423. [PMID: 38904934 PMCID: PMC11297072 DOI: 10.1007/s11882-024-01156-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/07/2024] [Indexed: 06/22/2024]
Abstract
PURPOSE OF REVIEW The human commensal microbiota is now widely accepted as a key regulator of human health and disease. The composition of the mucosal associated microbiota has been shown to play a critical role in the lung health. The role of the mucosal microbiota in the development and severity of allergy, asthma, and occupational lung disease is only beginning to take shape. However, advances in our understanding of these links have tremendous potential to led to new clinical interventions to reduce allergy, asthma, and occupational lung disease morbidity. RECENT FINDINGS We review recent work describing the relationship and role of the commensal microbiota in the development of allergy, asthma, and occupational lung disease. Our review primarily focuses on occupational exposures and the effects of the microbiome, both in composition and function. Data generated from these studies may lead to the development of interventions targeted at establishing and maintaining a healthy microbiota. We also highlight the role of environmental exposures and the effects on the commensal microbial community and their potential association with occupational lung disease. This review explores the current research describing the role of the human microbiome in the regulation of pulmonary health and disease, with a specific focus on the role of the mucosal microbiota in the development of allergy, asthma, and occupational lung disease.
Collapse
Affiliation(s)
- Ashley Peer
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep, University of Nebraska Medical Center, Omaha, NE, USA
| | - Derrick R Samuelson
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep, University of Nebraska Medical Center, Omaha, NE, USA.
- Nebraska Food for Health Center, University of Nebraska-Lincoln, Lincoln, NE, USA.
| |
Collapse
|
|
14
|
Bose D, Saha P, Roy S, Trivedi A, More M, Klimas N, Tuteja A, Chatterjee S. A Double-Humanized Mouse Model for Studying Host Gut Microbiome-Immune Interactions in Gulf War Illness. Int J Mol Sci 2024; 25:6093. [PMID: 38892281 PMCID: PMC11172868 DOI: 10.3390/ijms25116093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 05/25/2024] [Accepted: 05/29/2024] [Indexed: 06/21/2024] Open
Abstract
Unraveling the multisymptomatic Gulf War Illness (GWI) pathology and finding an effective cure have eluded researchers for decades. The chronic symptom persistence and limitations for studying the etiologies in mouse models that differ significantly from those in humans pose challenges for drug discovery and finding effective therapeutic regimens. The GWI exposome differs significantly in the study cohorts, and the above makes it difficult to recreate a model closely resembling the GWI symptom pathology. We have used a double engraftment strategy for reconstituting a human immune system coupled with human microbiome transfer to create a humanized-mouse model for GWI. Using whole-genome shotgun sequencing and blood immune cytokine enzyme linked immunosorbent assay (ELISA), we show that our double humanized mice treated with Gulf War (GW) chemicals show significantly altered gut microbiomes, similar to those reported in a Veteran cohort of GWI. The results also showed similar cytokine profiles, such as increased levels of IL-1β, IL-6, and TNF R-1, in the double humanized model, as found previously in a human cohort. Further, a novel GWI Veteran fecal microbiota transfer was used to create a second alternative model that closely resembled the microbiome and immune-system-associated pathology of a GWI Veteran. A GWI Veteran microbiota transplant in humanized mice showed a human microbiome reconstitution and a systemic inflammatory pathology, as reflected by increases in interleukins 1β, 6, 8 (IL-1β, IL-6, IL-8), tumor necrosis factor receptor 1 (TNF R-1), and endotoxemia. In conclusion, though preliminary, we report a novel in vivo model with a human microbiome reconstitution and an engrafted human immune phenotype that may help to better understand gut-immune interactions in GWI.
Collapse
Affiliation(s)
- Dipro Bose
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (D.B.); (P.S.); (S.R.); (A.T.); (M.M.)
| | - Punnag Saha
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (D.B.); (P.S.); (S.R.); (A.T.); (M.M.)
| | - Subhajit Roy
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (D.B.); (P.S.); (S.R.); (A.T.); (M.M.)
| | - Ayushi Trivedi
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (D.B.); (P.S.); (S.R.); (A.T.); (M.M.)
| | - Madhura More
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (D.B.); (P.S.); (S.R.); (A.T.); (M.M.)
| | - Nancy Klimas
- Institute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA;
| | - Ashok Tuteja
- Division of Gastroenterology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA;
| | - Saurabh Chatterjee
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (D.B.); (P.S.); (S.R.); (A.T.); (M.M.)
- Division of Infectious Disease, School of Medicine, University of California, Irvine, CA 92697, USA
- VA Research and Development, VA Long Beach Health Care, Long Beach, CA 90822, USA
| |
Collapse
|
|
15
|
Peddinti V, Avaghade MM, Suthar SU, Rout B, Gomte SS, Agnihotri TG, Jain A. Gut instincts: Unveiling the connection between gut microbiota and Alzheimer's disease. Clin Nutr ESPEN 2024; 60:266-280. [PMID: 38479921 DOI: 10.1016/j.clnesp.2024.02.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 02/16/2024] [Indexed: 04/13/2024]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder marked by neuroinflammation and gradual cognitive decline. Recent research has revealed that the gut microbiota (GM) plays an important role in the pathogenesis of AD through the microbiota-gut-brain axis. However, the mechanism by which GM and microbial metabolites alter brain function is not clearly understood. GM dysbiosis increases the permeability of the intestine, alters the blood-brain barrier permeability, and elevates proinflammatory mediators causing neurodegeneration. This review article introduced us to the composition and functions of GM along with its repercussions of dysbiosis in relation to AD. We also discussed the importance of the gut-brain axis and its role in communication. Later we focused on the mechanism behind gut dysbiosis and the progression of AD including neuroinflammation, oxidative stress, and changes in neurotransmitter levels. Furthermore, we highlighted recent developments in AD management, such as microbiota-based therapy, dietary interventions like prebiotics, probiotics, and fecal microbiota transplantation. Finally, we concluded with challenges and future directions in AD research based on GM.
Collapse
Affiliation(s)
- Vasu Peddinti
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, Gandhinagar, 382355, Gujarat, India
| | - Manoj Mohan Avaghade
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, Gandhinagar, 382355, Gujarat, India
| | - Sunil Umedmal Suthar
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, Gandhinagar, 382355, Gujarat, India
| | - Biswajit Rout
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, Gandhinagar, 382355, Gujarat, India
| | - Shyam Sudhakar Gomte
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, Gandhinagar, 382355, Gujarat, India
| | - Tejas Girish Agnihotri
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, Gandhinagar, 382355, Gujarat, India
| | - Aakanchha Jain
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, Gandhinagar, 382355, Gujarat, India.
| |
Collapse
|
|
16
|
Kharrazian D. Exposure to Environmental Toxins & Autoimmune Conditions. Integr Med (Encinitas) 2024; 23:22-26. [PMID: 38618165 PMCID: PMC11007618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2024]
Abstract
The incidence of autoimmunity is growing rapidly worldwide. Many epidemiological studies have found environmental factors, such as toxic chemicals, to be a key factor in this rapid progression. Many mechanisms that can cause immune dysregulation and autoimmune reactivity from toxic chemical exposure to subsets of individuals with genetic susceptibility in immune regulatory genes have been identified. In susceptible genotypes, toxic chemicals can induce epigenetic expressions, bind to immune and endocrine receptors throughout the body and promote immune dysregulation, bind to nucleic acids and promote anti-nuclear autoimmunity, deplete antioxidant reserves, promote immune barrier degradation, induce lymphocyte dysregulation, and alter normal antigen presenting responses. This paper reviews the specific immunological pathways involved with environmental toxins and autoimmunity exposure.
Collapse
Affiliation(s)
- Datis Kharrazian
- Harvard Medical School, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital, MA, USA; Department of Preventive Medicine, Loma Linda University School of Medicine, USA
| |
Collapse
|
|
17
|
Wei BR, Zhao YJ, Cheng YF, Huang C, Zhang F. Helicobacter pylori infection and Parkinson's Disease: etiology, pathogenesis and levodopa bioavailability. Immun Ageing 2024; 21:1. [PMID: 38166953 PMCID: PMC10759355 DOI: 10.1186/s12979-023-00404-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 12/11/2023] [Indexed: 01/05/2024]
Abstract
Parkinson's disease (PD), a neurodegenerative disorder with an unknown etiology, is primarily characterized by the degeneration of dopamine (DA) neurons. The prevalence of PD has experienced a significant surge in recent years. The unidentified etiology poses limitations to the development of effective therapeutic interventions for this condition. Helicobacter pylori (H. pylori) infection has affected approximately half of the global population. Mounting evidences suggest that H. pylori infection plays an important role in PD through various mechanisms. The autotoxin produced by H. pylori induces pro-inflammatory cytokines release, thereby facilitating the occurrence of central inflammation that leads to neuronal damage. Simultaneously, H. pylori disrupts the equilibrium of gastrointestinal microbiota with an overgrowth of bacteria in the small intestinal known as small intestinal bacterial overgrowth (SIBO). This dysbiosis of the gut flora influences the central nervous system (CNS) through microbiome-gut-brain axis. Moreover, SIBO hampers levodopa absorption and affects its therapeutic efficacy in the treatment of PD. Also, H. pylori promotes the production of defensins to regulate the permeability of the blood-brain barrier, facilitating the entry of harmful factors into the CNS. In addition, H. pylori has been found to induce gastroparesis, resulting in a prolonged transit time for levodopa to reach the small intestine. H. pylori may exploit levodopa to facilitate its own growth and proliferation, or it can inflict damage to the gastrointestinal mucosa, leading to gastrointestinal ulcers and impeding levodopa absorption. Here, this review focused on the role of H. pylori infection in PD from etiology, pathogenesis to levodopa bioavailability.
Collapse
Affiliation(s)
- Bang-Rong Wei
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education and Key Laboratory of Basic Pharmacology of Guizhou Province and Laboratory Animal Centre, Zunyi Medical University, Zunyi, Guizhou, China
| | - Yu-Jia Zhao
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education and Key Laboratory of Basic Pharmacology of Guizhou Province and Laboratory Animal Centre, Zunyi Medical University, Zunyi, Guizhou, China
| | - Yu-Feng Cheng
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education and Key Laboratory of Basic Pharmacology of Guizhou Province and Laboratory Animal Centre, Zunyi Medical University, Zunyi, Guizhou, China
| | - Chun Huang
- The Fifth People's Hospital of Chongqing, Chongqing, China
| | - Feng Zhang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education and Key Laboratory of Basic Pharmacology of Guizhou Province and Laboratory Animal Centre, Zunyi Medical University, Zunyi, Guizhou, China.
| |
Collapse
|
|
18
|
Sah RK, Nandan A, Kv A, S P, S S, Jose A, Venkidasamy B, Nile SH. Decoding the role of the gut microbiome in gut-brain axis, stress-resilience, or stress-susceptibility: A review. Asian J Psychiatr 2024; 91:103861. [PMID: 38134565 DOI: 10.1016/j.ajp.2023.103861] [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: 08/17/2023] [Revised: 12/01/2023] [Accepted: 12/08/2023] [Indexed: 12/24/2023]
Abstract
Increased exposure to stress is associated with stress-related disorders, including depression, anxiety, and neurodegenerative conditions. However, susceptibility to stress is not seen in every individual exposed to stress, and many of them exhibit resilience. Thus, developing resilience to stress could be a big breakthrough in stress-related disorders, with the potential to replace or act as an alternative to the available therapies. In this article, we have focused on the recent advancements in gut microbiome research and the potential role of the gut-brain axis (GBA) in developing resilience or susceptibility to stress. There might be a complex interaction between the autonomic nervous system (ANS), immune system, endocrine system, microbial metabolites, and bioactive lipids like short-chain fatty acids (SCFAs), neurotransmitters, and their metabolites that regulates the communication between the gut microbiota and the brain. High fiber intake, prebiotics, probiotics, plant supplements, and fecal microbiome transplant (FMT) could be beneficial against gut dysbiosis-associated brain disorders. These could promote the growth of SCFA-producing bacteria, thereby enhancing the gut barrier and reducing the gut inflammatory response, increase the expression of the claudin-2 protein associated with the gut barrier, and maintain the blood-brain barrier integrity by promoting the expression of tight junction proteins such as claudin-5. Their neuroprotective effects might also be related to enhancing the expression of brain-derived neurotrophic factor (BDNF) and glucagon-like peptide (GLP-1). Further investigations are needed in the field of the gut microbiome for the elucidation of the mechanisms by which gut dysbiosis contributes to the pathophysiology of neuropsychiatric disorders.
Collapse
Affiliation(s)
- Ranjay Kumar Sah
- Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi 682 041, Kerala, India
| | - Amritasree Nandan
- Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi 682 041, Kerala, India
| | - Athira Kv
- Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi 682 041, Kerala, India.
| | - Prashant S
- Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi 682 041, Kerala, India
| | - Sathianarayanan S
- NITTE (Deemed to be University), NGSM Institute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, Mangalore, India
| | - Asha Jose
- JSS College of Pharmacy, JSS Academy of Higher Education and research, Ooty 643001, Tamil Nadu, India
| | - Baskar Venkidasamy
- Department of Oral & Maxillofacial Surgery, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai 600 077, Tamil Nadu, India.
| | - Shivraj Hariram Nile
- Division of Food and Nutritional Biotechnology, National Agri-Food Biotechnology Institute (NABI), Sector-81, Mohali 140306, Punjab, India.
| |
Collapse
|
|
19
|
Trivedi A, Bose D, Saha P, Roy S, More M, Skupsky J, Klimas NG, Chatterjee S. Prolonged Antibiotic Use in a Preclinical Model of Gulf War Chronic Multisymptom-Illness Causes Renal Fibrosis-like Pathology via Increased micro-RNA 21-Induced PTEN Inhibition That Is Correlated with Low Host Lachnospiraceae Abundance. Cells 2023; 13:56. [PMID: 38201260 PMCID: PMC10777912 DOI: 10.3390/cells13010056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 12/21/2023] [Accepted: 12/25/2023] [Indexed: 01/12/2024] Open
Abstract
Gulf War (GW) veterans show gastrointestinal disturbances and gut dysbiosis. Prolonged antibiotic treatments commonly employed in veterans, especially the use of fluoroquinolones and aminoglycosides, have also been associated with dysbiosis. This study investigates the effect of prolonged antibiotic exposure on risks of adverse renal pathology and its association with gut bacterial species abundance in underlying GWI and aims to uncover the molecular mechanisms leading to possible renal dysfunction with aging. Using a GWI mouse model, administration of a prolonged antibiotic regimen involving neomycin and enrofloxacin treatment for 5 months showed an exacerbated renal inflammation with increased NF-κB activation and pro-inflammatory cytokines levels. Involvement of the high mobility group 1 (HMGB1)-mediated receptor for advanced glycation end products (RAGE) activation triggered an inflammatory phenotype and increased transforming growth factor-β (TGF-β) production. Mechanistically, TGF-β- induced microRNA-21 upregulation in the renal tissue leads to decreased phosphatase and tensin homolog (PTEN) expression. The above event led to the activation of protein kinase-B (AKT) signaling, resulting in increased fibronectin production and fibrosis-like pathology. Importantly, the increased miR-21 was associated with low levels of Lachnospiraceae in the host gut which is also a key to heightened HMGB1-mediated inflammation. Overall, though correlative, the study highlights the complex interplay between GWI, host gut dysbiosis, prolonged antibiotics usage, and renal pathology via miR-21/PTEN/AKT signaling.
Collapse
Affiliation(s)
- Ayushi Trivedi
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (A.T.); (D.B.); (P.S.); (S.R.); (M.M.)
| | - Dipro Bose
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (A.T.); (D.B.); (P.S.); (S.R.); (M.M.)
| | - Punnag Saha
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (A.T.); (D.B.); (P.S.); (S.R.); (M.M.)
| | - Subhajit Roy
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (A.T.); (D.B.); (P.S.); (S.R.); (M.M.)
| | - Madhura More
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (A.T.); (D.B.); (P.S.); (S.R.); (M.M.)
| | | | - Nancy G. Klimas
- Institute for Neuro-Immune Medicine, College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA;
| | - Saurabh Chatterjee
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (A.T.); (D.B.); (P.S.); (S.R.); (M.M.)
- Long Beach VA Medical Center, Long Beach, CA 90822, USA;
- Division of Infectious Diseases, Department of Medicine, School of Medicine, University of California, Irvine, CA 92697, USA
| |
Collapse
|
|
20
|
Zhu B, Zhou Y, Zhou W, Chen C, Wang J, Xu S, Wang Q. Electroacupuncture modulates gut microbiota in mice: A potential target in postoperative cognitive dysfunction. Anat Rec (Hoboken) 2023; 306:3131-3143. [PMID: 36094150 DOI: 10.1002/ar.25065] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/27/2022] [Accepted: 08/17/2022] [Indexed: 11/06/2022]
Abstract
The detailed mechanism of inflammation in postoperative cognitive dysfunction (POCD) is unclear. This study aimed to determine whether electroacupuncture (EA) ameliorates POCD by modulating gut microbial dysbiosis. Compared to the control group, mice in the EA group were treated at the acupoints Zusanli (ST36), Quchi (L111), Baihui (GV20), and Dazhui (GV14) 1 week before appendectomy. Novel object recognition and the Morris water maze tests were used to assess learning and spatial reference memory deficits, whereas hippocampus samples and stool samples were collected for central inflammatory tests and 16S-rRNA sequencing of intestinal flora, respectively. In amyloid precursor protein/presenilin 1 (APP/PS1) mice, EA enhanced spatial memory and learning deficits. The fecal microbial community was altered in APP/PS1 mice in the absence of EA following surgery. Among them, Coprococcus and Bacteroidetes were more abundant in the EA groups than in the control groups; however, Actinobacteriota, Helicobacteraceae, and Escherichia/shigella constitute the minor bacterial colonization in the EA groups. Furthermore, we found a significant negative correlation between Firmicutes and escape latency (Pearson correlation coefficient - 0.551, p < 0.01) and positive correlation between Proteobacteria and escape latency (Pearson correlation coefficient 0.462, p < 0.05). Electron microscopy revealed signs of blood-brain barrier (BBB) impairments and immunofluorescence images showed glial cells activated in the hippocampus of APP/PS mice without EA, and serum diamine oxidase levels were increased in these mice; whereas EA treatment significantly relieved the above pathological changes. Our findings implied that EA decreases hippocampal inflammation of APP/PS1 by upregulating benificial gut microbiota, reducing BBB and intestinal barrier dysfunction, thus alleviates postoperative cognitive dysfunction. This may provide a novel target in POCD management.
Collapse
Affiliation(s)
- Binbin Zhu
- The Department of Radiology and Anesthesiology, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang Province, China
| | - Yanling Zhou
- The Department of Radiology and Anesthesiology, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang Province, China
| | - Weijian Zhou
- The Department of Radiology and Anesthesiology, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang Province, China
| | - Chunqu Chen
- The Department of Radiology and Anesthesiology, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang Province, China
| | - Jianhua Wang
- The Department of Radiology and Anesthesiology, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang Province, China
| | - Shujun Xu
- Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Jiangbei District, China
| | - Qinwen Wang
- Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Jiangbei District, China
| |
Collapse
|
|
21
|
Ramya Ranjan Nayak SP, Boopathi S, Haridevamuthu B, Arockiaraj J. Toxic ties: Unraveling the complex relationship between endocrine disrupting chemicals and chronic kidney disease. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2023; 338:122686. [PMID: 37802289 DOI: 10.1016/j.envpol.2023.122686] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 10/01/2023] [Accepted: 10/02/2023] [Indexed: 10/08/2023]
Abstract
Environmental pollution is inherently linked to several metabolic diseases and high mortality. The kidney is more susceptible to environmental pollutants compared to other organs as it is involved in concentrating and filtering most of these toxins. Few epidemiological studies revealed the intrinsic relationship between exposure to Endocrine Disrupting Chemicals (EDCs) and CKD development. Though EDCs have the potential to cause severe pathologies, the specific molecular mechanisms by which they accelerate the progression of CKD remain elusive. In particular, our understanding of how pollutants affect the progression of chronic kidney disease (CKD) through the gut-kidney axis is currently limited. EDCs modulate the composition and function of the gut microbial community and favor the colonization of harmful gut pathogens. This alteration leads to an overproduction of uremic toxin and membrane vesicles. These vesicles carry several inflammatory molecules that exacerbate inflammation and renal tissue damage and aggravate the progression of CKD. Several experimental studies have revealed potential pathways by which uremic toxin further aggravates CKD. These include the induction of membrane vesicle production in host cells, which can trigger inflammatory pathways and insulin resistance. Reciprocally, CKD can also modulate gut bacterial composition that might further aggravate CKD condition. Thus, EDCs pose a significant threat to kidney health and the global CKD burden. Understanding this complicated issue necessitates multidisciplinary initiatives such as strict environmental controls, public awareness, and the development of novel therapeutic strategies targeting EDCs.
Collapse
Affiliation(s)
- S P Ramya Ranjan Nayak
- Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Kattankulathur, 603203, Chengalpattu District, Tamil Nadu, India
| | - Seenivasan Boopathi
- Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Kattankulathur, 603203, Chengalpattu District, Tamil Nadu, India
| | - B Haridevamuthu
- Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Kattankulathur, 603203, Chengalpattu District, Tamil Nadu, India
| | - Jesu Arockiaraj
- Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Kattankulathur, 603203, Chengalpattu District, Tamil Nadu, India.
| |
Collapse
|
|
22
|
Plummer AM, Matos YL, Lin HC, Ryman SG, Birg A, Quinn DK, Parada AN, Vakhtin AA. Gut-brain pathogenesis of post-acute COVID-19 neurocognitive symptoms. Front Neurosci 2023; 17:1232480. [PMID: 37841680 PMCID: PMC10568482 DOI: 10.3389/fnins.2023.1232480] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 09/01/2023] [Indexed: 10/17/2023] Open
Abstract
Approximately one third of non-hospitalized coronavirus disease of 2019 (COVID-19) patients report chronic symptoms after recovering from the acute stage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Some of the most persistent and common complaints of this post-acute COVID-19 syndrome (PACS) are cognitive in nature, described subjectively as "brain fog" and also objectively measured as deficits in executive function, working memory, attention, and processing speed. The mechanisms of these chronic cognitive sequelae are currently not understood. SARS-CoV-2 inflicts damage to cerebral blood vessels and the intestinal wall by binding to angiotensin-converting enzyme 2 (ACE2) receptors and also by evoking production of high levels of systemic cytokines, compromising the brain's neurovascular unit, degrading the intestinal barrier, and potentially increasing the permeability of both to harmful substances. Such substances are hypothesized to be produced in the gut by pathogenic microbiota that, given the profound effects COVID-19 has on the gastrointestinal system, may fourish as a result of intestinal post-COVID-19 dysbiosis. COVID-19 may therefore create a scenario in which neurotoxic and neuroinflammatory substances readily proliferate from the gut lumen and encounter a weakened neurovascular unit, gaining access to the brain and subsequently producing cognitive deficits. Here, we review this proposed PACS pathogenesis along the gut-brain axis, while also identifying specific methodologies that are currently available to experimentally measure each individual component of the model.
Collapse
Affiliation(s)
- Allison M. Plummer
- School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, United States
| | - Yvette L. Matos
- The Mind Research Network/Lovelace Biomedical and Environmental Research Institute, Albuquerque, NM, United States
| | - Henry C. Lin
- Division of Gastroenterology and Hepatology, University of New Mexico, Albuquerque, NM, United States
- Section of Gastroenterology, New Mexico Veterans Affairs Health Care System, Albuquerque, NM, United States
| | - Sephira G. Ryman
- The Mind Research Network/Lovelace Biomedical and Environmental Research Institute, Albuquerque, NM, United States
- Nene and Jamie Koch Comprehensive Movement Disorder Center, Department of Neurology, University of New Mexico, Albuquerque, NM, United States
| | - Aleksandr Birg
- Division of Gastroenterology and Hepatology, University of New Mexico, Albuquerque, NM, United States
- Section of Gastroenterology, New Mexico Veterans Affairs Health Care System, Albuquerque, NM, United States
| | - Davin K. Quinn
- Department of Psychiatry and Behavioral Sciences, University of New Mexico School of Medicine, Albuquerque, NM, United States
| | - Alisha N. Parada
- Division of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, United States
| | - Andrei A. Vakhtin
- The Mind Research Network/Lovelace Biomedical and Environmental Research Institute, Albuquerque, NM, United States
| |
Collapse
|
|
23
|
Dissanayake WMN, Chandanee MR, Lee SM, Heo JM, Yi YJ. Change in intestinal alkaline phosphatase activity is a hallmark of antibiotic-induced intestinal dysbiosis. Anim Biosci 2023; 36:1403-1413. [PMID: 37170509 PMCID: PMC10472154 DOI: 10.5713/ab.23.0052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/08/2023] [Accepted: 04/07/2023] [Indexed: 05/13/2023] Open
Abstract
OBJECTIVE Intestinal alkaline phosphatase (IAP) maintains intestinal homeostasis by detoxifying bacterial endotoxins and regulating gut microbiota, and lipid absorption. Antibiotics administered to animals can cause gut dysbiosis and barrier disruption affecting animal health. Therefore, the present study sought to investigate the role of IAP in the intestinal environment in dysbiosis. METHODS Young male mice aged 9 weeks were administered a high dose of antibiotics to induce dysbiosis. They were then sacrificed after 4 weeks to collect the serum and intestinal organs. The IAP activity in the ileum and the level of cytokines in the serum samples were measured. Quantitative real-time polymerase chain reaction analysis of RNA from the intestinal samples was performed using primers for tight junction proteins (TJPs) and proinflammatory cytokines. The relative intensity of IAP and toll-like receptor 4 (TLR4) in intestinal samples was evaluated by western blotting. RESULTS The IAP activity was significantly lower in the ileum samples of the dysbiosisinduced group compared to the control. The interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha concentrations were significantly higher in the ileum samples of the dysbiosis-induced group. The RNA expression levels of TJP2, claudin-3, and claudin-11 showed significantly lower values in the intestinal samples from the dysbiosis-induced mice. Results from western blotting revealed that the intensity of IAP expression was significantly lower in the ileum samples of the dysbiosis-induced group, while the intensity of TLR4 expression was significantly higher compared to that of the control group without dysbiosis. CONCLUSION The IAP activity and relative mRNA expression of the TJPs decreased, while the levels of proinflammatory cytokines increased, which can affect intestinal integrity and the function of the intestinal epithelial cells. This suggests that IAP is involved in mediating the intestinal environment in dysbiosis induced by antibiotics and is an enzyme that can potentially be used to maintain the intestinal environment in animal health care.
Collapse
Affiliation(s)
| | - Malavige Romesha Chandanee
- Department of Agricultural Education, College of Education, Sunchon National University, Suncheon 57922,
Korea
| | - Sang-Myeong Lee
- Laboratory of Veterinary Virology, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644,
Korea
| | - Jung Min Heo
- College of Agriculture and Life Sciences, Department of Animal Science and Biotechnology, Chungnam National University, Daejeon 34134,
Korea
| | - Young-Joo Yi
- Department of Agricultural Education, College of Education, Sunchon National University, Suncheon 57922,
Korea
| |
Collapse
|
|
24
|
Shepilov D, Osadchenko I, Kovalenko T, Yamada C, Chereshynska A, Smozhanyk K, Ostrovska G, Groppa S, Movila A, Skibo G. Maternal antibiotic administration during gestation can affect the memory and brain structure in mouse offspring. Front Cell Neurosci 2023; 17:1176676. [PMID: 37234915 PMCID: PMC10206017 DOI: 10.3389/fncel.2023.1176676] [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: 02/28/2023] [Accepted: 04/18/2023] [Indexed: 05/28/2023] Open
Abstract
Maternal antibiotics administration (MAA) is among the widely used therapeutic approaches in pregnancy. Although published evidence demonstrates that infants exposed to antibiotics immediately after birth have altered recognition memory responses at one month of age, very little is known about in utero effects of antibiotics on the neuronal function and behavior of children after birth. Therefore, this study aimed to evaluate the impact of MAA at different periods of pregnancy on memory decline and brain structural alterations in young mouse offspring after their first month of life. To study the effects of MAA on 4-week-old offspring, pregnant C57BL/6J mouse dams (2-3-month-old; n = 4/group) were exposed to a cocktail of amoxicillin (205 mg/kg/day) and azithromycin (51 mg/kg/day) in sterile drinking water (daily/1 week) during either the 2nd or 3rd week of pregnancy and stopped after delivery. A control group of pregnant dams was exposed to sterile drinking water alone during all three weeks of pregnancy. Then, the 4-week-old offspring mice were first evaluated for behavioral changes. Using the Morris water maze assay, we revealed that exposure of pregnant mice to antibiotics at the 2nd and 3rd weeks of pregnancy significantly altered spatial reference memory and learning skills in their offspring compared to those delivered from the control group of dams. In contrast, no significant difference in long-term associative memory was detected between offspring groups using the novel object recognition test. Then, we histologically evaluated brain samples from the same offspring individuals using conventional immunofluorescence and electron microscopy assays. To our knowledge, we observed a reduction in the density of the hippocampal CA1 pyramidal neurons and hypomyelination in the corpus callosum in groups of mice in utero exposed to antibiotics at the 2nd and 3rd weeks of gestation. In addition, offspring exposed to antibiotics at the 2nd or 3rd week of gestation demonstrated a decreased astrocyte cell surface area and astrocyte territories or depletion of neurogenesis in the dentate gyrus and hippocampal synaptic loss, respectively. Altogether, this study shows that MAA at different times of pregnancy can pathologically alter cognitive behavior and brain development in offspring at an early age after weaning.
Collapse
Affiliation(s)
- Dmytro Shepilov
- Department of Cytology, Bogomoletz Institute of Physiology, NAS of Ukraine, Kyiv, Ukraine
| | - Iryna Osadchenko
- Department of Cytology, Bogomoletz Institute of Physiology, NAS of Ukraine, Kyiv, Ukraine
| | - Tetiana Kovalenko
- Department of Cytology, Bogomoletz Institute of Physiology, NAS of Ukraine, Kyiv, Ukraine
| | - Chiaki Yamada
- Department of Biomedical Sciences and Comprehensive Care, School of Dentistry, Indiana University, Indianapolis, IN, United States
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Anastasiia Chereshynska
- Department of Biomedical Sciences and Comprehensive Care, School of Dentistry, Indiana University, Indianapolis, IN, United States
| | - Kateryna Smozhanyk
- Department of Cytology, Bogomoletz Institute of Physiology, NAS of Ukraine, Kyiv, Ukraine
| | - Galyna Ostrovska
- Department of Cytology, Histology, and Reproductive Medicine, Institute of Biology and Medicine, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
| | - Stanislav Groppa
- Department of Neurology, Institute of Emergency Medicine, Chisinau, Moldova
- Department of Neurology, State University of Medicine and Pharmacy “Nicolae Testemiţanu”, Chisinau, Moldova
| | - Alexandru Movila
- Department of Biomedical Sciences and Comprehensive Care, School of Dentistry, Indiana University, Indianapolis, IN, United States
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Galyna Skibo
- Department of Cytology, Bogomoletz Institute of Physiology, NAS of Ukraine, Kyiv, Ukraine
| |
Collapse
|
|
25
|
Kodali M, Jankay T, Shetty AK, Reddy DS. Pathophysiological basis and promise of experimental therapies for Gulf War Illness, a chronic neuropsychiatric syndrome in veterans. Psychopharmacology (Berl) 2023; 240:673-697. [PMID: 36790443 DOI: 10.1007/s00213-023-06319-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 01/17/2023] [Indexed: 02/16/2023]
Abstract
This article describes the pathophysiology and potential treatments for Gulf War Illness (GWI), which is a chronic neuropsychiatric illness linked to a combination of chemical exposures experienced by service personnel during the first Gulf War in 1991. However, there is currently no effective treatment for veterans with GWI. The article focuses on the current status and efficacy of existing therapeutic interventions in preclinical models of GWI, as well as potential perspectives of promising therapies. GWI stems from changes in brain and peripheral systems in veterans, leading to neurocognitive deficits, as well as physiological and psychological effects resulting from multifaceted changes such as neuroinflammation, oxidative stress, and neuronal damage. Aging not only renders veterans more susceptible to GWI symptoms, but also attenuates their immune capabilities and response to therapies. A variety of experimental models are being used to investigate the pathophysiology and develop therapies that have the ability to alleviate devastating symptoms. Over two dozen therapeutic interventions targeting neuroinflammation, mitochondrial dysfunction, neuronal injury, and neurogenesis are being tested, including agents such as curcumin, curcumin nanoparticles, monosodium luminol, melatonin, resveratrol, fluoxetine, rolipram, oleoylethanolamide, ketamine, levetiracetam, nicotinamide riboside, minocycline, pyridazine derivatives, and neurosteroids. Preclinical outcomes show that some agents have promise, including curcumin, resveratrol, and ketamine, which are being tested in clinical trials in GWI veterans. Neuroprotectants and other compounds such as monosodium luminol, melatonin, levetiracetam, oleoylethanolamide, and nicotinamide riboside appear promising for future clinical trials. Neurosteroids have been shown to have neuroprotective and disease-modifying properties, which makes them a promising medicine for GWI. Therefore, accelerated clinical studies are urgently needed to evaluate and launch an effective therapy for veterans displaying GWI.
Collapse
Affiliation(s)
- Maheedhar Kodali
- Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University School of Medicine, College Station, TX, USA
| | - Tanvi Jankay
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University School of Medicine, Bryan, TX, USA
| | - Ashok K Shetty
- Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University School of Medicine, College Station, TX, USA.,Texas A&M Health Institute of Pharmacology and Neurotherapeutics, Texas A&M University Health Science Center, 8447 Riverside Pkwy, Bryan, TX, 77807, USA
| | - Doodipala Samba Reddy
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University School of Medicine, Bryan, TX, USA. .,Texas A&M Health Institute of Pharmacology and Neurotherapeutics, Texas A&M University Health Science Center, 8447 Riverside Pkwy, Bryan, TX, 77807, USA.
| |
Collapse
|
|
26
|
Slevin E, Koyama S, Harrison K, Wan Y, Klaunig JE, Wu C, Shetty AK, Meng F. Dysbiosis in gastrointestinal pathophysiology: Role of the gut microbiome in Gulf War Illness. J Cell Mol Med 2023; 27:891-905. [PMID: 36716094 PMCID: PMC10064030 DOI: 10.1111/jcmm.17631] [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: 09/06/2022] [Revised: 11/11/2022] [Accepted: 11/18/2022] [Indexed: 01/31/2023] Open
Abstract
Gulf War Illness (GWI) has been reported in 25%-35% of veterans returned from the Gulf war. Symptoms of GWI are varied and include both neurological and gastrointestinal symptoms as well as chronic fatigue. Development of GWI has been associated with chemical exposure particularly with exposure to pyridostigmine bromide (PB) and permethrin. Recent studies have found that the pathology of GWI is connected to changes in the gut microbiota, that is the gut dysbiosis. In studies using animal models, the exposure to PB and permethrin resulted in similar changes in the gut microbiome as these found in GW veterans with GWI. Studies using animal models have also shown that phytochemicals like curcumin are beneficial in reducing the symptoms and that the extracellular vesicles (EV) released from gut bacteria and from the intestinal epithelium can both promote diseases and suppress diseases through the intercellular communication mechanisms. The intestinal epithelium cells produce EVs and these EVs of intestinal epithelium origin are found to suppress inflammatory bowel disease severity, suggesting the benefits of utilizing EV in treatments. On the contrary, EV from the plasma of septic mice enhanced the level of proinflammatory cytokines in vitro and neutrophils and macrophages in vivo, suggesting differences in the EV depending on the types of cells they were originated and/or influences of environmental changes. These studies suggest that targeting the EV that specifically have positive influences may become a new therapeutic strategy in the treatment of veterans with GWI.
Collapse
Affiliation(s)
- Elise Slevin
- Division of Gastroenterology and Hepatology, Department of MedicineIndiana University School of MedicineIndianapolisIndianaUSA
- Richard L. Roudebush VA Medical CenterIndianapolisIndianaUSA
| | - Sachiko Koyama
- Division of Gastroenterology and Hepatology, Department of MedicineIndiana University School of MedicineIndianapolisIndianaUSA
- Richard L. Roudebush VA Medical CenterIndianapolisIndianaUSA
| | - Kelly Harrison
- Department of Transplant SurgeryBaylor Scott & White Memorial HospitalTempleTexasUSA
| | - Ying Wan
- Department of Pathophysiology, School of Basic Medical ScienceSouthwest Medical UniversityLuzhouChina
| | - James E. Klaunig
- Laboratory of Investigative Toxicology and Pathology, Department of Environmental and Occupational Health, Indiana School of Public HealthIndiana UniversityBloomingtonIndianaUSA
| | - Chaodong Wu
- Department of NutritionTexas A&M UniversityCollege StationTexasUSA
| | - Ashok K. Shetty
- Department of Molecular and Cellular MedicineInstitute for Regenerative Medicine, Texas A&M College of MedicineCollege StationTexasUSA
| | - Fanyin Meng
- Division of Gastroenterology and Hepatology, Department of MedicineIndiana University School of MedicineIndianapolisIndianaUSA
- Richard L. Roudebush VA Medical CenterIndianapolisIndianaUSA
| |
Collapse
|
|
27
|
Malhotra D, Boyle SH, Gifford EJ, Sullivan BA, Nguyen Wenker TH, Abs ND, Ahmed ST, Upchurch J, Vahey J, Stafford C, Efird JT, Hunt SC, Bradford A, Sims KJ, Hauser ER, Helmer DA, Williams CD. Self-reported gastrointestinal disorders among veterans with gulf war illness with and without posttraumatic stress disorder. Neurogastroenterol Motil 2023; 35:e14548. [PMID: 36942766 DOI: 10.1111/nmo.14548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 11/08/2022] [Accepted: 01/11/2023] [Indexed: 03/23/2023]
Abstract
BACKGROUND Gulf War Illness (GWI) is a chronic, multi-symptom disorder affecting 25%-32% of Gulf War veterans. Veterans with GWI disproportionately suffer from gastrointestinal (GI) disorders. Given the increasing evidence supporting a gut-brain axis, we explore the relationship between post-traumatic stress disorder (PTSD), GWI, and self-reported GI disorders among GW veterans. METHODS Veterans from the Gulf War Era Cohort and Biorepository responded to a mail-based survey (N = 1058). They were stratified by GWI (Centers for Disease Control definition) and PTSD status. This yielded three groups: GWI-, GWI+/PTSD-, and GWI+/PTSD+. Multivariable logistic regression adjusting for demographic and military characteristics examined associations between GWI/PTSD groups and GI disorders. Results were expressed as adjusted odds ratios (aOR) with 95% confidence intervals (95% CI). KEY RESULTS The most frequently reported GI disorders were irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), and colon polyps (CP). The GWI+/PTSD+ group had a higher odds of these disorders than the GWI+/PTSD- group (aORIBS = 3.12, 95% CI: 1.93-5.05; aORGERD = 2.04, 95% CI: 1.44-2.90; aORCP = 1.85, 95% CI: 1.23-2.80), which had a higher odds of these disorders than the GWI- group (aORIBS = 4.38, 95% CI: 1.55-12.36; aORGERD = 2.51 95% CI: 1.63-3.87; aORCP = 2.57, 95% CI: 1.53-4.32). CONCLUSIONS & INFERENCES GW veterans with GWI and PTSD have significantly higher odds of specific self-reported GI disorders than the other groups. Given the known bidirectional influences of the gut and brain, these veterans may benefit from a holistic healthcare approach that considers biopsychosocial contributors to the assessment and management of disease.
Collapse
Affiliation(s)
- D Malhotra
- Duke University School of Medicine, Durham, North Carolina, USA
- Cooperative Studies Program Epidemiology Center, Durham VA Medical Center, Durham VA Health Care System, Durham, North Carolina, USA
| | - S H Boyle
- Cooperative Studies Program Epidemiology Center, Durham VA Medical Center, Durham VA Health Care System, Durham, North Carolina, USA
| | - E J Gifford
- Cooperative Studies Program Epidemiology Center, Durham VA Medical Center, Durham VA Health Care System, Durham, North Carolina, USA
- Center for Child and Family Policy, Duke Margolis Center for Health Policy, Duke University Sanford School of Public Policy, Durham, North Carolina, USA
| | - B A Sullivan
- Duke University School of Medicine, Durham, North Carolina, USA
- Cooperative Studies Program Epidemiology Center, Durham VA Medical Center, Durham VA Health Care System, Durham, North Carolina, USA
| | - T H Nguyen Wenker
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
- VA HSR&D Center for Innovations in Quality, Effectiveness and Safety (IQuEST), Michael E. DeBakey VA Medical Center, Houston, Texas, USA
| | - Nono-Djotsa Abs
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
- VA HSR&D Center for Innovations in Quality, Effectiveness and Safety (IQuEST), Michael E. DeBakey VA Medical Center, Houston, Texas, USA
- Big Data Scientist Training Enhancement Program (BD-STEP), VA Office of Research and Development, Washington, DC, Washington, USA
| | - S T Ahmed
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
- VA HSR&D Center for Innovations in Quality, Effectiveness and Safety (IQuEST), Michael E. DeBakey VA Medical Center, Houston, Texas, USA
| | - J Upchurch
- Cooperative Studies Program Epidemiology Center, Durham VA Medical Center, Durham VA Health Care System, Durham, North Carolina, USA
| | - J Vahey
- Cooperative Studies Program Epidemiology Center, Durham VA Medical Center, Durham VA Health Care System, Durham, North Carolina, USA
- Computational Biology and Bioinformatics Program, Duke University School of Medicine, Durham, North Carolina, USA
| | - C Stafford
- Cooperative Studies Program Epidemiology Center, Durham VA Medical Center, Durham VA Health Care System, Durham, North Carolina, USA
| | - J T Efird
- VA Cooperative Studies Program Coordinating Center, Boston, Massachusetts, USA
- Department of Radiation Oncology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
| | - S C Hunt
- VA Puget Sound Health Care System, Seattle, Washington, USA
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - A Bradford
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - K J Sims
- Cooperative Studies Program Epidemiology Center, Durham VA Medical Center, Durham VA Health Care System, Durham, North Carolina, USA
| | - E R Hauser
- Cooperative Studies Program Epidemiology Center, Durham VA Medical Center, Durham VA Health Care System, Durham, North Carolina, USA
- Department of Biostatistics and Bioinformatics, Duke University Medical Center, Duke Molecular Physiology Institute, Durham, North Carolina, USA
| | - D A Helmer
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
- VA HSR&D Center for Innovations in Quality, Effectiveness and Safety (IQuEST), Michael E. DeBakey VA Medical Center, Houston, Texas, USA
| | - C D Williams
- Cooperative Studies Program Epidemiology Center, Durham VA Medical Center, Durham VA Health Care System, Durham, North Carolina, USA
| |
Collapse
|
|
28
|
Raue KD, David BT, Fessler RG. Spinal Cord-Gut-Immune Axis and its Implications Regarding Therapeutic Development for Spinal Cord Injury. J Neurotrauma 2023; 40:793-806. [PMID: 36509451 DOI: 10.1089/neu.2022.0264] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Spinal cord injury (SCI) affects ∼1,300,000 people living in the United States. Most research efforts have been focused on reversing paralysis, as this is arguably the most defining feature of SCI. The damage caused by SCI, however, extends past paralysis and includes other debilitating outcomes including immune dysfunction and gut dysbiosis. Recent efforts are now investigating the pathophysiology of and developing therapies for these more distal manifestations of SCI. One exciting avenue is the spinal cord-gut-immune axis, which proposes that gut dysbiosis amplifies lesion inflammation and impairs SCI recovery. This review will highlight the most recent findings regarding gut and immune dysfunction following SCI, and discuss how the central nervous system (CNS), gut, and immune system all coalesce to form a bidirectional axis that can impact SCI recovery. Finally, important considerations regarding how the spinal cord-gut-immune axis fits within the larger framework of therapeutic development (i.e., probiotics, fecal transplants, dietary modifications) will be discussed, emphasizing the lack of interdepartmental investigation and the missed opportunity to maximize therapeutic benefit in SCI.
Collapse
Affiliation(s)
- Kristen D Raue
- Department of Neurosurgery, Rush University Medical Center, Chicago, Illinois, USA
| | - Brian T David
- Department of Neurosurgery, Rush University Medical Center, Chicago, Illinois, USA
| | - Richard G Fessler
- Department of Neurosurgery, Rush University Medical Center, Chicago, Illinois, USA
| |
Collapse
|
|
29
|
Elhaj R, Reynolds JM. Chemical exposures and suspected impact on Gulf War Veterans. Mil Med Res 2023; 10:11. [PMID: 36882803 PMCID: PMC9993698 DOI: 10.1186/s40779-023-00449-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 02/24/2023] [Indexed: 03/09/2023] Open
Abstract
Gulf War Illness (GWI) encompass a spectrum of maladies specific to troops deployed during the Persian Gulf War (1990-1991). There are several hypothesized factors believed to contribute to GWI, including (but not limited to) exposures to chemical agents and a foreign environment (e.g., dust, pollens, insects, and microbes). Moreover, the inherent stress associated with deployment and combat has been associated with GWI. While the etiology of GWI remains uncertain, several studies have provided strong evidence that chemical exposures, especially neurotoxicants, may be underlying factors for the development of GWI. This mini style perspective article will focus on some of the major evidence linking chemical exposures to GWI development and persistence decades after exposure.
Collapse
Affiliation(s)
- Rami Elhaj
- Center for Cancer Biology, Immunology and Infection, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA
| | - Joseph M Reynolds
- Center for Cancer Biology, Immunology and Infection, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA.
| |
Collapse
|
|
30
|
Reddy DS, Wu X, Singh T, Neff M. Experimental Models of Gulf War Illness, a Chronic Neuropsychiatric Disorder in Veterans. Curr Protoc 2023; 3:e707. [PMID: 36947687 DOI: 10.1002/cpz1.707] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/24/2023]
Abstract
Gulf War illness (GWI) is a chronic multifaceted condition with debilitating pain and fatigue, as well as sleep, behavioral, and cognitive impairments in war veterans. Currently, there is no effective treatment or cure for GWI; therefore, there is a critical need to develop experimental models to help better understand its mechanisms and interventions related to GWI-associated neuropsychiatric disorders. Chemical neurotoxicity appears to be one cause of GWI, and its symptoms manifest as disruptions in neuronal function. However, the mechanisms underlying such incapacitating neurologic and psychiatric symptoms are poorly understood. The etiology of GWI is complex, and many factors including chemical exposure, psychological trauma, and environmental stressors have been associated with its development. Attempts have been made to create GWI-like symptomatic models, including through chronic induction in mice and rats. Here, we present a brief protocol of GWI in rats and mice, which exhibit robust neuropsychiatric signs and neuropathologic changes reminiscent of GWI. This article provides a guide to working protocols, application of therapeutic drugs, outcomes, troubleshooting, and data analysis. Our broad profiling of GWI-like symptoms in rodents reveals features of progressive morphologic and long-lasting neuropsychiatric features. Together, the GWI model in rodents shows striking consistency in recapitulating major hallmark features of GWI in veterans. These models help identify mechanisms and interventions for GWI. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Experimental induction of Gulf War illness in rats Support Protocol 1: Monitoring of Gulf War illness signs and neuroimaging analysis in rats Basic Protocol 2: Experimental induction of Gulf War illness in mice Support Protocol 2: Monitoring of Gulf War illness signs and neuropathology analysis in mice.
Collapse
Affiliation(s)
- Doodipala Samba Reddy
- Department of Neuroscience and Experimental Therapeutics, School of Medicine, Texas A&M University Health Science Center, Bryan, Texas
- Institute of Pharmacology and Neurotherapeutics, School of Medicine, Texas A&M University Health Science Center, Bryan, Texas
- School of Engineering Medicine (EnMed), Texas A&M University, Houston, Texas
- Department of Biomedical Engineering, College of Engineering, Texas A&M University, College Station, Texas
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, Texas
| | - Xin Wu
- Department of Neuroscience and Experimental Therapeutics, School of Medicine, Texas A&M University Health Science Center, Bryan, Texas
- Institute of Pharmacology and Neurotherapeutics, School of Medicine, Texas A&M University Health Science Center, Bryan, Texas
| | - Tanveer Singh
- Department of Neuroscience and Experimental Therapeutics, School of Medicine, Texas A&M University Health Science Center, Bryan, Texas
- Institute of Pharmacology and Neurotherapeutics, School of Medicine, Texas A&M University Health Science Center, Bryan, Texas
| | - Michael Neff
- Department of Neuroscience and Experimental Therapeutics, School of Medicine, Texas A&M University Health Science Center, Bryan, Texas
- Institute of Pharmacology and Neurotherapeutics, School of Medicine, Texas A&M University Health Science Center, Bryan, Texas
| |
Collapse
|
|
31
|
Bose D, Stebliankin V, Cickovski T, Saha P, Trivedi A, Roy S, More M, Tuteja A, Mathee K, Narasimhan G, Chatterjee S. Microbiome Dysbiosis Shows Strong Association of Gut-Derived Altered Metabolomic Profile in Gulf War Chronic Multisymptom Illness Symptom Persistence Following Western Diet Feeding and Development of Obesity. Int J Mol Sci 2023; 24:4245. [PMID: 36835663 PMCID: PMC9962797 DOI: 10.3390/ijms24044245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/12/2023] [Accepted: 02/14/2023] [Indexed: 02/23/2023] Open
Abstract
The pathophysiology of Gulf War Illness (GWI) remains elusive even after three decades. The persistence of multiple complex symptoms along with metabolic disorders such as obesity worsens the health of present Gulf War (GW) Veterans often by the interactions of the host gut microbiome and inflammatory mediators. In this study, we hypothesized that the administration of a Western diet might alter the host metabolomic profile, which is likely associated with the altered bacterial species. Using a five-month symptom persistence GWI model in mice and whole-genome sequencing, we characterized the species-level dysbiosis and global metabolomics, along with heterogenous co-occurrence network analysis, to study the bacteriome-metabolomic association. Microbial analysis at the species level showed a significant alteration of beneficial bacterial species. The beta diversity of the global metabolomic profile showed distinct clustering due to the Western diet, along with the alteration of metabolites associated with lipid, amino acid, nucleotide, vitamin, and xenobiotic metabolism pathways. Network analysis showed novel associations of gut bacterial species with metabolites and biochemical pathways that could be used as biomarkers or therapeutic targets to ameliorate symptom persistence in GW Veterans.
Collapse
Affiliation(s)
- Dipro Bose
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA
| | - Vitalli Stebliankin
- Knight Foundation School of Computing and Information Sciences, College of Engineering and Computing, Florida International University, Miami, FL 33199, USA
| | - Trevor Cickovski
- Knight Foundation School of Computing and Information Sciences, College of Engineering and Computing, Florida International University, Miami, FL 33199, USA
| | - Punnag Saha
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA
| | - Ayushi Trivedi
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA
| | - Subhajit Roy
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA
| | - Madhura More
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA
| | - Ashok Tuteja
- Division of Internal Medicine, University of Utah School of Medicine, Salt Lake City VAMC, Salt Lake City, UT 84132, USA
| | - Kalai Mathee
- Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
- Biomolecular Sciences Institute, Florida International University, Miami, FL 33199, USA
| | - Giri Narasimhan
- Knight Foundation School of Computing and Information Sciences, College of Engineering and Computing, Florida International University, Miami, FL 33199, USA
- Biomolecular Sciences Institute, Florida International University, Miami, FL 33199, USA
| | - Saurabh Chatterjee
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA
- Department of Medicine, Infectious Disease, UCI School of Medicine, Irvine, CA 92697, USA
- VA Research and Development, VA Long Beach Health Care System, Long Beach, CA 90822, USA
| |
Collapse
|
|
32
|
Antoine D, Venigalla G, Truitt B, Roy S. Linking the gut microbiome to microglial activation in opioid use disorder. Front Neurosci 2022; 16:1050661. [PMID: 36590299 PMCID: PMC9800800 DOI: 10.3389/fnins.2022.1050661] [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: 09/22/2022] [Accepted: 11/30/2022] [Indexed: 12/23/2022] Open
Abstract
Substance use disorder (SUD) is a physical and psychological disorder globally prevalent today that has resulted in over 107,000 drug overdose deaths in 2021 in the United States alone. This manuscript reviews the potential relationship between opioid use disorder (OUD), a prevalent subset of SUD, and the microglia, the resident macrophages of the central nervous system (CNS), as they have been found to become significantly more activated during opioid exposure. The inflammatory response mediated by the microglia could contribute to the pathophysiology of SUDs, in particular OUD. Further understanding of the microglia and how they respond to not only signals in the CNS but also signals from other areas of the body, such as the gut microbiome, could explain how the microglia are involved in drug use. Several studies have shown extensive communication between the gut microbiome and the microglia, which may be an important factor in the initiation and development of OUD. Particularly, strategies seeking to manipulate and restore the gut microbiome have been shown to reduce microglial activation and attenuate inflammation. In this review, we discuss the evidence for a link between the microglia and OUD and how the gut microbiome might influence microglial activation to drive the disorder and its associated behaviors. Understanding this connection between microglia and the gut microbiome in the context of drug use may present additional therapeutic targets to treat the different stages of drug use.
Collapse
Affiliation(s)
- Danielle Antoine
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, United States,Department of Neuroscience, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Greeshma Venigalla
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Bridget Truitt
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, United States,Department of Neuroscience, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Sabita Roy
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, United States,*Correspondence: Sabita Roy,
| |
Collapse
|
|
33
|
Subchronic Oral Cylindrospermopsin Exposure Alters the Host Gut Microbiome and Is Associated with Progressive Hepatic Inflammation, Stellate Cell Activation, and Mild Fibrosis in a Preclinical Study. Toxins (Basel) 2022; 14:toxins14120835. [PMID: 36548732 PMCID: PMC9785749 DOI: 10.3390/toxins14120835] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 11/20/2022] [Accepted: 11/21/2022] [Indexed: 12/02/2022] Open
Abstract
Epidemiological studies have reported a strong association between liver injury and incidences of hepatocellular carcinoma in sections of humans globally. Several preclinical studies have shown a strong link between cyanotoxin exposure and the development of nonalcoholic steatohepatitis, a precursor of hepatocellular carcinoma. Among the emerging threats from cyanotoxins, new evidence shows cylindrospermopsin release in freshwater lakes. A known hepatotoxin in higher concentrations, we examined the possible role of cylindrospermopsin in causing host gut dysbiosis and its association with liver pathology in a mouse model of toxico-pharmacokinetics and hepatic pathology. The results showed that oral exposure to cylindrospermopsin caused decreased diversity of gut bacteria phyla accompanied by an increased abundance of Clostridioides difficile and decreased abundance of probiotic flora such as Roseburia, Akkermanssia, and Bacteroides thetaiotamicron, a signature most often associated with intestinal and hepatic pathology and underlying gastrointestinal disease. The altered gut dysbiosis was also associated with increased Claudin2 protein in the intestinal lumen, a marker of gut leaching and endotoxemia. The study of liver pathology showed marked liver inflammation, the release of damage-associated molecular patterns, and activation of toll-like receptors, a hallmark of consistent and progressive liver damage. Hepatic pathology was also linked to increased Kupffer cell activation and stellate cell activation, markers of progressive liver damage often linked to the development of liver fibrosis and carcinoma. In conclusion, the present study provides additional evidence of cylindrospermopsin-linked progressive liver pathology that may be very well-linked to gut dysbiosis, though definitive evidence involving this link needs to be studied further.
Collapse
|
|
34
|
Long COVID and the Neuroendocrinology of Microbial Translocation Outside the GI Tract: Some Treatment Strategies. ENDOCRINES 2022. [DOI: 10.3390/endocrines3040058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Similar to previous pandemics, COVID-19 has been succeeded by well-documented post-infectious sequelae, including chronic fatigue, cough, shortness of breath, myalgia, and concentration difficulties, which may last 5 to 12 weeks or longer after the acute phase of illness. Both the psychological stress of SARS-CoV-2 infection and being diagnosed with COVID-19 can upregulate cortisol, a stress hormone that disrupts the efferocytosis effectors, macrophages, and natural killer cells, leading to the excessive accumulation of senescent cells and disruption of biological barriers. This has been well-established in cancer patients who often experience unrelenting fatigue as well as gut and blood–brain barrier dysfunction upon treatment with senescence-inducing radiation or chemotherapy. In our previous research from 2020 and 2021, we linked COVID-19 to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) via angiotensin II upregulation, premature endothelial senescence, intestinal barrier dysfunction, and microbial translocation from the gastrointestinal tract into the systemic circulation. In 2021 and 2022, these hypotheses were validated and SARS-CoV-2-induced cellular senescence as well as microbial translocation were documented in both acute SARS-CoV-2 infection, long COVID, and ME/CFS, connecting intestinal barrier dysfunction to disabling fatigue and specific infectious events. The purpose of this narrative review is to summarize what is currently known about host immune responses to translocated gut microbes and how these responses relate to fatiguing illnesses, including long COVID. To accomplish this goal, we examine the role of intestinal and blood–brain barriers in long COVID and other illnesses typified by chronic fatigue, with a special emphasis on commensal microbes functioning as viral reservoirs. Furthermore, we discuss the role of SARS-CoV-2/Mycoplasma coinfection in dysfunctional efferocytosis, emphasizing some potential novel treatment strategies, including the use of senotherapeutic drugs, HMGB1 inhibitors, Toll-like receptor 4 (TLR4) blockers, and membrane lipid replacement.
Collapse
|
|
35
|
Kandpal M, Indari O, Baral B, Jakhmola S, Tiwari D, Bhandari V, Pandey RK, Bala K, Sonawane A, Jha HC. Dysbiosis of Gut Microbiota from the Perspective of the Gut-Brain Axis: Role in the Provocation of Neurological Disorders. Metabolites 2022; 12:1064. [PMID: 36355147 PMCID: PMC9692419 DOI: 10.3390/metabo12111064] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/29/2022] [Accepted: 11/01/2022] [Indexed: 11/06/2022] Open
Abstract
The gut-brain axis is a bidirectional communication network connecting the gastrointestinal tract and central nervous system. The axis keeps track of gastrointestinal activities and integrates them to connect gut health to higher cognitive parts of the brain. Disruption in this connection may facilitate various neurological and gastrointestinal problems. Neurodegenerative diseases are characterized by the progressive dysfunction of specific populations of neurons, determining clinical presentation. Misfolded protein aggregates that cause cellular toxicity and that aid in the collapse of cellular proteostasis are a defining characteristic of neurodegenerative proteinopathies. These disorders are not only caused by changes in the neural compartment but also due to other factors of non-neural origin. Mounting data reveal that the majority of gastrointestinal (GI) physiologies and mechanics are governed by the central nervous system (CNS). Furthermore, the gut microbiota plays a critical role in the regulation and physiological function of the brain, although the mechanism involved has not yet been fully interpreted. One of the emerging explanations of the start and progression of many neurodegenerative illnesses is dysbiosis of the gut microbial makeup. The present understanding of the literature surrounding the relationship between intestinal dysbiosis and the emergence of certain neurological diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis, is the main emphasis of this review. The potential entry pathway of the pathogen-associated secretions and toxins into the CNS compartment has been explored in this article at the outset of neuropathology. We have also included the possible mechanism of undelaying the synergistic effect of infections, their metabolites, and other interactions based on the current understanding.
Collapse
Affiliation(s)
- Meenakshi Kandpal
- Infection Bioengineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore 453552, Madhya Pradesh, India
| | - Omkar Indari
- Infection Bioengineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore 453552, Madhya Pradesh, India
| | - Budhadev Baral
- Infection Bioengineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore 453552, Madhya Pradesh, India
| | - Shweta Jakhmola
- Infection Bioengineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore 453552, Madhya Pradesh, India
| | - Deeksha Tiwari
- Infection Bioengineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore 453552, Madhya Pradesh, India
| | - Vasundhra Bhandari
- Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Hyderabad 500037, Telengana, India
| | - Rajan Kumar Pandey
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17165 Stockholm, Sweden
| | - Kiran Bala
- Algal Ecotechnology & Sustainability Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore 453552, Madhya Pradesh, India
| | - Avinash Sonawane
- Disease Biology & Cellular Immunology Lab, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore 453552, Madhya Pradesh, India
| | - Hem Chandra Jha
- Infection Bioengineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore 453552, Madhya Pradesh, India
| |
Collapse
|
|
36
|
Wang W, Jiang S, Xu C, Tang L, Liang Y, Zhao Y, Zhu G. Interactions between gut microbiota and Parkinson's disease: The role of microbiota-derived amino acid metabolism. Front Aging Neurosci 2022; 14:976316. [PMID: 36408101 PMCID: PMC9667037 DOI: 10.3389/fnagi.2022.976316] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 08/29/2022] [Indexed: 11/05/2022] Open
Abstract
Non-motor symptoms (NMS) of Parkinson's disease (PD), such as constipation, sleep disorders, and olfactory deficits, may emerge up to 20 years earlier than motor symptoms. A series of evidence indicates that the pathology of PD may occur from the gastrointestinal tract to the brain. Numerous studies support that the gut microbiota communicates with the brain through the immune system, special amino acid metabolism, and the nervous system in PD. Recently, there is growing recognition that the gut microbiota plays a vital role in the modulation of multiple neurochemical pathways via the “gut microbiota-brain axis” (GMBA). Many gut microbiota metabolites, such as fatty acids, amino acids, and bile acids, convey signaling functions as they mediate the crosstalk between gut microbiota and host physiology. Amino acids' abundance and species alteration, including glutamate and tryptophan, may disturb the signaling transmission between nerve cells and disrupt the normal basal ganglia function in PD. Specific amino acids and their receptors are considered new potential targets for ameliorating PD. The present study aimed to systematically summarize all available evidence on the gut microbiota-derived amino acid metabolism alterations associated with PD.
Collapse
Affiliation(s)
- Wang Wang
- Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shujun Jiang
- Chinese Medicine Modernization and Big Data Research Center, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Chengcheng Xu
- Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Lili Tang
- Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yan Liang
- Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yang Zhao
- Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- *Correspondence: Yang Zhao
| | - Guoxue Zhu
- Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Chinese Medicine Modernization and Big Data Research Center, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Guoxue Zhu
| |
Collapse
|
|
37
|
Chompre G, Sambolin L, Cruz ML, Sanchez R, Rodriguez Y, Rodríguez-Santiago RE, Yamamura Y, Appleyard CB. A one month high fat diet disrupts the gut microbiome and integrity of the colon inducing adiposity and behavioral despair in male Sprague Dawley rats. Heliyon 2022; 8:e11194. [PMID: 36387539 PMCID: PMC9663868 DOI: 10.1016/j.heliyon.2022.e11194] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 06/17/2022] [Accepted: 10/17/2022] [Indexed: 11/05/2022] Open
Abstract
High-fat diet (HFD) is associated with gut microbiome dysfunction and mental disorders. However, the time-dependence as to when this occurs is unclear. We hypothesized that a short-term HFD causes colonic tissue integrity changes resulting in behavioral changes. Rats were fed HFD or low-fat diet (LFD) for a month and gut microbiome, colon, and behavior were evaluated. Behavioral despair was found in the HFD group. Although obesity was absent, the HFD group showed increased percent weight gain, epididymal fat tissue, and leptin expression. Moreover, the HFD group had increased colonic damage, decreased expression of the tight junction proteins, and higher lipopolysaccharides (LPS) in serum. Metagenomic analysis revealed that the HFD group had more Bacteroides and less S24-7 which correlated with the decreased claudin-5. Finally, HFD group showed an increase of microglia percent area, increased astrocytic projections, and decreased phospho-mTOR. In conclusion, HFD consumption in a short period is still sufficient to disrupt gut integrity resulting in LPS infiltration, alterations in the brain, and behavioral despair even in the absence of obesity.
Collapse
Affiliation(s)
- Gladys Chompre
- Biology and Biotechnology Department, Pontifical Catholic University of Puerto Rico, Ponce, Puerto Rico
- Basic Sciences Department, Division of Physiology, Ponce Health Sciences University/Ponce Research Institute, Ponce, Puerto Rico
| | - Lubriel Sambolin
- Basic Sciences Department, Division of Pharmacology, Ponce Health Sciences University/Ponce Research Institute, Ponce, Puerto Rico
| | - Myrella L. Cruz
- Basic Sciences Department, Division of Physiology, Ponce Health Sciences University/Ponce Research Institute, Ponce, Puerto Rico
| | - Rafael Sanchez
- AIDS Research Infrastructure Program, Ponce Health Sciences University/Ponce Research Institute, Ponce, Puerto Rico
| | - Yarelis Rodriguez
- Basic Sciences Department, Division of Physiology, Ponce Health Sciences University/Ponce Research Institute, Ponce, Puerto Rico
| | - Ronald E. Rodríguez-Santiago
- AIDS Research Infrastructure Program, Ponce Health Sciences University/Ponce Research Institute, Ponce, Puerto Rico
| | - Yasuhiro Yamamura
- AIDS Research Infrastructure Program, Ponce Health Sciences University/Ponce Research Institute, Ponce, Puerto Rico
| | - Caroline B. Appleyard
- Basic Sciences Department, Division of Physiology, Ponce Health Sciences University/Ponce Research Institute, Ponce, Puerto Rico
| |
Collapse
|
|
38
|
Tuteja AK, Talley NJ, Murtaugh MA, Loc-Carrillo CM, Stoddard GJ, Anderson GL. Randomized, Double-Blind Placebo-Controlled Trial to Assess the Effect of Probiotics on Irritable Bowel Syndrome in Veterans With Gulf War Illness. Fed Pract 2022; 39:410-417. [PMID: 36744017 PMCID: PMC9896367 DOI: 10.12788/fp.0322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Background Many veterans who served in Operation Desert Storm (August 1990 to March 1991) experienced a complex of symptoms of unknown etiology called Gulf War illness (GWI), which significantly impacts the health and quality of life (QOL) and may have contributed to irritable bowel syndrome (IBS). Methods We performed a prospective, double-blind placebocontrolled study to determine the efficacy of the multistrain De Simone Formulation probiotic containing 8 strains of bacteria on symptoms of IBS and GWI. Veterans of Operation Desert Storm who had IBS and ≥ 2 nonintestinal symptoms of GWI were included. The primary study endpoint was change in bowel symptom score. The secondary endpoints were mean change in symptoms, QOL, and extra-intestinal and posttraumatic stress disorder (PTSD) symptoms. Results A total of 101 Gulf War veterans with IBS and GWI were screened at the Veteran Affairs Medical Center in Salt Lake City, Utah. The study was completed by 53 veterans; 47 (89%) were male with a mean (SD) age of 55 (8) years. The probiotic did not improve IBS symptoms or other extra-intestinal symptoms common to IBS and GWI. Conclusions Our study did not demonstrate statistically significant improvement in IBS symptoms or QOL after treatment with the probiotic. We also did not find any improvement in symptoms of GWI or PTSD.
Collapse
Affiliation(s)
- Ashok K Tuteja
- George E. Whalen Veterans Affairs Medical Center, Salt Lake City, Utah
- University of Utah, Salt Lake City
| | | | | | - Catherine M Loc-Carrillo
- George E. Whalen Veterans Affairs Medical Center, Salt Lake City, Utah
- University of Utah, Salt Lake City
| | - Gregory J Stoddard
- George E. Whalen Veterans Affairs Medical Center, Salt Lake City, Utah
- University of Utah, Salt Lake City
| | | |
Collapse
|
|
39
|
Hao X, Ding N, Zhang Y, Yang Y, Zhao Y, Zhao J, Li Y, Li Z. Benign regulation of the gut microbiota: The possible mechanism through which the beneficial effects of manual acupuncture on cognitive ability and intestinal mucosal barrier function occur in APP/PS1 mice. Front Neurosci 2022; 16:960026. [PMID: 35992924 PMCID: PMC9382294 DOI: 10.3389/fnins.2022.960026] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 07/11/2022] [Indexed: 11/22/2022] Open
Abstract
Background Gut microbiota dysbiosis and intestinal barrier injury play vital roles in Alzheimer's disease (AD) onset and development. Our previous studies have demonstrated that manual acupuncture (MA) could improve the cognitive abilities of APP/PS1 mice. However, the effect of MA on the intestinal mucosal barrier and the gut microbiota mechanism through which this effect occurs remain to be clarified. Methods In the APP/PS1 manual acupuncture (Am) group, MA was applied in Baihui (GV20), Yintang (GV29), and Zusanli (ST36). Mice in the APP/PS1 antibiotic + manual acupuncture (Aa) group were treated with an antibiotic mixture and MA at the same time. Probiotics were delivered to the APP/PS1 probiotics (Ap) group. Alterations in spatial learning and memory, the gut microbiota, the intestinal barrier function, and the expression of glial fibrillary acidic protein (GFAP), lipopolysaccharide (LPS), and TNF-α were evaluated in each group. Results Compared with the C57BL/6 control (Cc) group, cognitive ability was significantly decreased, the gut microbiota structure was obviously disrupted, intestinal barrier integrity was drastically impaired, and the intestinal inflammatory response was enhanced in the APP/PS1 control (Ac) group (P < 0.01). These changes were reversed by MA and probiotics (P < 0.01 or P < 0.05), whereas antibiotics inhibited the benign regulation by MA (P < 0.01 or P < 0.05). Conclusion Manual acupuncture can benignly modulate gut microbiota dysbiosis, significantly reduce intestinal inflammation, and effectively alleviate the destruction of the intestinal mucosal barrier in APP/PS1 mice, and the effects are comparable to those of probiotics. The gut microbiota may play an important role in the improvement of the cognitive function and intestinal barrier function by MA.
Collapse
Affiliation(s)
- Xin Hao
- School of Acupuncture, Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Ning Ding
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yue Zhang
- School of Acupuncture, Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Yichen Yang
- School of Acupuncture, Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Yali Zhao
- School of Acupuncture, Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Jun Zhao
- School of Acupuncture, Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Yiran Li
- International School, Beijing University of Chinese Medicine, Beijing, China
| | - Zhigang Li
- School of Acupuncture, Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| |
Collapse
|
|
40
|
Kates A, Keating J, Baubie K, Putman-Buehler N, Watson L, Godfrey J, Deblois CL, Suen G, Cook DB, Rabago D, Gangnon R, Safdar N. Examining the association between the gastrointestinal microbiota and Gulf War illness: A prospective cohort study. PLoS One 2022; 17:e0268479. [PMID: 35901037 PMCID: PMC9333223 DOI: 10.1371/journal.pone.0268479] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 05/01/2022] [Indexed: 12/04/2022] Open
Abstract
Gulf War Illness (GWI) affects 25–35% of the 1991 Gulf War Veteran (GWV) population. Patients with GWI experience pain, fatigue, cognitive impairments, gastrointestinal dysfunction, skin disorders, and respiratory issues. In longitudinal studies, many patients with GWI have shown little to no improvement in symptoms since diagnosis. The gut microbiome and diet play an important role in human health and disease, and preliminary studies suggest it may play a role in GWI. To examine the relationship between the gut microbiota, diet, and GWI, we conducted an eight-week prospective cohort study collecting stool samples, medications, health history, and dietary data. Sixty-nine participants were enrolled into the study, 36 of which met the case definition for GWI. The gut microbiota of participants, determined by 16S rRNA sequencing of stool samples, was stable over the duration of the study and showed no within person (alpha diversity) differences. Between group analyses (beta diversity) identified statistically significant different between those with and without GWI. Several taxonomic lineages were identified as differentially abundant between those with and without GWI (n = 9) including a greater abundance of Lachnospiraceae and Ruminococcaceae in those without GWI. Additionally, there were taxonomic differences between those with high and low healthy eating index (HEI) scores including a greater abundance of Ruminococcaceae in those with higher HEI scores. This longitudinal cohort study of GWVs found that participants with GWI had significantly different microbiomes from those without GWI. Further studies are needed to determine the role these differences may play in the development and treatment of GWI.
Collapse
Affiliation(s)
- Ashley Kates
- Research, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, United States of America
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- * E-mail:
| | - Julie Keating
- Research, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, United States of America
| | - Kelsey Baubie
- Research, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, United States of America
| | - Nathan Putman-Buehler
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Lauren Watson
- SSM Health, St. Mary’s Hospital, Madison, Wisconsin, United States of America
| | - Jared Godfrey
- Research, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, United States of America
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Courtney L. Deblois
- Research, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, United States of America
- Department of Bacteriology, College of Agriculture and Life Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Microbiology Doctoral Training Program, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Garret Suen
- Department of Bacteriology, College of Agriculture and Life Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Dane B. Cook
- Research, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, United States of America
- Department of Kinesiology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - David Rabago
- Department of Family and Community Medicine, College of Medicine, Penn State University, Hershey, Pennsylvania, United States of America
| | - Ronald Gangnon
- Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Nasia Safdar
- Research, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, United States of America
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| |
Collapse
|
|
41
|
Doms S, Fokt H, Rühlemann MC, Chung CJ, Kuenstner A, Ibrahim SM, Franke A, Turner LM, Baines JF. Key features of the genetic architecture and evolution of host-microbe interactions revealed by high-resolution genetic mapping of the mucosa-associated gut microbiome in hybrid mice. eLife 2022; 11:75419. [PMID: 35866635 PMCID: PMC9307277 DOI: 10.7554/elife.75419] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 06/14/2022] [Indexed: 12/13/2022] Open
Abstract
Determining the forces that shape diversity in host-associated bacterial communities is critical to understanding the evolution and maintenance of metaorganisms. To gain deeper understanding of the role of host genetics in shaping gut microbial traits, we employed a powerful genetic mapping approach using inbred lines derived from the hybrid zone of two incipient house mouse species. Furthermore, we uniquely performed our analysis on microbial traits measured at the gut mucosal interface, which is in more direct contact with host cells and the immune system. Several mucosa-associated bacterial taxa have high heritability estimates, and interestingly, 16S rRNA transcript-based heritability estimates are positively correlated with cospeciation rate estimates. Genome-wide association mapping identifies 428 loci influencing 120 taxa, with narrow genomic intervals pinpointing promising candidate genes and pathways. Importantly, we identified an enrichment of candidate genes associated with several human diseases, including inflammatory bowel disease, and functional categories including innate immunity and G-protein-coupled receptors. These results highlight key features of the genetic architecture of mammalian host-microbe interactions and how they diverge as new species form. The digestive system, particularly the large intestine, hosts many types of bacteria which together form the gut microbiome. The exact makeup of different bacterial species is specific to an individual, but microbiomes are often more similar between related individuals, and more generally, across related species. Whether this is because individuals share similar environments or similar genetic backgrounds remains unclear. These two factors can be disentangled by breeding different animal lineages – which have different genetic backgrounds while belonging to the same species – and then raising the progeny in the same environment. To investigate this question, Doms et al. studied the genes and microbiomes of mice resulting from breeding strains from multiple locations in a natural hybrid zone between different subspecies. The experiments showed that 428 genetic regions affected the makeup of the microbiome, many of which were known to be associated with human diseases. Further analysis revealed 79 genes that were particularly interesting, as they were involved in recognition and communication with bacteria. These results show how the influence of the host genome on microbiome composition becomes more specialized as animals evolve. Overall, the work by Doms et al. helps to pinpoint the genes that impact the microbiome; this knowledge could be helpful to examine how these interactions contribute to the emergence of conditions such as diabetes or inflammatory bowel disease, which are linked to perturbations in gut bacteria.
Collapse
Affiliation(s)
- Shauni Doms
- Max Planck Institute for Evolutionary Biology, Plön, Germany.,Section of Evolutionary Medicine, Institute for Experimental Medicine, Kiel University, Kiel, Germany
| | - Hanna Fokt
- Max Planck Institute for Evolutionary Biology, Plön, Germany.,Section of Evolutionary Medicine, Institute for Experimental Medicine, Kiel University, Kiel, Germany
| | - Malte Christoph Rühlemann
- Institute for Clinical Molecular Biology (IKMB), Kiel University, Kiel, Germany.,Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
| | - Cecilia J Chung
- Max Planck Institute for Evolutionary Biology, Plön, Germany.,Section of Evolutionary Medicine, Institute for Experimental Medicine, Kiel University, Kiel, Germany
| | - Axel Kuenstner
- Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany
| | - Saleh M Ibrahim
- Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.,Sharjah Institute of Medical Research, Sharjah, United Arab Emirates
| | - Andre Franke
- Institute for Clinical Molecular Biology (IKMB), Kiel University, Kiel, Germany
| | - Leslie M Turner
- Milner Centre for Evolution, Department of Biology & Biochemistry, University of Bath, Bath, United Kingdom
| | - John F Baines
- Max Planck Institute for Evolutionary Biology, Plön, Germany.,Section of Evolutionary Medicine, Institute for Experimental Medicine, Kiel University, Kiel, Germany
| |
Collapse
|
|
42
|
Zhang X, Yang G, Chen Y, Mu Z, Zhou H, Zhang L. Resveratrol pre-treatment alleviated caerulein-induced acute pancreatitis in high-fat diet-feeding mice via suppressing the NF-κB proinflammatory signaling and improving the gut microbiota. BMC Complement Med Ther 2022; 22:189. [PMID: 35842665 PMCID: PMC9288014 DOI: 10.1186/s12906-022-03664-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 06/09/2022] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND hyperlipidemia acute pancreatitis (HTG-AP) is a major hidden danger affecting human health, however, whether there is a protective effect of resveratrol on HTG-AP is unclear. Therefore our study was aimed to investigate the preventive effect and the underlying mechanism of resveratrol in the HTG-AP mice model. METHODS This research was divided into two parts. In the first part, mice were adaptively fed with normal chow or HFD for 6 weeks. From the second week, resveratrol-treated mice were in intragastric administration with resveratrol (45 mg/kg/d) for 4 weeks. In the second part, the procedures were the same as the first part. After the last intragastric administration with resveratrol, all mice were intraperitoneal injections of cerulean. RESULTS We found resveratrol effectively inhibited pancreatic pathological injury in the HFD, AP, and HTG-AP mice. Resveratrol reduced the LPS, IL-6, TNF-α, and MCP-1 expressions in the HFD mice. Resveratrol also reduced TNF-α, MDA, and MCP-1 expressions and increased SOD and T-AOC expressions in the AP and HTG-AP mice. Furthermore, resveratrol suppressed the NF-κB pro-inflammatory signaling pathway in pancreatic tissues in the AP and HTG-AP mice. Moreover, resveratrol improved the gut microbiota in the HFD mice. CONCLUSION The resveratrol pre-treatment could attenuate pancreas injury, inflammation, and oxidative stress in the HTG-AP mice, via restraining the NF-κB signaling pathway and regulating gut microbiota. Therefore, Our study proved that the resveratrol pre-treatment had a preventive effect on HTG-AP.
Collapse
Affiliation(s)
- Xiaoying Zhang
- School of Basic Medicine, North Sichuan Medical College, Nanchong, 637000, Sichuan, China
| | - Guodong Yang
- Department of Gastroenterology and Hepatology, Affiliated Hospital of North Sichuan Medical College, No.63, Cultural Rd., Shunqing Dist, Nanchong, 637000, Sichuan Province, China.
| | - Yulin Chen
- North Sichuan Medical College, Nanchong, 637000, Sichuan, China
| | - Zhao Mu
- North Sichuan Medical College, Nanchong, 637000, Sichuan, China
| | - Haiyue Zhou
- North Sichuan Medical College, Nanchong, 637000, Sichuan, China
| | - Luoyao Zhang
- North Sichuan Medical College, Nanchong, 637000, Sichuan, China
| |
Collapse
|
|
43
|
Bose D, Chatterjee S, Older E, Seth R, Janulewicz P, Saha P, Mondal A, Carlson JM, Decho AW, Sullivan K, Klimas N, Lasley S, Li J, Chatterjee S. Host gut resistome in Gulf War chronic multisymptom illness correlates with persistent inflammation. Commun Biol 2022; 5:552. [PMID: 35672382 PMCID: PMC9174162 DOI: 10.1038/s42003-022-03494-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 05/17/2022] [Indexed: 11/29/2022] Open
Abstract
Chronic multisymptom illness (CMI) affects a subsection of elderly and war Veterans and is associated with systemic inflammation. Here, using a mouse model of CMI and a group of Gulf War (GW) Veterans' with CMI we show the presence of an altered host resistome. Results show that antibiotic resistance genes (ARGs) are significantly altered in the CMI group in both mice and GW Veterans when compared to control. Fecal samples from GW Veterans with persistent CMI show a significant increase of resistance to a wide class of antibiotics and exhibited an array of mobile genetic elements (MGEs) distinct from normal healthy controls. The altered resistome and gene signature is correlated with mouse serum IL-6 levels. Altered resistome in mice also is correlated strongly with intestinal inflammation, decreased synaptic plasticity, reversible with fecal microbiota transplant (FMT). The results reported might help in understanding the risks to treating hospital acquired infections in this population.
Collapse
Affiliation(s)
- Dipro Bose
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA
| | - Somdatta Chatterjee
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA
| | - Ethan Older
- Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, USA
| | - Ratanesh Seth
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA
| | - Patricia Janulewicz
- Department of Environmental Health, Boston University School of Public Health, Boston, MA, USA
| | - Punnag Saha
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA
| | - Ayan Mondal
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA
| | - Jeffrey M Carlson
- Department of Environmental Health, Boston University School of Public Health, Boston, MA, USA
| | - Alan W Decho
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA
| | - Kimberly Sullivan
- Department of Environmental Health, Boston University School of Public Health, Boston, MA, USA
| | - Nancy Klimas
- Department of Clinical Immunology, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Stephen Lasley
- Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, IL, USA
| | - Jie Li
- Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, USA
| | - Saurabh Chatterjee
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA.
- Columbia VA Medical Center, Columbia, SC, USA.
| |
Collapse
|
|
44
|
François S, Mondot S, Gerard Q, Bel R, Knoertzer J, Berriche A, Cavallero S, Baati R, Orset C, Dal Bo G, Thibault K. Long-Term Anxiety-Like Behavior and Microbiota Changes Induced in Mice by Sublethal Doses of Acute Sarin Surrogate Exposure. Biomedicines 2022; 10:biomedicines10051167. [PMID: 35625901 PMCID: PMC9138233 DOI: 10.3390/biomedicines10051167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 05/07/2022] [Accepted: 05/16/2022] [Indexed: 12/10/2022] Open
Abstract
Anxiety disorder is one of the most reported complications following organophosphorus (OP) nerve agent (NA) exposure. The goal of this study was to characterize the long-term behavioral impact of a single low dose exposure to 4-nitrophenyl isopropyl methylphosphonate (NIMP), a sarin surrogate. We chose two different sublethal doses of NIMP, each corresponding to a fraction of the median lethal dose (one mild and one convulsive), and evaluated behavioral changes over a 6-month period following exposure. Mice exposed to both doses showed anxious behavior which persisted for six-months post-exposure. A longitudinal magnetic resonance imaging examination did not reveal any anatomical changes in the amygdala throughout the 6-month period. While no cholinesterase activity change or neuroinflammation could be observed at the latest timepoint in the amygdala of NIMP-exposed mice, important modifications in white blood cell counts were noted, reflecting a perturbation of the systemic immune system. Furthermore, intestinal inflammation and microbiota changes were observed at 6-months in NIMP-exposed animals regardless of the dose received. This is the first study to identify long-term behavioral impairment, systemic homeostasis disorganization and gut microbiota alterations following OP sublethal exposure. Our findings highlight the importance of long-term care for victims of NA exposure, even in asymptomatic cases.
Collapse
Affiliation(s)
- Sabine François
- Department of Radiation Biological Effects, Armed Forces Biomedical Research Institute, 91220 Bretigny sur Orge, France; (S.F.); (S.C.)
| | - Stanislas Mondot
- Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, 78350 Jouy-en-Josas, France;
| | - Quentin Gerard
- Department of Toxicology and Chemical Risks, Armed Forces Biomedical Research Institute, 91220 Bretigny sur Orge, France; (Q.G.); (R.B.); (J.K.); (A.B.)
- Institut Blood and Brain@caen-normandie Cyceron, Caen-Normandie University, UNICAEN, INSERM, UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), 14000 Caen, France;
| | - Rosalie Bel
- Department of Toxicology and Chemical Risks, Armed Forces Biomedical Research Institute, 91220 Bretigny sur Orge, France; (Q.G.); (R.B.); (J.K.); (A.B.)
| | - Julie Knoertzer
- Department of Toxicology and Chemical Risks, Armed Forces Biomedical Research Institute, 91220 Bretigny sur Orge, France; (Q.G.); (R.B.); (J.K.); (A.B.)
| | - Asma Berriche
- Department of Toxicology and Chemical Risks, Armed Forces Biomedical Research Institute, 91220 Bretigny sur Orge, France; (Q.G.); (R.B.); (J.K.); (A.B.)
- CEA, 92260 Fontenay aux Roses, France
| | - Sophie Cavallero
- Department of Radiation Biological Effects, Armed Forces Biomedical Research Institute, 91220 Bretigny sur Orge, France; (S.F.); (S.C.)
| | - Rachid Baati
- ICPEES UMR CNRS 7515, Institut de Chimie des Procédés, pour l’Energie, l’Environnement, et la Santé, 67000 Strasbourg, France;
| | - Cyrille Orset
- Institut Blood and Brain@caen-normandie Cyceron, Caen-Normandie University, UNICAEN, INSERM, UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), 14000 Caen, France;
| | - Gregory Dal Bo
- Department of Toxicology and Chemical Risks, Armed Forces Biomedical Research Institute, 91220 Bretigny sur Orge, France; (Q.G.); (R.B.); (J.K.); (A.B.)
- Correspondence: (G.D.B.); (K.T.)
| | - Karine Thibault
- Department of Toxicology and Chemical Risks, Armed Forces Biomedical Research Institute, 91220 Bretigny sur Orge, France; (Q.G.); (R.B.); (J.K.); (A.B.)
- Correspondence: (G.D.B.); (K.T.)
| |
Collapse
|
|
45
|
Attaluri S, Upadhya R, Kodali M, Madhu LN, Upadhya D, Shuai B, Shetty AK. Brain-Specific Increase in Leukotriene Signaling Accompanies Chronic Neuroinflammation and Cognitive Impairment in a Model of Gulf War Illness. Front Immunol 2022; 13:853000. [PMID: 35572589 PMCID: PMC9099214 DOI: 10.3389/fimmu.2022.853000] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 04/05/2022] [Indexed: 11/13/2022] Open
Abstract
Persistent cognitive impairment is a primary central nervous system-related symptom in veterans afflicted with chronic Gulf War Illness (GWI). Previous studies in a rat model have revealed that cognitive dysfunction in chronic GWI is associated with neuroinflammation, typified by astrocyte hypertrophy, activated microglia, and enhanced proinflammatory cytokine levels. Studies in a mouse model of GWI have also shown upregulation of several phospholipids that serve as reservoirs of arachidonic acid, a precursor of leukotrienes (LTs). However, it is unknown whether altered LT signaling is a component of chronic neuroinflammatory conditions in GWI. Therefore, this study investigated changes in LT signaling in the brain of rats displaying significant cognitive impairments six months after exposure to GWI-related chemicals and moderate stress. The concentration of cysteinyl LTs (CysLTs), LTB4, and 5-Lipoxygenase (5-LOX), the synthesizing enzyme of LTs, were evaluated. CysLT and LTB4 concentrations were elevated in the hippocampus and the cerebral cortex, along with enhanced 5-LOX expression in neurons and microglia. Such changes were also associated with increased proinflammatory cytokine levels in the hippocampus and the cerebral cortex. Enhanced CysLT and LTB4 levels in the brain could also be gleaned from their concentrations in brain-derived extracellular vesicles in the circulating blood. The circulating blood in GWI rats displayed elevated proinflammatory cytokines with no alterations in CysLT and LTB4 concentrations. The results provide new evidence that a brain-specific increase in LT signaling is another adverse alteration that potentially contributes to the maintenance of chronic neuroinflammation in GWI. Therefore, drugs capable of modulating LT signaling may reduce neuroinflammation and improve cognitive function in GWI. Additional findings demonstrate that altered LT levels in the brain could be tracked efficiently by analyzing brain-derived EVs in the circulating blood.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Ashok K. Shetty
- Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, TX, United States
| |
Collapse
|
|
46
|
Varesi A, Carrara A, Pires VG, Floris V, Pierella E, Savioli G, Prasad S, Esposito C, Ricevuti G, Chirumbolo S, Pascale A. Blood-Based Biomarkers for Alzheimer's Disease Diagnosis and Progression: An Overview. Cells 2022; 11:1367. [PMID: 35456047 PMCID: PMC9044750 DOI: 10.3390/cells11081367] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/12/2022] [Accepted: 04/15/2022] [Indexed: 01/10/2023] Open
Abstract
Alzheimer's Disease (AD) is a progressive neurodegenerative disease characterized by amyloid-β (Aβ) plaque deposition and neurofibrillary tangle accumulation in the brain. Although several studies have been conducted to unravel the complex and interconnected pathophysiology of AD, clinical trial failure rates have been high, and no disease-modifying therapies are presently available. Fluid biomarker discovery for AD is a rapidly expanding field of research aimed at anticipating disease diagnosis and following disease progression over time. Currently, Aβ1-42, phosphorylated tau, and total tau levels in the cerebrospinal fluid are the best-studied fluid biomarkers for AD, but the need for novel, cheap, less-invasive, easily detectable, and more-accessible markers has recently led to the search for new blood-based molecules. However, despite considerable research activity, a comprehensive and up-to-date overview of the main blood-based biomarker candidates is still lacking. In this narrative review, we discuss the role of proteins, lipids, metabolites, oxidative-stress-related molecules, and cytokines as possible disease biomarkers. Furthermore, we highlight the potential of the emerging miRNAs and long non-coding RNAs (lncRNAs) as diagnostic tools, and we briefly present the role of vitamins and gut-microbiome-related molecules as novel candidates for AD detection and monitoring, thus offering new insights into the diagnosis and progression of this devastating disease.
Collapse
Affiliation(s)
- Angelica Varesi
- Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy
- Almo Collegio Borromeo, 27100 Pavia, Italy
| | - Adelaide Carrara
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy; (A.C.); (V.F.)
| | - Vitor Gomes Pires
- Department of Biological Sciences, Columbia University, New York, NY 10027, USA;
| | - Valentina Floris
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy; (A.C.); (V.F.)
| | - Elisa Pierella
- School of Medicine, Faculty of Clinical and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK;
| | - Gabriele Savioli
- Emergency Department, IRCCS Policlinico San Matteo, 27100 Pavia, Italy;
| | - Sakshi Prasad
- Faculty of Medicine, National Pirogov Memorial Medical University, 21018 Vinnytsya, Ukraine;
| | - Ciro Esposito
- Unit of Nephrology and Dialysis, ICS Maugeri, University of Pavia, 27100 Pavia, Italy;
| | - Giovanni Ricevuti
- Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy
| | - Salvatore Chirumbolo
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37129 Verona, Italy;
| | - Alessia Pascale
- Department of Drug Sciences, Section of Pharmacology, University of Pavia, 27100 Pavia, Italy;
| |
Collapse
|
|
47
|
Dash S, Syed YA, Khan MR. Understanding the Role of the Gut Microbiome in Brain Development and Its Association With Neurodevelopmental Psychiatric Disorders. Front Cell Dev Biol 2022; 10:880544. [PMID: 35493075 PMCID: PMC9048050 DOI: 10.3389/fcell.2022.880544] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 03/28/2022] [Indexed: 12/12/2022] Open
Abstract
The gut microbiome has a tremendous influence on human physiology, including the nervous system. During fetal development, the initial colonization of the microbiome coincides with the development of the nervous system in a timely, coordinated manner. Emerging studies suggest an active involvement of the microbiome and its metabolic by-products in regulating early brain development. However, any disruption during this early developmental process can negatively impact brain functionality, leading to a range of neurodevelopment and neuropsychiatric disorders (NPD). In this review, we summarize recent evidence as to how the gut microbiome can influence the process of early human brain development and its association with major neurodevelopmental psychiatric disorders such as autism spectrum disorders, attention-deficit hyperactivity disorder, and schizophrenia. Further, we discuss how gut microbiome alterations can also play a role in inducing drug resistance in the affected individuals. We propose a model that establishes a direct link of microbiome dysbiosis with the exacerbated inflammatory state, leading to functional brain deficits associated with NPD. Based on the existing research, we discuss a framework whereby early diet intervention can boost mental wellness in the affected subjects and call for further research for a better understanding of mechanisms that govern the gut-brain axis may lead to novel approaches to the study of the pathophysiology and treatment of neuropsychiatric disorders.
Collapse
Affiliation(s)
- Somarani Dash
- Life Sciences Division, Institute of Advanced Study in Science and Technology (IASST), Guwahati, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Yasir Ahmed Syed
- School of Biosciences and Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Cardiff, United Kingdom
| | - Mojibur R. Khan
- Life Sciences Division, Institute of Advanced Study in Science and Technology (IASST), Guwahati, India
- *Correspondence: Mojibur R. Khan,
| |
Collapse
|
|
48
|
Yang Z, Wei F, Zhang B, Luo Y, Xing X, Wang M, Chen R, Sun G, Sun X. Cellular Immune Signal Exchange From Ischemic Stroke to Intestinal Lesions Through Brain-Gut Axis. Front Immunol 2022; 13:688619. [PMID: 35432368 PMCID: PMC9010780 DOI: 10.3389/fimmu.2022.688619] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 03/16/2022] [Indexed: 12/24/2022] Open
Abstract
As a vital pivot for the human circulatory system, the brain-gut axis is now being considered as an important channel for many of the small immune molecules’ transductions, including interleukins, interferons, neurotransmitters, peptides, and the chemokines penetrating the mesentery and blood brain barrier (BBB) during the development of an ischemic stroke (IS). Hypoxia-ischemia contributes to pituitary and neurofunctional disorders by interfering with the molecular signal release and communication then providing feedback to the gut. Suffering from such a disease on a long-term basis may cause the peripheral system’s homeostasis to become imbalanced, and it can also lead to multiple intestinal complications such as gut microbiota dysbiosis (GMD), inflammatory bowel disease (IBD), necrotizing enterocolitis (NEC), and even the tumorigenesis of colorectal carcinoma (CRC). Correspondingly, these complications will deteriorate the cerebral infarctions and, in patients suffering with IS, it can even ruin the brain’s immune system. This review summarized recent studies on abnormal immunological signal exchange mediated polarization subtype changes, in both macrophages and microglial cells as well as T-lymphocytes. How gut complications modulate the immune signal transduction from the brain are also elucidated and analyzed. The conclusions drawn in this review could provide guidance and novel strategies to benefit remedies for both IS and relative gut lesions from immune-prophylaxis and immunotherapy aspects.
Collapse
Affiliation(s)
- Zizhao Yang
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, National University of Singapore, Singapore, Singapore
| | - Fei Wei
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bin Zhang
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yun Luo
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaoyan Xing
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Min Wang
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Rongchang Chen
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guibo Sun
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Guibo Sun, ; Xiaobo Sun,
| | - Xiaobo Sun
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Guibo Sun, ; Xiaobo Sun,
| |
Collapse
|
|
49
|
Attaluri S, Arora M, Madhu LN, Kodali M, Shuai B, Melissari L, Upadhya R, Rao X, Bates A, Mitra E, Ghahfarouki KR, Ravikumar MNV, Shetty AK. Oral Nano-Curcumin in a Model of Chronic Gulf War Illness Alleviates Brain Dysfunction with Modulation of Oxidative Stress, Mitochondrial Function, Neuroinflammation, Neurogenesis, and Gene Expression. Aging Dis 2022; 13:583-613. [PMID: 35371600 PMCID: PMC8947830 DOI: 10.14336/ad.2021.0829] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 08/29/2021] [Indexed: 12/14/2022] Open
Abstract
Unrelenting cognitive and mood impairments concomitant with incessant oxidative stress and neuroinflammation are among the significant symptoms of chronic Gulf War Illness (GWI). Curcumin (CUR), an antiinflammatory compound, has shown promise to alleviate brain dysfunction in a model of GWI following intraperitoneal administrations at a high dose. However, low bioavailability after oral treatment has hampered its clinical translation. Therefore, this study investigated the efficacy of low-dose, intermittent, oral polymer nanoparticle encapsulated CUR (nCUR) for improving brain function in a rat model of chronic GWI. Intermittent administration of 10 or 20 mg/Kg nCUR for 8 weeks in the early phase of GWI improved brain function and reduced oxidative stress (OS) and neuroinflammation. We next examined the efficacy of 12-weeks of intermittent nCUR at 10 mg/Kg in GWI animals, with treatment commencing 8 months after exposure to GWI-related chemicals and stress, mimicking treatment for the persistent cognitive and mood dysfunction displayed by veterans with GWI. GWI rats receiving nCUR exhibited better cognitive and mood function associated with improved mitochondrial function and diminished neuroinflammation in the hippocampus. Improved mitochondrial function was evident from normalized expression of OS markers, antioxidants, and mitochondrial electron transport genes, and complex proteins. Lessened neuroinflammation was noticeable from reductions in astrocyte hypertrophy, NF-kB, activated microglia with NLRP3 inflammasomes, and multiple proinflammatory cytokines. Moreover, nCUR treated animals displayed enhanced neurogenesis with a normalized expression of synaptophysin puncta, and multiple genes linked to cognitive dysfunction. Thus, low-dose, intermittent, oral nCUR therapy has promise for improving brain function in veterans with GWI.
Collapse
Affiliation(s)
- Sahithi Attaluri
- Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University College of Medicine, College Station, Texas, USA.
| | - Meenakshi Arora
- Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University, College Station, Texas, USA
| | - Leelavathi N Madhu
- Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University College of Medicine, College Station, Texas, USA.
| | - Maheedhar Kodali
- Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University College of Medicine, College Station, Texas, USA.
| | - Bing Shuai
- Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University College of Medicine, College Station, Texas, USA.
| | - Laila Melissari
- Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University College of Medicine, College Station, Texas, USA.
| | - Raghavendra Upadhya
- Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University College of Medicine, College Station, Texas, USA.
| | - Xiaolan Rao
- Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University College of Medicine, College Station, Texas, USA.
| | - Adrian Bates
- Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University College of Medicine, College Station, Texas, USA.
| | - Eeshika Mitra
- Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University College of Medicine, College Station, Texas, USA.
| | - Keyhan R Ghahfarouki
- Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University College of Medicine, College Station, Texas, USA.
| | - M. N. V Ravikumar
- Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University, College Station, Texas, USA
| | - Ashok K Shetty
- Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University College of Medicine, College Station, Texas, USA.
| |
Collapse
|
|
50
|
Gokulakrishnan K, Nikhil J, VS S, Holla B, Thirumoorthy C, Sandhya N, Nichenametla S, Pathak H, Shivakumar V, Debnath M, Venkatasubramanian G, Varambally S. Altered Intestinal Permeability Biomarkers in Schizophrenia: A Possible Link with Subclinical Inflammation. Ann Neurosci 2022; 29:151-158. [PMID: 36419512 PMCID: PMC9676334 DOI: 10.1177/09727531221108849] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/18/2022] [Indexed: 09/12/2023] Open
Abstract
Background and Purpose Emerging studies have shown that gut-derived endotoxins might play a role in intestinal and systemic inflammation. Although the significance of intestinal permeability in modulating the pathogenesis of Schizophrenia (SCZ) is recognized, not much data on the specific role of intestinal permeability biomarkers, viz., zonulin, lipopolysaccharide-binding protein (LBP), and intestinal alkaline phosphatase (IAP) in SCZ is available. Therefore, we measured the plasma levels of zonulin, LBP, and IAP and its correlation with neutrophil-to-lymphocyte ratio (NLR); a marker of systemic inflammation in patients with SCZ. Methods We recruited 60 individuals, patients with SCZ (n = 40) and healthy controls (n = 20), from a large tertiary neuropsychiatry center. Plasma levels of zonulin, IAP, and LBP were quantified by enzyme-linked immunosorbent assay. Results Plasma levels of both LBP and zonulin were significantly increased (P <0.05), whereas the IAP levels (P <0.05) were significantly decreased in patients with SCZ compared to healthy controls. Pearson correlation analysis revealed that zonulin and LBP had a significant positive correlation with NLR, and IAP negatively correlated with NLR. Individuals with SCZ had higher independent odds of zonulin [odds ratio (OR): 10.32, 95% CI: 1.85-57.12], LBP [OR: 1.039, 95% CI: 1.02-1.07], and IAP [OR: 0.643, 95% CI: 0.471-0.879], even after adjusting for potential confounders. Conclusion Our study demonstrates an association of zonulin, LBP, and IAP in Asian Indian SCZ patients and correlates with NLR. Our results indicate that low-grade inflammation induced by metabolic endotoxemia might be implicated in the pathoetiology of SCZ.
Collapse
Affiliation(s)
- Kuppan Gokulakrishnan
- Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bengaluru, Karnataka, India
| | - Joyappa Nikhil
- Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bengaluru, Karnataka, India
| | - Sreeraj VS
- Department of Psychiatry, National Institute of Mental Health and Neuro Sciences, Bengaluru, Karnataka India
| | - Bharath Holla
- Department of Integrative Medicine, National Institute of Mental Health and Neuro Sciences, Bengaluru, Karnataka, India
| | - Chinnasamy Thirumoorthy
- Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bengaluru, Karnataka, India
| | - Narasimhan Sandhya
- Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bengaluru, Karnataka, India
| | - Sonika Nichenametla
- Department of Psychiatry, National Institute of Mental Health and Neuro Sciences, Bengaluru, Karnataka India
| | - Harsh Pathak
- Department of Psychiatry, National Institute of Mental Health and Neuro Sciences, Bengaluru, Karnataka India
| | - Venkataram Shivakumar
- Department of Integrative Medicine, National Institute of Mental Health and Neuro Sciences, Bengaluru, Karnataka, India
| | - Monojit Debnath
- Department of Human Genetics, National Institute of Mental Health and Neuro Sciences, Bengaluru, Karnataka, India
| | - Ganesan Venkatasubramanian
- Department of Psychiatry, National Institute of Mental Health and Neuro Sciences, Bengaluru, Karnataka India
| | - Shivarama Varambally
- Department of Psychiatry, National Institute of Mental Health and Neuro Sciences, Bengaluru, Karnataka India
- Department of Integrative Medicine, National Institute of Mental Health and Neuro Sciences, Bengaluru, Karnataka, India
| |
Collapse
|