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Seguella L, Corpetti C, Lu J, Pesce M, Franzin SB, Palenca I, Zilli A, Vincenzi M, Caprioli D, Paytuví-Gallart A, Sanseverino W, Rurgo S, Sarnelli G, Esposito G. Oleoylethanolamide-producing Lactobacillus paracasei F19 improves metabolic and behavioral disorders by restoring intestinal permeability and microbiota-gut-brain axis in high-fat diet-induced obese male mice. Brain Behav Immun 2025:S0889-1591(25)00053-4. [PMID: 39988008 DOI: 10.1016/j.bbi.2025.02.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 02/04/2025] [Accepted: 02/17/2025] [Indexed: 02/25/2025] Open
Abstract
Metabolic and mood disorders elicited by chronic exposure of high-fat diet (HFD) are often associated with intestinal dysbiosis and persistent low-grade inflammation in the small intestine. This leads to remodeling of the epithelial barrier with disruption of the neuroepithelial circuits that control energy homeostasis by the gut-brain axis. Therefore, therapies that restoreintestinal microbial niche and barrier function are promising candidates to counter peripheral metabolic challenges that affect behaviors controlled by the brain. The endogenous oleoylethanolamine (OEA) was found to shape the intestinal microbiota profile towards a "lean-like phenotype", ameliorating pathological profiles of metabolic diseases. Further, OEA displays beneficial effects in several cognitive paradigms and preserves the epithelial barrier integrity, acting as an intestinal "gate-keeper". Here, we developed an "intestinal OEA factory" for the in-situ and controlled release of OEA by using a probiotic-based delivery system. We engineered the Lactobacillus paracasei F19 (LP) to express the human N-acylphosphatidylethanolamine-preferring phospholipase D (NAPEpld) gene and to produce OEA in response to dietary ultra-low oleate supply. We treated 12-week HFD male mice with oleate-probiotic formulations and assessed their impact on metabolic and behavioral dysfunctions, and microbiota-gut-brain signaling after 8 weeks of treatment. NAPE-expressing LP (pNAPE-LP) led to significant reduced weight loss and improved metabolic dysfunction in HFD-treated mice. Further, a parallel improvement in depressive- and anxiety-like phenotypes was associated with the duodenal barrier function retrieval, the restoration of the Firmicutes/Bacteroidetes ratio, and an increase in beneficial bacteria, such as Lactobacillus, Prevotella, and Parabacteroides. The HFD-driven changes both in the enteric and central nervous system were prevented by pNAPE-LP/oleate treatment. Collectively, our data suggest that these effects were mediated by the oleate-dependent release of OEA by pNAPE-LP since no significant effects were observed in HFD mice treated with the native probiotic alone (pLP). This oleate-regulated delivery system of OEA is a safe and efficient probiotic-based strategy for the treatment of metabolic syndrome and related behavioral disorders.
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Affiliation(s)
- Luisa Seguella
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | - Chiara Corpetti
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | - Jie Lu
- Department of Anatomy and Cell Biology, China Medical University, N0.77 Puhe Road, Shenbei New District, Shenyang City, Liaoning Province, PR China.
| | - Marcella Pesce
- Department of Clinical Medicine and Surgery, University of Naples "Federico II", Via Pansini 5, 80131 Naples, Italy.
| | - Silvia Basili Franzin
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | - Irene Palenca
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | - Aurora Zilli
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | - Martina Vincenzi
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | - Daniele Caprioli
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | | | - Walter Sanseverino
- Sequentia Biotech SL, Carrer del Dr. Trueta, 179, 08005 Barcelona, Spain.
| | - Sara Rurgo
- Department of Clinical Medicine and Surgery, University of Naples "Federico II", Via Pansini 5, 80131 Naples, Italy.
| | - Giovanni Sarnelli
- Department of Clinical Medicine and Surgery, University of Naples "Federico II", Via Pansini 5, 80131 Naples, Italy.
| | - Giuseppe Esposito
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
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Ramírez-Maldonado LM, Guerrero-Castro J, Rodríguez-Mejía JL, Cárdenas-Conejo Y, Bonales-Alatorre EO, Valencia-Cruz G, Anguiano-García PT, Vega-Juárez II, Dagnino-Acosta A, Ruvalcaba-Galindo J, Valdez-Morales EE, Ochoa-Cortes F, Barajas-Espinosa A, Guerrero-Alba R, Liñán-Rico A. Obesogenic cafeteria diet induces dynamic changes in gut microbiota, reduces myenteric neuron excitability, and impairs gut contraction in mice. Am J Physiol Gastrointest Liver Physiol 2025; 328:G32-G48. [PMID: 39499253 DOI: 10.1152/ajpgi.00198.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 10/08/2024] [Accepted: 10/22/2024] [Indexed: 11/07/2024]
Abstract
The cafeteria diet (CAF) is a superior diet model in animal experiments compared with the conventional high-fat diet (HFD), effectively inducing obesity, metabolic disturbances, and multi-organ damage. Nevertheless, its impact on gut microbiota composition during the progression of obesity, along with its repercussions on the enteric nervous system (ENS) and gastrointestinal motility has not been completely elucidated. To gain more insight into the effects of CAF diet in the gut, C57BL/6 mice were fed with CAF or a standard diet for 2 or 8 wk. CAF-fed mice experienced weight gain, disturbed glucose metabolism, dysregulated expression of colonic IL-6, IL-22, TNFα, and TPH1, and altered colon morphology, starting at week 2. Fecal DNA was isolated and gut microbiota composition was monitored by sequencing the V3-V4 16S rRNA region. Sequence analysis revealed that Clostridia and Proteobacteria were specific biomarkers associated with CAF-feeding at week 2, while Bacteroides and Actinobacteria were prominent at week 8. In addition, the impact of CAF diet on ENS was investigated (week 8), where HuC/D+ neurons were measured and counted, and their biophysical properties were evaluated by patch clamp. Gut contractility was tested in whole-mount preparations. Myenteric neurons in CAF-fed mice exhibited reduced body size, incremented cell density, and decreased excitability. The amplitude and frequency of the rhythmic spontaneous contractions in the colon and ileum were affected by the CAF diet. Our findings demonstrate, for the first time, that CAF diet gradually changes the gut microbiota and promotes low-grade inflammation, impacting the functional properties of myenteric neurons and gut contractility in mice.NEW & NOTEWORTHY The gut microbiota changes gradually following the consumption of CAF diet. An increase in Clostridia and Proteobacteria is a hallmark of dysbiosis at the early onset of gut inflammation and obesity. The CAF diet was effective in inducing intestinal low-grade inflammation and alterations in myenteric neuronal excitability in mice. CAF diet is a reliable strategy to study the interplay between gut dysbiosis and low-grade inflammation, in addition to the mechanisms underlying gastrointestinal dysmotility associated with obesity.
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Affiliation(s)
- Luis M Ramírez-Maldonado
- Centro Universitario de Investigaciones Biomédicas (CUIB), Universidad de Colima, Colima, México
| | - Julio Guerrero-Castro
- Centro Universitario de Investigaciones Biomédicas (CUIB), Universidad de Colima, Colima, México
| | - José L Rodríguez-Mejía
- Centro Universitario de Investigaciones Biomédicas (CUIB), Universidad de Colima, Colima, México
| | - Yair Cárdenas-Conejo
- Laboratorio de Biología Sintética Estructural y Molecular, Universidad de Colima-Consejo Nacional de Humanidades, Ciencias y Tecnologías, Colima, México
| | - Edgar O Bonales-Alatorre
- Centro Universitario de Investigaciones Biomédicas (CUIB), Universidad de Colima, Colima, México
| | - Georgina Valencia-Cruz
- Centro Universitario de Investigaciones Biomédicas (CUIB), Universidad de Colima, Colima, México
| | | | - Irving I Vega-Juárez
- Centro Universitario de Investigaciones Biomédicas (CUIB), Universidad de Colima, Colima, México
| | - Adán Dagnino-Acosta
- Centro Universitario de Investigaciones Biomédicas (CUIB), Universidad de Colima, Colima, México
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima-Consejo Nacional de Humanidades, Ciencias y Tecnologías, Colima, México
| | | | - Eduardo E Valdez-Morales
- Departamento de Fisiología y Farmacología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes-Consejo Nacional de Humanidades, Ciencias y Tecnologías, Aguascalientes, México
| | - Fernando Ochoa-Cortes
- Escuela Superior de Huejutla, Universidad Autónoma del Estado de Hidalgo, Huejutla de Reyes, Hidalgo, México
| | - Alma Barajas-Espinosa
- Escuela Superior de Huejutla, Universidad Autónoma del Estado de Hidalgo, Huejutla de Reyes, Hidalgo, México
| | - Raquel Guerrero-Alba
- Departamento de Fisiología y Farmacología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, México
| | - Andrómeda Liñán-Rico
- Centro Universitario de Investigaciones Biomédicas (CUIB), Universidad de Colima, Colima, México
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima-Consejo Nacional de Humanidades, Ciencias y Tecnologías, Colima, México
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Almeida PP, Brito ML, Thomasi B, Mafra D, Fouque D, Knauf C, Tavares-Gomes AL, Stockler-Pinto MB. Is the enteric nervous system a lost piece of the gut-kidney axis puzzle linked to chronic kidney disease? Life Sci 2024; 351:122793. [PMID: 38848938 DOI: 10.1016/j.lfs.2024.122793] [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: 02/12/2024] [Revised: 05/20/2024] [Accepted: 06/04/2024] [Indexed: 06/09/2024]
Abstract
The enteric nervous system (ENS) regulates numerous functional and immunological attributes of the gastrointestinal tract. Alterations in ENS cell function have been linked to intestinal outcomes in various metabolic, intestinal, and neurological disorders. Chronic kidney disease (CKD) is associated with a challenging intestinal environment due to gut dysbiosis, which further affects patient quality of life. Although the gut-related repercussions of CKD have been thoroughly investigated, the involvement of the ENS in this puzzle remains unclear. ENS cell dysfunction, such as glial reactivity and alterations in cholinergic signaling in the small intestine and colon, in CKD are associated with a wide range of intestinal pathways and responses in affected patients. This review discusses how the ENS is affected in CKD and how it is involved in gut-related outcomes, including intestinal permeability, inflammation, oxidative stress, and dysmotility.
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Affiliation(s)
| | - Michele Lima Brito
- Pathology Post Graduate Program, Fluminense Federal University (UFF), Niterói, RJ, Brazil
| | - Beatriz Thomasi
- Department of Physiology, Neuroscience Program, Michigan State University (MSU), East Lansing, MI, USA
| | - Denise Mafra
- Graduate Program in Biological Sciences - Physiology, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Denis Fouque
- Department of Nephrology, Centre Hopitalier Lyon Sud, INSERM 1060, CENS, Université de Lyon, France
| | - Claude Knauf
- INSERM U1220 Institut de Recherche en Santé Digestive, CHU Purpan, Université Toulouse III Paul Sabatier Toulouse, Toulouse, France
| | - Ana Lúcia Tavares-Gomes
- Neurosciences Post Graduate Program, Fluminense Federal University (UFF), Niterói, RJ, Brazil
| | - Milena Barcza Stockler-Pinto
- Pathology Post Graduate Program, Fluminense Federal University (UFF), Niterói, RJ, Brazil; INSERM U1220 Institut de Recherche en Santé Digestive, CHU Purpan, Université Toulouse III Paul Sabatier Toulouse, Toulouse, France
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Cingolani F, Balasubramaniam A, Srinivasan S. Molecular mechanisms of enteric neuropathies in high-fat diet feeding and diabetes. Neurogastroenterol Motil 2024:e14897. [PMID: 39119749 PMCID: PMC11807233 DOI: 10.1111/nmo.14897] [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: 02/07/2024] [Revised: 07/12/2024] [Accepted: 07/31/2024] [Indexed: 08/10/2024]
Abstract
BACKGROUND Obesity and diabetes are associated with altered gastrointestinal function and with the development of abdominal pain, nausea, diarrhea, and constipation among other symptoms. The enteric nervous system (ENS) regulates gastrointestinal motility. Enteric neuropathies defined as damage or loss of enteric neurons can lead to motility disorders. PURPOSE Here, we review the molecular mechanisms that drive enteric neurodegeneration in diabetes and obesity, including signaling pathways leading to neuronal cell death, oxidative stress, and microbiota alteration. We also highlight potential approaches to treat enteric neuropathies including antioxidant therapy to prevent oxidative stress-induced damage and the use of stem cells.
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Affiliation(s)
- Francesca Cingolani
- Division of Digestive Diseases, Emory University School of Medicine, Atlanta, GA, United States
- Atlanta Veterans Affairs Health Care System, Decatur, GA, United States
| | - Arun Balasubramaniam
- Division of Digestive Diseases, Emory University School of Medicine, Atlanta, GA, United States
- Atlanta Veterans Affairs Health Care System, Decatur, GA, United States
| | - Shanthi Srinivasan
- Division of Digestive Diseases, Emory University School of Medicine, Atlanta, GA, United States
- Atlanta Veterans Affairs Health Care System, Decatur, GA, United States
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Abdalla MMI. Enteric neuropathy in diabetes: Implications for gastrointestinal function. World J Gastroenterol 2024; 30:2852-2865. [PMID: 38947292 PMCID: PMC11212710 DOI: 10.3748/wjg.v30.i22.2852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 05/04/2024] [Accepted: 05/21/2024] [Indexed: 06/05/2024] Open
Abstract
Diabetes, commonly known for its metabolic effects, also critically affects the enteric nervous system (ENS), which is essential in regulating gastrointestinal (GI) motility, secretion, and absorption. The development of diabetes-induced enteric neuropathy can lead to various GI dysfunctions, such as gastroparesis and irregular bowel habits, primarily due to disruptions in the function of neuronal and glial cells within the ENS, as well as oxidative stress and inflammation. This editorial explores the pathophysiological mechanisms underlying the development of enteric neuropathy in diabetic patients. Additionally, it discusses the latest advances in diagnostic approaches, emphasizing the need for early detection and intervention to mitigate GI complications in diabetic individuals. The editorial also reviews current and emerging therapeutic strategies, focusing on pharmacological treatments, dietary management, and potential neuromodulatory interventions. Ultimately, this editorial highlights the necessity of a multidisciplinary approach in managing enteric neuropathy in diabetes, aiming to enhance patient quality of life and address a frequently overlooked complication of this widespread disease.
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Affiliation(s)
- Mona Mohamed Ibrahim Abdalla
- Department of Human Biology, School of Medicine, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
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Varley AN, Browning KN. Gastrointestinal dysfunction in the valproic acid induced model of social deficit in rats. Auton Neurosci 2024; 253:103161. [PMID: 38461695 PMCID: PMC11128350 DOI: 10.1016/j.autneu.2024.103161] [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: 12/06/2023] [Revised: 02/28/2024] [Accepted: 02/28/2024] [Indexed: 03/12/2024]
Abstract
Autism spectrum disorder (ASD) has increased in incidence over the past several decades, and is associated with a range of co-morbidities including gastrointestinal (GI) dysfunctions including gastroesophageal reflux, abdominal pain, bloating, constipation and/or diarrhea. Several animal models have been used that replicate several aspects of ASD but no single model has been able to replicate the entire disease pathophysiology. In humans, prenatal exposure to valproic acid (VPA) has been identified as a significant risk factor and rodent models have shown that in utero VPA exposure leads to behavioral deficits in offspring. The present study aimed to investigate whether in utero exposure to VPA induces GI dysfunction in rats. Timed pregnant Sprague-Dawley rats were injected with a single dose of VPA at embryonic day 12.5. Both male and female offspring subsequently underwent behavioral studies and assessment of GI function in adulthood. In utero VPA treatment induced social deficits in both male and female offspring, decreasing sociability and social novelty. Histological examination showed that VPA treated offspring had decreased thickness of GI muscle and mucosa, while immunohistochemical studies showed a decrease in myenteric neuron number in the fundus. Functional studies showed that both male and female VPA offspring had a delay in gastric emptying compared to vehicle treated offspring. Results of the current study suggest that the rat VPA model of behavioral deficits may be a convenient model by which both mechanistic and functional insights into GI dysfunction may be studied.
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Affiliation(s)
- Ashley N Varley
- Department of Comparative Medicine, Penn State College of Medicine, Hershey, PA, United States of America
| | - Kirsteen N Browning
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA, United States of America.
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Cao Y, Ibrahim KS, Li X, Wong A, Wu Y, Yu XD, Zhou X, Tan Z, He Z, Craft JA, Shu X. Chinese medicine, Qijudihuang pill, mediates cholesterol metabolism and regulates gut microbiota in high-fat diet-fed mice, implications for age-related macular degeneration. Front Immunol 2023; 14:1274401. [PMID: 37901244 PMCID: PMC10602650 DOI: 10.3389/fimmu.2023.1274401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 09/21/2023] [Indexed: 10/31/2023] Open
Abstract
BACKGROUND Traditional Chinese Medicines have been used for thousands of years but without any sound empirical basis. One such preparation is the Qijudihuang pill (QP), a mixture of eight herbs, that has been used in China for the treatment of various conditions including age-related macular degeneration (AMD), the most common cause of blindness in the aged population. In order to explain the mechanism behind the effect of QP, we used an AMD model of high-fat diet (HFD) fed mice to investigate cholesterol homeostasis, oxidative stress, inflammation and gut microbiota. METHODS Mice were randomly divided into three groups, one group was fed with control diet (CD), the other two groups were fed with high-fat-diet (HFD). One HFD group was treated with QP, both CD and the other HFD groups were treated with vehicles. Tissue samples were collected after the treatment. Cholesterol levels in retina, retinal pigment epithelium (RPE), liver and serum were determined using a commercial kit. The expression of enzymes involved in cholesterol metabolism, inflammation and oxidative stress was measured with qRT-PCR. Gut microbiota was analyzed using 16S rRNA sequencing. RESULTS In the majority of the lipid determinations, analytes were elevated by HFD but this was reversed by QP. Cholesterol metabolism including the enzymes of bile acid (BA) formation was suppressed by HFD but again this was reversed by QP. BAs play a major role in signaling between host and microbiome and this is disrupted by HFD resulting in major changes in the composition of colonic bacterial communities. Associated with these changes are predictions of the metabolic pathway complexity and abundance of individual pathways. These concerned substrate breakdowns, energy production and the biosynthesis of pro-inflammatory factors but were changed back to control characteristics by QP. CONCLUSION We propose that the ability of QP to reverse these HFD-induced effects is related to mechanisms acting to lower cholesterol level, oxidative stress and inflammation, and to modulate gut microbiota.
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Affiliation(s)
- Yanqun Cao
- Pu Ai Medical School, Shaoyang University, Shaoyang, Hunan, China
| | - Khalid S. Ibrahim
- Department of Biological and Biomedical Sciences , Glasgow Caledonian University, Glasgow, United Kingdom
- Department of Biology, Faculty of Science, University of Zakho, Zakho, Iraq
| | - Xing Li
- Pu Ai Medical School, Shaoyang University, Shaoyang, Hunan, China
| | - Aileen Wong
- Department of Biological and Biomedical Sciences , Glasgow Caledonian University, Glasgow, United Kingdom
| | - Yi Wu
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Xu-Dong Yu
- Pu Ai Medical School, Shaoyang University, Shaoyang, Hunan, China
| | - Xinzhi Zhou
- Department of Biological and Biomedical Sciences , Glasgow Caledonian University, Glasgow, United Kingdom
| | - Zhoujin Tan
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Zhiming He
- Pu Ai Medical School, Shaoyang University, Shaoyang, Hunan, China
| | - John A. Craft
- Department of Biological and Biomedical Sciences , Glasgow Caledonian University, Glasgow, United Kingdom
| | - Xinhua Shu
- Pu Ai Medical School, Shaoyang University, Shaoyang, Hunan, China
- Department of Biological and Biomedical Sciences , Glasgow Caledonian University, Glasgow, United Kingdom
- Department of Vision Science , Glasgow Caledonian University, Glasgow, United Kingdom
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Pei Y, Wang R, Chen W, Yi S, Huang C, Liang S, Cao H, Xu Y, Tan B. Impaired colonic motility in high-glycemic diet-induced diabetic mice is associated with disrupted gut microbiota and neuromuscular function. Endocr Connect 2023; 12:e230078. [PMID: 37399524 PMCID: PMC10448599 DOI: 10.1530/ec-23-0078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 06/30/2023] [Indexed: 07/05/2023]
Abstract
BACKGROUND Similar to the high-fat diet (HFD), the high-glycemic diet (HGD) contributes to the development and progression of type 2 diabetes mellitus (T2DM). However, the effect of HGD on gastrointestinal motility in T2DM and its underlying mechanisms remain unclear. METHODS Thirty C57BL/6J mice were randomly designated into the normal-feeding diet (NFD) group, HFD group, and HGD group. The plasma glucose, plasma insulin, and gastrointestinal motility were examined. Meanwhile, the tension of isolated colonic smooth muscle rings was calculated, and the gut microbiota was analyzed by 16s rDNA high-throughput sequencing. RESULT After 16 weeks of HGD feeding, obesity, hyperglycemia, insulin resistance, and constipation were observed in HGD mice. Autonomic contraction frequency of the colonic neuromuscular system and electrical field stimulation-induced contractions were reduced in HGD mice. On the contrary, neuronal nitric oxide synthase activity and neuromuscular relaxation were found to be enhanced. Finally, gut microbiota analysis revealed that Rhodospirillaceae abundance significantly increased at the family level in HGD mice. At the genus level, the abundance of Insolitispirillum increased remarkably, whereas Turicibacter abundance decreased significantly in HGD mice. CONCLUSION HGD induced constipation in obese diabetic mice, which we speculated that it may be related to neuromuscular dysmotility and intestinal microbiota dysbiosis.
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Affiliation(s)
- Ying Pei
- Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Rui Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wanyu Chen
- Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shulin Yi
- Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chen Huang
- Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shaochan Liang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hongying Cao
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yifei Xu
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Bo Tan
- Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
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Graves CL, Norloff E, Thompson D, Kosyk O, Sang Y, Chen A, Zannas AS, Wallet SM. Chronic early life stress alters the neuroimmune profile and functioning of the developing zebrafish gut. Brain Behav Immun Health 2023; 31:100655. [PMID: 37449287 PMCID: PMC10336164 DOI: 10.1016/j.bbih.2023.100655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 05/30/2023] [Accepted: 06/15/2023] [Indexed: 07/18/2023] Open
Abstract
Chronic early life stress (ELS) potently impacts the developing central nervous and immune systems and is associated with the onset of gastrointestinal disease in humans. Though the gut-brain axis is appreciated to be a major target of the stress response, the underlying mechanisms linking ELS to gut dysfunction later in life is incompletely understood. Zebrafish are a powerful model validated for stress research and have emerged as an important tool in delineating neuroimmune mechanisms in the developing gut. Here, we developed a novel model of ELS and utilized a comparative transcriptomics approach to assess how chronic ELS modulated expression of neuroimmune genes in the developing gut and brain. Zebrafish exposed to ELS throughout larval development exhibited anxiety-like behavior and altered expression of neuroimmune genes in a time- and tissue-dependent manner. Further, the altered gut neuroimmune profile, which included increased expression of genes associated with neuronal modulation, correlated with a reduction in enteric neuronal density and delayed gut transit. Together, these findings provide insights into the mechanisms linking ELS with gastrointestinal dysfunction and highlight the zebrafish model organism as a valuable tool in uncovering how "the body keeps the score."
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Affiliation(s)
- Christina L. Graves
- Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Carolina Stress Initiative, University of North Carolina School of Medicine, Chapel Hill, NC, 27514, USA
| | - Erik Norloff
- Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Darius Thompson
- Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Oksana Kosyk
- Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Yingning Sang
- Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Angela Chen
- Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Anthony S. Zannas
- Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA
- Carolina Stress Initiative, University of North Carolina School of Medicine, Chapel Hill, NC, 27514, USA
| | - Shannon M. Wallet
- Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
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Sharkey KA, Mawe GM. The enteric nervous system. Physiol Rev 2023; 103:1487-1564. [PMID: 36521049 PMCID: PMC9970663 DOI: 10.1152/physrev.00018.2022] [Citation(s) in RCA: 132] [Impact Index Per Article: 66.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 12/12/2022] [Accepted: 12/15/2022] [Indexed: 12/23/2022] Open
Abstract
Of all the organ systems in the body, the gastrointestinal tract is the most complicated in terms of the numbers of structures involved, each with different functions, and the numbers and types of signaling molecules utilized. The digestion of food and absorption of nutrients, electrolytes, and water occurs in a hostile luminal environment that contains a large and diverse microbiota. At the core of regulatory control of the digestive and defensive functions of the gastrointestinal tract is the enteric nervous system (ENS), a complex system of neurons and glia in the gut wall. In this review, we discuss 1) the intrinsic neural control of gut functions involved in digestion and 2) how the ENS interacts with the immune system, gut microbiota, and epithelium to maintain mucosal defense and barrier function. We highlight developments that have revolutionized our understanding of the physiology and pathophysiology of enteric neural control. These include a new understanding of the molecular architecture of the ENS, the organization and function of enteric motor circuits, and the roles of enteric glia. We explore the transduction of luminal stimuli by enteroendocrine cells, the regulation of intestinal barrier function by enteric neurons and glia, local immune control by the ENS, and the role of the gut microbiota in regulating the structure and function of the ENS. Multifunctional enteric neurons work together with enteric glial cells, macrophages, interstitial cells, and enteroendocrine cells integrating an array of signals to initiate outputs that are precisely regulated in space and time to control digestion and intestinal homeostasis.
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Affiliation(s)
- Keith A Sharkey
- Hotchkiss Brain Institute and Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Gary M Mawe
- Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, Vermont
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Perinatal and post-weaning exposure to a high-fat diet causes histomorphometric, neuroplastic, and histopathological changes in the rat ileum. J Dev Orig Health Dis 2023; 14:231-241. [PMID: 36073012 DOI: 10.1017/s2040174422000514] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Exposure to a diet with a high saturated fat content can influence the characteristics of the gastrointestinal tract, causing losses in the absorption of nutrients and favoring the appearance of diseases. The objective was to assess the effects of a high-fat diet (HFD) in the perinatal (pregnancy and lactation) and post-weaning period on the histomorphometry, neuroplasticity, and histopathology of the ileum. Wistar rats were divided into four subgroups: Control/Control (CC, n = 10) rats fed a control diet (C) throughout the trial period; Control/HFD (CH, n = 9) rats fed diet C (perinatal) and HFD after weaning; HFD/Control (HC, n = 10) rats fed HFD (perinatal) and diet C (post-weaning); HFD/HFD (HH, n = 9) rats fed HFD throughout the experimental period. There was atrophy of the Ileum wall with a reduction in the muscular tunic, submucosa, and mucosa thickness in the HH group of 37%, 28%, and 46%, respectively (p < 0.0001). The depth of the crypts decreased by 29% (p < 0.0001) and height increased by 5% (p < 0.0013). Villus height decreased by 41% and 18% in HH and HC groups (p < 0.0001) and width decreased by 11% in the HH (p < 0.0001). The height of the enterocytes decreased by 18% in the HH (p < 0.0001). There was a decrease in the area of the myenteric and submucosal plexus ganglia in the HH and HC groups (p < 0.0001). The number, occupation, and granules of Paneth cells increased in the HH and HC groups (p < 0.0001). Intraepithelial lymphocytes (IELs) increased in all groups exposed to the HFD. Goblet cells decreased in groups CH and HH (p < 0.0001). The evidence from this study suggests that the HFD had altered the histomorphometry, neuroplasticity, and histopathology of the ileum of the rats.
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12
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Almeida PP, Valdetaro L, Thomasi BBDM, Stockler-Pinto MB, Tavares-Gomes AL. High-fat diets on the enteric nervous system: Possible interactions and mechanisms underlying dysmotility. Obes Rev 2022; 23:e13404. [PMID: 34873814 DOI: 10.1111/obr.13404] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/25/2021] [Accepted: 11/15/2021] [Indexed: 01/09/2023]
Abstract
Obesity is a chronic disease that affects various physiological systems. Among them, the gastrointestinal tract appears to be a main target of this disease. High-fat diet (HFD) animal models can help recapitulate the classic signs of obesity and present a series of gastrointestinal alterations, mainly dysmotility. Because intestinal motility is governed by the enteric nervous system (ENS), enteric neurons, and glial cells have been studied in HFD models. Given the importance of the ENS in general gut physiology, this review aims to discuss the relationship between HFD-induced neuroplasticity and gut dysmotility observed in experimental models. Furthermore, we highlight components of the gut environment that might influence enteric neuroplasticity, including gut microbiota, enteric glio-epithelial unit, serotonin release, immune cells, and disturbances such as inflammation and oxidative stress.
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Affiliation(s)
| | - Luisa Valdetaro
- Postgraduate Program in Neurosciences, Fluminense Federal University, Niterói, Brazil
| | | | - Milena Barcza Stockler-Pinto
- Postgraduate Program in Cardiovascular Sciences, Fluminense Federal University, Niterói, Brazil.,Postgraduate Program in Nutrition Sciences, Fluminense Federal University, Niterói, Brazil
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13
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Interactions between the microbiota and enteric nervous system during gut-brain disorders. Neuropharmacology 2021; 197:108721. [PMID: 34274348 DOI: 10.1016/j.neuropharm.2021.108721] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 07/13/2021] [Accepted: 07/13/2021] [Indexed: 02/08/2023]
Abstract
For the last 20 years, researchers have focused their intention on the impact of gut microbiota in healthy and pathological conditions. This year (2021), more than 25,000 articles can be retrieved from PubMed with the keywords "gut microbiota and physiology", showing the constant progress and impact of gut microbes in scientific life. As a result, numerous therapeutic perspectives have been proposed to modulate the gut microbiota composition and/or bioactive factors released from microbes to restore our body functions. Currently, the gut is considered a primary site for the development of pathologies that modify brain functions such as neurodegenerative (Parkinson's, Alzheimer's, etc.) and metabolic (type 2 diabetes, obesity, etc.) disorders. Deciphering the mode of interaction between microbiota and the brain is a real original option to prevent (and maybe treat in the future) the establishment of gut-brain pathologies. The objective of this review is to describe recent scientific elements that explore the communication between gut microbiota and the brain by focusing our interest on the enteric nervous system (ENS) as an intermediate partner. The ENS, which is known as the "second brain", could be under the direct or indirect influence of the gut microbiota and its released factors (short-chain fatty acids, neurotransmitters, gaseous factors, etc.). Thus, in addition to their actions on tissue (adipose tissue, liver, brain, etc.), microbes can have an impact on local ENS activity. This potential modification of ENS function has global repercussions in the whole body via the gut-brain axis and represents a new therapeutic strategy.
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High-fat diet impairs duodenal barrier function and elicits glia-dependent changes along the gut-brain axis that are required for anxiogenic and depressive-like behaviors. J Neuroinflammation 2021; 18:115. [PMID: 33993886 PMCID: PMC8126158 DOI: 10.1186/s12974-021-02164-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 04/30/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Mood and metabolic disorders are interrelated and may share common pathological processes. Autonomic neurons link the brain with the gastrointestinal tract and constitute a likely pathway for peripheral metabolic challenges to affect behaviors controlled by the brain. The activities of neurons along these pathways are regulated by glia, which exhibit phenotypic shifts in response to changes in their microenvironment. How glial changes might contribute to the behavioral effects of consuming a high-fat diet (HFD) is uncertain. Here, we tested the hypothesis that anxiogenic and depressive-like behaviors driven by consuming a HFD involve compromised duodenal barrier integrity and subsequent phenotypic changes to glia and neurons along the gut-brain axis. METHODS C57Bl/6 male mice were exposed to a standard diet or HFD for 20 weeks. Bodyweight was monitored weekly and correlated with mucosa histological damage and duodenal expression of tight junction proteins ZO-1 and occludin at 0, 6, and 20 weeks. The expression of GFAP, TLR-4, BDNF, and DCX were investigated in duodenal myenteric plexus, nodose ganglia, and dentate gyrus of the hippocampus at the same time points. Dendritic spine number was measured in cultured neurons isolated from duodenal myenteric plexuses and hippocampi at weeks 0, 6, and 20. Depressive and anxiety behaviors were also assessed by tail suspension, forced swimming, and open field tests. RESULTS HFD mice exhibited duodenal mucosa damage with marked infiltration of immune cells and decreased expression of ZO-1 and occludin that coincided with increasing body weight. Glial expression of GFAP and TLR4 increased in parallel in the duodenal myenteric plexuses, nodose ganglia, and hippocampus in a time-dependent manner. Glial changes were associated with a progressive decrease in BDNF, and DCX expression, fewer neuronal dendritic spines, and anxiogenic/depressive symptoms in HFD-treated mice. Fluorocitrate (FC), a glial metabolic poison, abolished these effects both in the enteric and central nervous systems and prevented behavioral alterations at week 20. CONCLUSIONS HFD impairs duodenal barrier integrity and produces behavioral changes consistent with depressive and anxiety phenotypes. HFD-driven changes in both peripheral and central nervous systems are glial-dependent, suggesting a potential glial role in the alteration of the gut-brain signaling that occurs during metabolic disorders and psychiatric co-morbidity.
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Özdemir-Kumral ZN, Koyuncuoğlu T, Arabacı-Tamer S, Çilingir-Kaya ÖT, Köroğlu AK, Yüksel M, Yeğen BÇ. High-fat Diet Enhances Gastric Contractility, but Abolishes Nesfatin-1-induced Inhibition of Gastric Emptying. J Neurogastroenterol Motil 2021; 27:265-278. [PMID: 33795544 PMCID: PMC8026381 DOI: 10.5056/jnm20206] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 10/30/2020] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND/AIMS Gastrointestinal motility changes contribute to development and maintenance of obesity. Nesfatin-1 (NES-1) is involved in central appetite control. The aim is to elucidate effects of NES-1 and high-fat diet (HFD) on gastrointestinal motility and to explore myenteric neuron expressions of tyrosine hydroxylase (TH), vasoactive intestinal peptide (VIP), and neuronal nitric oxide synthase (nNOS) in HFDinduced oxidative injury. METHODS Sprague-Dawley rats were fed with normal diet (ND) or HFD. Gastric emptying rate was measured following NES-1 (5 pmol/rat, intracerebroventricular) preceded by subcutaneous injections of glucagon-like peptide 1 (GLP-1), cholecystokinin 1 (CCK-1), and gastrin/CCK-2 receptor antagonists. In carbachol-contracted gastric and ileal strips, contractile changes were recorded by adding NES- 1 (0.3 nmol/L), GLP-1, CCK-1, and gastrin/CCK-2 antagonists. RESULTS Neither HFD nor NES-1 changed methylcellulose emptying, but NES-1 delayed saline emptying in cannulated ND-rats. Inhibitory effect of NES-1 on gastric emptying in ND-rats was reversed by all antagonists, and abolished in HFD-rats. In HFD-rats, carbachol-induced contractility was enhanced in gastric, but inhibited in ileal strips. HFD increased body weight, while serum triglycerides, alanine transaminase, aspartate aminotransferase, glucose, and levels of malondialdehyde, glutathione, myeloperoxidase activity, and luminolchemiluminescence in hepatic, ileal, and adipose tissues were similar in ND- and HFD-rats, but only lucigenin-chemiluminescence was increased in HFD-rats. Vasoactive intestinal peptide (VIP) and TH immunoreactivities were depressed and nNOS immunoreactivity was increased in gastric tissues of HFD-rats, while VIP and TH were enhanced, but nNOS was reduced in their intestines. CONCLUSIONS HFD caused mild systemic inflammation, disrupted enteric innervation, enhanced gastric contractility, inhibited ileal contractility, and eliminated inhibitory effect of NES-1 on gastric motility.
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Affiliation(s)
| | - Türkan Koyuncuoğlu
- Departments of Physiology, Marmara University School of Medicine, Istanbul, Turkey
| | - Sevil Arabacı-Tamer
- Departments of Physiology, Marmara University School of Medicine, Istanbul, Turkey
| | - Özlem T Çilingir-Kaya
- Departments of Histology and Embryology, Marmara University School of Medicine, Istanbul, Turkey
| | - Ayça K Köroğlu
- Departments of Histology and Embryology, Marmara University School of Medicine, Istanbul, Turkey
- Department of Histology and Embryology, Istinye University Faculty of Medicine; Istanbul, Turkey
| | - Meral Yüksel
- Marmara University Vocational School of Health Sciences, Istanbul, Turkey
| | - Berrak Ç Yeğen
- Departments of Physiology, Marmara University School of Medicine, Istanbul, Turkey
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Castañeda-Corral G, Velázquez-Salazar NB, Martínez-Martínez A, Taboada-Serrano JN, Núñez-Aragón PN, González-Palomares L, Acosta-González RI, Petricevich VL, Acevedo-Fernández JJ, Montes S, Jiménez-Andrade JM. Characterization of Mechanical Allodynia and Skin Innervation in a Mouse Model of Type-2 Diabetes Induced by Cafeteria-Style Diet and Low-Doses of Streptozotocin. Front Pharmacol 2021; 11:628438. [PMID: 33732147 PMCID: PMC7957928 DOI: 10.3389/fphar.2020.628438] [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: 11/11/2020] [Accepted: 12/31/2020] [Indexed: 01/14/2023] Open
Abstract
Background: Painful distal symmetrical polyneuropathy (DPN) is a frequent complication of type-2 diabetes mellitus (T2DM) that commonly presents as neuropathic pain and loss of skin nerve fibers. However, there are limited therapies to effectively treat DPN and many of the current animal models of T2DM-induced DPN do not appear to mirror the human disease. Thus, we validated a DPN mouse model induced by a cafeteria-style diet plus low-doses of streptozotocin (STZ). Methods: Female C57BL/6J mice were fed either standard (STD) diet or obesogenic cafeteria (CAF) diet for 32 weeks, starting at 8 weeks old. Eight weeks after starting diets, CAF or STD mice received either four low-doses of STZ or vehicle. Changes in body weight, blood glucose and insulin levels, as well as oral glucose- and insulin-tolerance tests (OGTT and ITT) were determined. The development of mechanical hypersensitivity of the hindpaws was determined using von Frey filaments. Moreover, the effect of the most common neuropathic pain drugs was evaluated on T2DM-induced mechanical allodynia. Finally, the density of PGP -9.5+ (a pan-neuronal marker) axons in the epidermis from the hindpaw glabrous skin was quantified. Results: At 22–24 weeks after STZ injections, CAF + STZ mice had significantly higher glucose and insulin levels compared to CAF + VEH, STD + STZ, and STD + VEH mice, and developed glucose tolerance and insulin resistance. Skin mechanical sensitivity was detected as early as 12 weeks post-STZ injections and it was significantly attenuated by intraperitoneal acute treatment with amitriptyline, gabapentin, tramadol, duloxetine, or carbamazepine but not by diclofenac. The density of PGP-9.5+ nerve fibers was reduced in CAF + STZ mice compared to other groups. Conclusion: This reverse translational study provides a painful DPN mouse model which may help in developing a better understanding of the factors that generate and maintain neuropathic pain and denervation of skin under T2DM and to identify mechanism-based new treatments.
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Affiliation(s)
| | | | - Arisai Martínez-Martínez
- Unidad Académica Multidisciplinaria Reynosa Aztlán, Universidad Autónoma de Tamaulipas, Reynosa, México
| | | | - Pablo N Núñez-Aragón
- Facultad de Medicina, Universidad Autónoma del Estado de Morelos, Cuernavaca, México
| | | | | | - Vera L Petricevich
- Facultad de Medicina, Universidad Autónoma del Estado de Morelos, Cuernavaca, México
| | | | - Sergio Montes
- Departamento de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía "Dr. Manuel Velasco Suárez", Ciudad de México México
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Huang Z, Liao L, Wang Z, Lu Y, Yan W, Cao H, Tan B. An efficient approach for wholemount preparation of the myenteric plexus of rat colon. J Neurosci Methods 2021; 348:109012. [PMID: 33249181 DOI: 10.1016/j.jneumeth.2020.109012] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 11/15/2020] [Accepted: 11/24/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND The nerve plexus of the enteric nervous system (ENS) plays a crucial part in regulating gastrointestinal functions, such as muscle contractile activity and nutrient absorption. Studying the nerve plexus can provide vital information for research on ENS disorders. Whole-mount preparation is an important technique for investigating the nerve plexus. However, currently available methods are time consuming and highly technical. NEW METHOD This study describes a simple and rapid method for preparing whole mounts of the longitudinal muscle and myenteric plexuses (LMMPs) of rat colon. Integral LMMPs can be easily separated from the underlying layer by using glass rods and wet cotton swabs. RESULTS The proposed method allows the easy separation of the LMMPs in intact sheets. Immunofluorescence histochemical staining of whole mounts enable clear visualization of enteric ganglia, nerve fibers, and several subtypes of neuronal populations residing in the myenteric plexus. COMPARISON WITH EXISTING METHODS Compared with existing procedures for whole-mount preparations, the proposed method achieves a quicker and more efficient preparation of high-quality LMMPs from intestinal segments in sufficient quantity. CONCLUSIONS This work provides a rapid method for efficiently preparing whole mounts of the intestines. Our method can be used for in situ observation of the morphological and functional alterations of the myenteric plexus for further studies on the ENS.
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Affiliation(s)
- Zitong Huang
- Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, PR China
| | - Lu Liao
- Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, PR China
| | - Zhesheng Wang
- Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, PR China
| | - Yulin Lu
- Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, PR China
| | - Weiming Yan
- The Third Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, PR China
| | - Hongying Cao
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, PR China
| | - Bo Tan
- Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, PR China.
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Chandramowlishwaran P, Vijay A, Abraham D, Li G, Mwangi SM, Srinivasan S. Role of Sirtuins in Modulating Neurodegeneration of the Enteric Nervous System and Central Nervous System. Front Neurosci 2020; 14:614331. [PMID: 33414704 PMCID: PMC7783311 DOI: 10.3389/fnins.2020.614331] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 12/02/2020] [Indexed: 12/12/2022] Open
Abstract
Neurodegeneration of the central and enteric nervous systems is a common feature of aging and aging-related diseases, and is accelerated in individuals with metabolic dysfunction including obesity and diabetes. The molecular mechanisms of neurodegeneration in both the CNS and ENS are overlapping. Sirtuins are an important family of histone deacetylases that are important for genome stability, cellular response to stress, and nutrient and hormone sensing. They are activated by calorie restriction (CR) and by the coenzyme, nicotinamide adenine dinucleotide (NAD+). Sirtuins, specifically the nuclear SIRT1 and mitochondrial SIRT3, have been shown to have predominantly neuroprotective roles in the CNS while the cytoplasmic sirtuin, SIRT2 is largely associated with neurodegeneration. A systematic study of sirtuins in the ENS and their effect on enteric neuronal growth and survival has not been conducted. Recent studies, however, also link sirtuins with important hormones such as leptin, ghrelin, melatonin, and serotonin which influence many important processes including satiety, mood, circadian rhythm, and gut homeostasis. In this review, we address emerging roles of sirtuins in modulating the metabolic challenges from aging, obesity, and diabetes that lead to neurodegeneration in the ENS and CNS. We also highlight a novel role for sirtuins along the microbiota-gut-brain axis in modulating neurodegeneration.
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Affiliation(s)
- Pavithra Chandramowlishwaran
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
- Research-Gastroenterology, Atlanta Veterans Affairs Health Care System, Decatur, GA, United States
| | - Anitha Vijay
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United States
| | - Daniel Abraham
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States
| | - Ge Li
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
- Research-Gastroenterology, Atlanta Veterans Affairs Health Care System, Decatur, GA, United States
| | - Simon Musyoka Mwangi
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
- Research-Gastroenterology, Atlanta Veterans Affairs Health Care System, Decatur, GA, United States
| | - Shanthi Srinivasan
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
- Research-Gastroenterology, Atlanta Veterans Affairs Health Care System, Decatur, GA, United States
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Tanase DM, Gosav EM, Neculae E, Costea CF, Ciocoiu M, Hurjui LL, Tarniceriu CC, Maranduca MA, Lacatusu CM, Floria M, Serban IL. Genetic Basis of Tiller Dynamics of Rice Revealed by Genome-Wide Association Studies. Nutrients 2020; 12:nu12123719. [PMID: 33276482 PMCID: PMC7760723 DOI: 10.3390/nu12123719] [Citation(s) in RCA: 118] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 11/27/2020] [Accepted: 11/30/2020] [Indexed: 12/12/2022] Open
Abstract
A tiller number is the key determinant of rice plant architecture and panicle number and consequently controls grain yield. Thus, it is necessary to optimize the tiller number to achieve the maximum yield in rice. However, comprehensive analyses of the genetic basis of the tiller number, considering the development stage, tiller type, and related traits, are lacking. In this study, we sequence 219 Korean rice accessions and construct a high-quality single nucleotide polymorphism (SNP) dataset. We also evaluate the tiller number at different development stages and heading traits involved in phase transitions. By genome-wide association studies (GWASs), we detected 20 significant association signals for all traits. Five signals were detected in genomic regions near known candidate genes. Most of the candidate genes were involved in the phase transition from vegetative to reproductive growth. In particular, HD1 was simultaneously associated with the productive tiller ratio and heading date, indicating that the photoperiodic heading gene directly controls the productive tiller ratio. Multiple linear regression models of lead SNPs showed coefficients of determination (R2) of 0.49, 0.22, and 0.41 for the tiller number at the maximum tillering stage, productive tiller number, and productive tiller ratio, respectively. Furthermore, the model was validated using independent japonica rice collections, implying that the lead SNPs included in the linear regression model were generally applicable to the tiller number prediction. We revealed the genetic basis of the tiller number in rice plants during growth, By GWASs, and formulated a prediction model by linear regression. Our results improve our understanding of tillering in rice plants and provide a basis for breeding high-yield rice varieties with the optimum the tiller number.
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Affiliation(s)
- Daniela Maria Tanase
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700111 Iasi, Romania; (D.M.T.); (M.F.)
- Internal Medicine Clinic, “St. Spiridon” County Clinical Emergency Hospital Iasi, 700115 Iasi, Romania
| | - Evelina Maria Gosav
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700111 Iasi, Romania; (D.M.T.); (M.F.)
- Internal Medicine Clinic, “St. Spiridon” County Clinical Emergency Hospital Iasi, 700115 Iasi, Romania
- Correspondence:
| | - Ecaterina Neculae
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Institute of Gastroenterology and Hepatology, “St. Spiridon” County Clinical Emergency Hospital Iasi, 700111 Iasi, Romania
| | - Claudia Florida Costea
- Department of Ophthalmology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- 2nd Ophthalmology Clinic, “Nicolae Oblu” Emergency Clinical Hospital, 700309 Iași, Romania
| | - Manuela Ciocoiu
- Department of Pathophysiology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
| | - Loredana Liliana Hurjui
- Department of Morpho-Functional Sciences II, Physiology Discipline, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (L.L.H.); (M.A.M.); (I.L.S.)
- Hematology Laboratory, “St. Spiridon” County Clinical Emergency Hospital, 700111 Iasi, Romania
| | - Claudia Cristina Tarniceriu
- Department of Morpho-Functional Sciences I, Discipline of Anatomy, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Hematology Clinic, “St. Spiridon” County Clinical Emergency Hospital, 700111 Iasi, Romania
| | - Minela Aida Maranduca
- Department of Morpho-Functional Sciences II, Physiology Discipline, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (L.L.H.); (M.A.M.); (I.L.S.)
| | - Cristina Mihaela Lacatusu
- Unit of Diabetes, Nutrition and Metabolic Diseases, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Clinical Center of Diabetes, Nutrition and Metabolic Diseases, “St. Spiridon” County Clinical Emergency Hospital, 700111 Iasi, Romania
| | - Mariana Floria
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700111 Iasi, Romania; (D.M.T.); (M.F.)
- Internal Medicine Clinic, Emergency Military Clinical Hospital, 700483 Iasi, Romania
| | - Ionela Lacramioara Serban
- Department of Morpho-Functional Sciences II, Physiology Discipline, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (L.L.H.); (M.A.M.); (I.L.S.)
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Sprouse J, Sampath C, Gangula PR. Role of sex hormones and their receptors on gastric Nrf2 and neuronal nitric oxide synthase function in an experimental hyperglycemia model. BMC Gastroenterol 2020; 20:313. [PMID: 32967621 PMCID: PMC7513483 DOI: 10.1186/s12876-020-01453-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 09/15/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Gastroparesis, a condition of abnormal gastric emptying, is most commonly observed in diabetic women. To date, the role of ovarian hormones and/or gastric hormone receptors on regulating nitrergic-mediated gastric motility remains inconclusive. AIM The purpose of this study is to investigate whether sex hormones/their receptors can attenuate altered Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), neuronal Nitric Oxide Synthase (nNOS) expression and nitrergic relaxation in gastric neuromuscular tissues exposed to in-vitro hyperglycemia (HG). METHODS Gastric neuromuscular sections from adult female C57BL/6 J mice were incubated in normoglycemic (NG, 5 mM) or hyperglycemic (30 mM or 50 mM) conditions in the presence or absence of selective estrogen receptor (ER) agonists (ERα /PPT or ERβ: DPN); or non-selective sex hormone receptor antagonists (ER/ICI 182,780, or progesterone receptor (PR)/ RU486) for 48 h. mRNA, protein expression and nitrergic relaxation of circular gastric neuromuscular strips were assessed. RESULTS Our findings in HG, compared to NG, demonstrate a significant reduction in ER, Nrf2, and nNOS expression in gastric specimens. In addition, in-vitro treatment with sex hormones and/or their agonists significantly (*p < 0.05) restored Nrf2/nNOSα expression and total nitrite production. Conversely, ER, but not PR, antagonist significantly reduced Nrf2/nNOSα expression and nitrergic relaxation. CONCLUSIONS Our data suggest that ER's can regulate nitrergic function by improving Nrf2/nNOS expression in experimental hyperglycemia.
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Affiliation(s)
- Jeremy Sprouse
- School of Graduate Studies, Meharry Medical College, Nashville, TN, 37208, USA.,Department of ODS & Research, School of Dentistry, Nashville, TN, 37208, USA
| | - Chethan Sampath
- Department of ODS & Research, School of Dentistry, Nashville, TN, 37208, USA
| | - Pandu R Gangula
- Department of ODS & Research, School of Dentistry, Nashville, TN, 37208, USA.
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21
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Etifoxine reverses weight gain and alters the colonic bacterial community in a mouse model of obesity. Biochem Pharmacol 2020; 180:114151. [PMID: 32679124 DOI: 10.1016/j.bcp.2020.114151] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 07/09/2020] [Accepted: 07/10/2020] [Indexed: 12/21/2022]
Abstract
Obesity is intimately associated with diet and dysbiosis of gut microorganisms but anxiolytics, widely used in treatment of psychiatric conditions, frequently result in weight gain and associated metabolic disorders. We are interested in effects of the anxiolytic etifoxine, which has not been studied with respect to weight gain or effects on gut microorganisms. Here we induced obesity in mice by feeding a high-fat diet but found that intraperitoneal administration of etifoxine resulted in weight loss and decreased serum cholesterol and triglycerides. Obese mice had increased hepatic transcripts associated with lipid metabolism (cyp7a1, cyp27a1, abcg1 and LXRα) and inflammatory factors (TNFα and IL18) but these effects were reversed after etifoxine treatment other than cyp7a1. Taxonomic profiles of the organisms from the caecum were generated by 16S rRNA gene sequencing and Obese and etifoxine mice show differences by diversity metrics, Differential Abundance and functional metagenomics. Organisms in genus Oscillospira and genera from Lachnospiraceae family and Clostridiales order are higher in Control than Obese and at intermediate levels with etifoxine treatment. With respect to community metabolic potential, etifoxine mice have characteristics similar to Control and particularly with respect to metabolism of butanoate, sphingolipid, lipid biosynthesis and xenobiotic metabolism. We suggest mechanisms where-by etifoxine influences processes of host, such as on bile acid synthesis, and microbiota, such as signalling from production of butanoate and sphingosine, resulting in decreased cholesterol, lipids and inflammatory factors. We speculate that the indirect effect of etifoxine on microbial composition is mediated by microbial β-glucuronidases that metabolise excreted etifoxine glucuronides.
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22
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Ye L, Li G, Goebel A, Raju AV, Kong F, Lv Y, Li K, Zhu Y, Raja S, He P, Li F, Mwangi SM, Hu W, Srinivasan S. Caspase-11-mediated enteric neuronal pyroptosis underlies Western diet-induced colonic dysmotility. J Clin Invest 2020; 130:3621-3636. [PMID: 32484462 PMCID: PMC7324173 DOI: 10.1172/jci130176] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 03/24/2020] [Indexed: 02/06/2023] Open
Abstract
Enteric neuronal degeneration, as seen in inflammatory bowel disease, obesity, and diabetes, can lead to gastrointestinal dysmotility. Pyroptosis is a novel form of programmed cell death but little is known about its role in enteric neuronal degeneration. We observed higher levels of cleaved caspase-1, a marker of pyroptosis, in myenteric ganglia of overweight and obese human subjects compared with normal-weight subjects. Western diet-fed (WD-fed) mice exhibited increased myenteric neuronal pyroptosis, delayed colonic transit, and impaired electric field stimulation-induced colonic relaxation responses. WD increased TLR4 expression and cleaved caspase-1 in myenteric nitrergic neurons. Overactivation of nitrergic neuronal NF-κB signaling resulted in increased pyroptosis and delayed colonic motility. In caspase-11-deficient mice, WD did not induce nitrergic myenteric neuronal pyroptosis and colonic dysmotility. To understand the contributions of saturated fatty acids and bacterial products to the steps leading to enteric neurodegeneration, we performed in vitro experiments using mouse enteric neurons. Palmitate and lipopolysaccharide (LPS) increased nitrergic, but not cholinergic, enteric neuronal pyroptosis. LPS gained entry to the cytosol in the presence of palmitate, activating caspase-11 and gasdermin D, leading to pyroptosis. These results support a role of the caspase-11-mediated pyroptotic pathway in WD-induced myenteric nitrergic neuronal degeneration and colonic dysmotility, providing important therapeutic targets for enteric neuropathy.
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Affiliation(s)
- Lan Ye
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
- Gastroenterology Research, Atlanta VA Health Care System, Decatur, Georgia, USA
| | - Ge Li
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
- Gastroenterology Research, Atlanta VA Health Care System, Decatur, Georgia, USA
| | - Anna Goebel
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
- Gastroenterology Research, Atlanta VA Health Care System, Decatur, Georgia, USA
| | - Abhinav V. Raju
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
- Gastroenterology Research, Atlanta VA Health Care System, Decatur, Georgia, USA
| | - Feng Kong
- Second Hospital of Shandong University, Jinan, China
| | - Yanfei Lv
- Second Hospital of Shandong University, Jinan, China
| | - Kailin Li
- Second Hospital of Shandong University, Jinan, China
| | - Yuanjun Zhu
- Center for Metabolic Disease Research, Department of Pathology and Laboratory Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania, USA
| | - Shreya Raja
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
- Gastroenterology Research, Atlanta VA Health Care System, Decatur, Georgia, USA
| | - Peijian He
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Fang Li
- Center for Metabolic Disease Research, Department of Pathology and Laboratory Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania, USA
| | - Simon Musyoka Mwangi
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
- Gastroenterology Research, Atlanta VA Health Care System, Decatur, Georgia, USA
| | - Wenhui Hu
- Center for Metabolic Disease Research, Department of Pathology and Laboratory Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania, USA
| | - Shanthi Srinivasan
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
- Gastroenterology Research, Atlanta VA Health Care System, Decatur, Georgia, USA
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23
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Nyavor Y, Brands CR, May G, Kuther S, Nicholson J, Tiger K, Tesnohlidek A, Yasuda A, Starks K, Litvinenko D, Linden DR, Bhattarai Y, Kashyap PC, Forney LJ, Balemba OB. High-fat diet-induced alterations to gut microbiota and gut-derived lipoteichoic acid contributes to the development of enteric neuropathy. Neurogastroenterol Motil 2020; 32:e13838. [PMID: 32168415 PMCID: PMC7319907 DOI: 10.1111/nmo.13838] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 01/28/2020] [Accepted: 02/21/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND High-fat diet, microbial alterations and lipopolysaccharide (LPS) are thought to cause enteric diabetic neuropathy and intestinal dysmotility. However, the role of the gut microbiota, lipoteichoic acid (LTA) from Gram-positive bacteria and short-chain fatty acids (SCFAs) in the development of diabetic enteric neuropathy and intestinal dysmotility is not well understood. Our aim was to examine the role of the gut microbiota, LTA and SCFAs in the development of diabetic enteric neuropathy and intestinal dysmotility. METHODS We fed germ-free (GF) and conventionally raised (CR) mice either a high-fat (HFD) or standard chow diet (SCD) for 8 weeks. We analyzed the microbial community composition in CR mice using 16S rRNA sequencing and damage to myenteric neurons using immunohistochemistry. We also studied the effects of LPS, LTA, and SCFAs on duodenal muscularis externa contractions and myenteric neurons using cultured preparations. KEY RESULTS High-fat diet ingestion reduced the total number and the number of nitrergic myenteric neurons per ganglion in the duodenum of CR but not in GF-HFD mice. GF mice had fewer neurons per ganglion compared with CR mice. CR mice fed a HFD had increased abundance of Gram-positive bacteria. LTA and LPS did not affect the frequency of duodenal muscularis contractions after 24 hours of cultured but reduced the density of nitrergic myenteric neurons and increased oxidative stress and TNFα production in myenteric ganglia. SCFAs did not affect muscularis contractions or injure myenteric neurons. CONCLUSIONS & INFERENCES Gut microbial alterations induced increase in Gram-positive bacterial LTA may contribute to enteric neuropathy.
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Affiliation(s)
- Yvonne Nyavor
- University of Idaho, 875 Perimeter Drive, LSS 252 Moscow, ID 83844
| | | | - George May
- University of Idaho, 875 Perimeter Drive, LSS 252 Moscow, ID 83844
| | - Sydney Kuther
- University of Idaho, 875 Perimeter Drive, LSS 252 Moscow, ID 83844
| | | | - Kathryn Tiger
- University of Idaho, 875 Perimeter Drive, LSS 252 Moscow, ID 83844
| | | | - Allysha Yasuda
- University of Idaho, 875 Perimeter Drive, LSS 252 Moscow, ID 83844
| | - Kiefer Starks
- University of Idaho, 875 Perimeter Drive, LSS 252 Moscow, ID 83844
| | - Diana Litvinenko
- University of Idaho, 875 Perimeter Drive, LSS 252 Moscow, ID 83844
| | - David R. Linden
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
| | - Yogesh Bhattarai
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA
| | - Purna C. Kashyap
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA,Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
| | - Larry J. Forney
- University of Idaho, 875 Perimeter Drive, LSS 252 Moscow, ID 83844
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Zhang H, Liang Q, Wang N, Wang Q, Leng L, Mao J, Wang Y, Wang S, Zhang J, Liang H, Zhou X, Li Y, Cao Z, Luan P, Wang Z, Yuan H, Wang Z, Zhou X, Lamont SJ, Da Y, Li R, Tian S, Du Z, Li H. Microevolutionary Dynamics of Chicken Genomes under Divergent Selection for Adiposity. iScience 2020; 23:101193. [PMID: 32554187 PMCID: PMC7303556 DOI: 10.1016/j.isci.2020.101193] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 04/19/2020] [Accepted: 05/19/2020] [Indexed: 01/01/2023] Open
Abstract
Decades of artificial selection have significantly improved performance and efficiency of animal production systems. However, little is known about the microevolution of genomes due to intensive breeding. Using whole-genome sequencing, we document dynamic changes of chicken genomes under divergent selection on adiposity over 19 generations. Directional selection reduced within-line but increased between-line genomic differences. We observed that artificial selection tended to result in recruitment of preexisting variations of genes related to adipose tissue growth. In addition, novel mutations contributed to divergence of phenotypes under selection but contributed significantly less than preexisting genomic variants. Integration of 15 generations genome sequencing, genome-wide association study, and multi-omics data further identified that genes involved in signaling pathways important to adipogenesis, such as autophagy and lysosome (URI1, MBL2), neural system (CHAT), and endocrine (PCSK1) pathways, were under strong selection. Our study provides insights into the microevolutionary dynamics of domestic animal genomes under artificial selection.
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Affiliation(s)
- Hui Zhang
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs; Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province; College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, P. R. China
| | - Qiqi Liang
- Novogene Bioinformatics Institute, Beijing 10089, P. R. China
| | - Ning Wang
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs; Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province; College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, P. R. China
| | - Qigui Wang
- Chongqing Academy of Animal Science, Chongqing 402460, P. R. China
| | - Li Leng
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs; Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province; College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, P. R. China
| | - Jie Mao
- Novogene Bioinformatics Institute, Beijing 10089, P. R. China
| | - Yuxiang Wang
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs; Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province; College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, P. R. China
| | - Shouzhi Wang
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs; Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province; College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, P. R. China
| | - Jiyang Zhang
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs; Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province; College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, P. R. China
| | - Hao Liang
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs; Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province; College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, P. R. China
| | - Xun Zhou
- Novogene Bioinformatics Institute, Beijing 10089, P. R. China
| | - Yumao Li
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs; Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province; College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, P. R. China
| | - Zhiping Cao
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs; Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province; College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, P. R. China
| | - Peng Luan
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs; Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province; College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, P. R. China
| | - Zhipeng Wang
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs; Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province; College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, P. R. China
| | - Hui Yuan
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs; Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province; College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, P. R. China
| | - Zhiquan Wang
- Department of Agricultural, Food and Nutritional Sciences, University of Alberta, Edmonton, AB T6G 2C8, Canada
| | - Xuming Zhou
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, P. R. China
| | - Susan J Lamont
- Department of Animal Science, Iowa State University, Ames 50011, USA
| | - Yang Da
- Department of Animal Science, University of Minnesota, Saint Paul, MN 55108, USA
| | - Ruiqiang Li
- Novogene Bioinformatics Institute, Beijing 10089, P. R. China
| | - Shilin Tian
- Novogene Bioinformatics Institute, Beijing 10089, P. R. China.
| | - Zhiqiang Du
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs; Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province; College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, P. R. China.
| | - Hui Li
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs; Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province; College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, P. R. China.
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Ameku T, Beckwith H, Blackie L, Miguel-Aliaga I. Food, microbes, sex and old age: on the plasticity of gastrointestinal innervation. Curr Opin Neurobiol 2020; 62:83-91. [PMID: 32028080 PMCID: PMC7294223 DOI: 10.1016/j.conb.2019.12.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 12/18/2019] [Accepted: 12/20/2019] [Indexed: 12/20/2022]
Abstract
The gastrointestinal tract is innervated by its own enteric nervous system and by extrinsic neurons that connect it with the central nervous system. Innervation allows the gastrointestinal tract to sense and respond to diverse stimuli, adjusting motility and secretion, but also affecting our physiology, behaviour and immunity. The mechanisms underlying the formation of gastrointestinal neurons are beginning to be elucidated; those that keep them plastic over an organism's lifetime remain to be explored. Here, we review the effects of microbiota, nutrients, sex and ageing on the morphology and function of gastrointestinal innervation in mammals, and discuss how this plasticity shapes gut-brain crosstalk and whole-body physiology. We also highlight insights gained by nascent studies of the enteric innervation of Drosophila melanogaster.
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Affiliation(s)
- Tomotsune Ameku
- MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK; Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK
| | - Hannah Beckwith
- MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK; Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK
| | - Laura Blackie
- MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK; Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK
| | - Irene Miguel-Aliaga
- MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK; Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
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26
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Parathan P, Wang Y, Leembruggen AJL, Bornstein JC, Foong JPP. The enteric nervous system undergoes significant chemical and synaptic maturation during adolescence in mice. Dev Biol 2020; 458:75-87. [DOI: 10.1016/j.ydbio.2019.10.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 10/14/2019] [Accepted: 10/15/2019] [Indexed: 12/17/2022]
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27
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Beraldi EJ, Borges SC, de Almeida FLA, Dos Santos A, Saad MJA, Buttow NC. Colonic neuronal loss and delayed motility induced by high-fat diet occur independently of changes in the major groups of microbiota in Swiss mice. Neurogastroenterol Motil 2020; 32:e13745. [PMID: 31721393 DOI: 10.1111/nmo.13745] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 09/16/2019] [Accepted: 09/24/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Obesity has been linked to gastrointestinal disorders, and the loss of myenteric neurons in the intestine caused by high-fat diets (HFD) has been attributed to changes in microbiota and lipotoxicity. We investigated whether the prebiotic inulin modulates bacterial populations and alleviates neuronal loss in mice fed HFD. METHODS Swiss mice were fed purified rodent diet or HFD (59% kcal fat), or both diets supplemented with inulin for 17 weeks. Intestinal motility was assessed and a metagenome analysis of the colonic microbiota was performed. The gene expression of inflammatory markers was evaluated, and immunofluorescence was performed for different types of myenteric neurons and glial cells in the distal colon. KEY RESULTS The HFD caused obesity and delayed colonic motility. The loss of myenteric neurons and glial cells in obese mice affected all of the studied neuronal populations, including neurons positive for myosin-V, neuronal nitric oxide synthase, vasoactive intestinal peptide, and calretinin. Although obese mice supplemented with inulin exhibited improvements in colonic motility, neuronal, and glial cell loss persisted. The HFD did not altered the expression levels of inflammatory cytokines in the intestine or the prevalence of the major groups in microbiota, but inulin increased the proportion of the genus Akkermansia in the obese mice. CONCLUSIONS AND INFERENCES In Swiss mice, the HFD-induced neuronal loss but did not change the major groups in microbiota. This suggests that, despite the increase in the beneficial bacteria, other factors that are directly linked to excess dietary lipid intake affect the enteric nervous system.
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Affiliation(s)
- Evandro José Beraldi
- Graduate Program in Biological Sciences (PBC), State University of Maringá, Maringá, Brazil
| | | | | | - Andrey Dos Santos
- Department of Internal Medicine, State University of Campinas, Campinas, Brazil
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28
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Dou D, Chen QQ, Zhong ZQ, Xia XW, Ding WJ. Regulating the Enteric Nervous System against Obesity in Mice by Electroacupuncture. Neuroimmunomodulation 2020; 27:48-57. [PMID: 32516787 DOI: 10.1159/000506483] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Accepted: 02/06/2020] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND AND OBJECTIVES The enteric nervous system (ENS) dominates the onset of obesity and has been shown to regulate nutrient absorption and energy metabolism. METHODS AND STUDY DESIGN This study was performed to investigate the role of electroacupuncture in regulating ENS function in obese mice. Obese mice were obtained by high-fat diet. 16S rRNA pyrosequencing, Western blotting, quantitative PCR, and neurotransmitter analysis were used for this purpose. RESULTS Body weight, Lee index, serum lipid, leptin, and adiponectin levels, and other basic indices were significantly ameliorated after electroacupuncture intervention. The pathological ENS scores, serum neurotransmitter levels, and intestinal transit rate were markedly changed in obese mice. Moreover, electroacupuncture promoted the diversity of gut microbiota. No significant differences were observed 21 and 28 days after electroacupuncture. CONCLUSIONS These results suggested ENS may be a new treatment approach to obesity.
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Affiliation(s)
- Ding Dou
- Department of Fundamental Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Department of Traditional Chinese Medicine, Zunyi Medical and Pharmaceutical College, Zunyi, China
| | - Qiao Qiao Chen
- Department of Fundamental Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhan-Qiong Zhong
- Department of Fundamental Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiu-Wen Xia
- Department of Fundamental Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wei-Jun Ding
- Department of Fundamental Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China,
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Knauf C, Abot A, Wemelle E, Cani PD. Targeting the Enteric Nervous System to Treat Metabolic Disorders? "Enterosynes" as Therapeutic Gut Factors. Neuroendocrinology 2020; 110:139-146. [PMID: 31280267 DOI: 10.1159/000500602] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 04/28/2019] [Indexed: 11/19/2022]
Abstract
The gut-brain axis is of crucial importance for controlling glucose homeostasis. Alteration of this axis promotes the type 2 diabetes (T2D) phenotype (hyperglycaemia, insulin resistance). Recently, a new concept has emerged to demonstrate the crucial role of the enteric nervous system in the control of glycaemia via the hypothalamus. In diabetic patients and mice, modification of enteric neurons activity in the proximal part of the intestine generates a duodenal hyper-contractility that generates an aberrant message from the gut to the brain. In turn, the hypothalamus sends an aberrant efferent message that provokes a state of insulin resistance, which is characteristic of a T2D state. Targeting the enteric nervous system of the duodenum is now recognized as an innovative strategy for treatment of diabetes. By acting in the intestine, bioactive gut molecules that we called "enterosynes" can modulate the function of a specific type of neurons of the enteric nervous system to decrease the contraction of intestinal smooth muscle cells. Here, we focus on the origins of enterosynes (hormones, neurotransmitters, nutrients, microbiota, and immune factors), which could be considered therapeutic factors, and we describe their modes of action on enteric neurons. This unsuspected action of enterosynes is proposed for the treatment of T2D, but it could be applied for other therapeutic solutions that implicate communication between the gut and brain.
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Affiliation(s)
- Claude Knauf
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1220, Université Paul Sabatier, UPS, Institut de Recherche en Santé Digestive et Nutrition (IRSD), Toulouse, France,
- NeuroMicrobiota, European Associated Laboratory (EAL) INSERM, Toulouse, France,
| | - Anne Abot
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1220, Université Paul Sabatier, UPS, Institut de Recherche en Santé Digestive et Nutrition (IRSD), Toulouse, France
- NeuroMicrobiota, European Associated Laboratory (EAL) INSERM, Toulouse, France
| | - Eve Wemelle
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1220, Université Paul Sabatier, UPS, Institut de Recherche en Santé Digestive et Nutrition (IRSD), Toulouse, France
- NeuroMicrobiota, European Associated Laboratory (EAL) INSERM, Toulouse, France
| | - Patrice D Cani
- NeuroMicrobiota, European Associated Laboratory (EAL) INSERM, Toulouse, France
- UCLouvain, Université Catholique de Louvain, WELBIO - Walloon Excellence in Life Sciences and BIOtechnology, Louvain Drug Research Institute, Metabolism and Nutrition Research Group, Brussels, Belgium
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McMenamin CA, Clyburn C, Browning KN. High-Fat Diet During the Perinatal Period Induces Loss of Myenteric Nitrergic Neurons and Increases Enteric Glial Density, Prior to the Development of Obesity. Neuroscience 2019; 393:369-380. [PMID: 30454864 DOI: 10.1016/j.neuroscience.2018.09.033] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 09/19/2018] [Accepted: 09/24/2018] [Indexed: 02/07/2023]
Abstract
Diet-induced obesity induces peripheral inflammation accompanied by a loss of myenteric neurons. Few studies, however, have investigated the effects of a high-fat diet (HFD) on either the development of myenteric neurons or prior to the occurrence of obesity. The present study assessed the effects of maternal HFD on the density and neurochemical phenotype of myenteric ganglia in the upper gastrointestinal tract. Sprague-Dawley rats were fed either a control or HFD (14% or 60% kcal from fat, respectively) from embryonic day 13; the fundus, corpus and duodenum were fixed thereafter at postnatal 2, 4, 6 and 12 weeks of age for subsequent immunohistochemical studies. While myenteric ganglion size did not differ throughout the study, HFD exposure decreased the number of nitrergic neurons by 6 weeks of age in all regions. This decrease was accompanied by a loss of PGP-immunoreactive neurons, suggesting a decline in myenteric neuronal number. HFD also increased myenteric plexus glial cell density in all regions by 4 weeks of age. These changes occurred in the absence of an increase in serum or gastric inflammatory markers. The present study suggests that exposure to a HFD during the perinatal time period results in glial proliferation and loss of inhibitory nitrergic neurons prior to the onset of obesity, suggesting that dietary alterations may affect gastrointestinal functions independently of increased adiposity or glycemic dysregulation.
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Affiliation(s)
- Caitlin A McMenamin
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA 17033, United States
| | - Courtney Clyburn
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA 17033, United States
| | - Kirsteen N Browning
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA 17033, United States.
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Meister AL, Doheny KK, Travagli RA. Necrotizing enterocolitis attenuates developmental heart rate variability increases in newborn rats. Neurogastroenterol Motil 2019; 31:e13484. [PMID: 30298607 PMCID: PMC6386597 DOI: 10.1111/nmo.13484] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 09/04/2018] [Accepted: 09/04/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND We have shown previously that a decreased high-frequency spectrum of heart rate variability (HF-HRV), indicative of reduced vagal tone, shows promise in predicting neonates likely to develop necrotizing enterocolitis (NEC) before its clinical onset. We hypothesized that NEC induction in rat pups decreases HF-HRV power; subdiaphragmatic vagotomy worsens the severity of the NEC phenotype, increases levels of pro-inflammatory cytokines, and alters the myenteric phenotype. METHODS Newborn Sprague-Dawley rats, representative of preterm human neonates, were subjected to 7-8 days of brief periods of cold stress and hypoxia to induce NEC with or without unilateral subdiaphragmatic vagotomy. HRV was measured at postnatal days one and five, pups were sacrificed at day 8/9, and gastrointestinal tissues and blood were collected for immunohistochemical, corticosterone, and cytokine analysis. KEY RESULTS Compared to control, NEC-induced rats showed the following: (a) typical histological signs of grade 2 NEC, which were more severe in rats that underwent vagotomy; (b) reduced developmental increases in time (RMSSD) and frequency (HF) HRV spectra when combined with the stress of laparotomy/vagotomy; (c) increases in nitric oxide synthase-immunoreactivity in the myenteric plexus of jejunum and ileum; furthermore, compared to mild NEC and controls, vagotomized NEC rats had increased plasma values of pro-inflammatory cytokines IL-1β and IL-6. CONCLUSIONS AND INFERENCES Our data suggest that in rodents, similar to neonatal observations, NEC induction attenuated developmental HF-HRV increases, furthermore, subdiaphragmatic vagotomy worsened the histological severity, increased pro-inflammatory cytokines, and altered the nitrergic myenteric phenotype, suggesting a role of the vagus in the development of NEC pathology.
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Affiliation(s)
- Alissa L. Meister
- Neural and Behavioral Sciences, Penn State College of Medicine, Hershey PA
| | - Kim K. Doheny
- Neural and Behavioral Sciences, Penn State College of Medicine, Hershey PA,Neonatal-Perinatal Medicine, Penn State College of Medicine, Hershey PA
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Nyavor Y, Estill R, Edwards H, Ogden H, Heideman K, Starks K, Miller C, May G, Flesch L, McMillan J, Gericke M, Forney L, Balemba O. Intestinal nerve cell injury occurs prior to insulin resistance in female mice ingesting a high-fat diet. Cell Tissue Res 2019; 376:325-340. [PMID: 30778729 DOI: 10.1007/s00441-019-03002-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 01/30/2019] [Indexed: 12/11/2022]
Abstract
Diabetic patients suffer from gastrointestinal disorders associated with dysmotility, enteric neuropathy and dysbiosis of gut microbiota; however, gender differences are not fully known. Previous studies have shown that a high-fat diet (HFD) causes type two diabetes (T2D) in male mice after 4-8 weeks but only does so in female mice after 16 weeks. This study seeks to determine whether sex influences the development of intestinal dysmotility, enteric neuropathy and dysbiosis in mice fed HFD. We fed 8-week-old C57BL6 male and female mice a standard chow diet (SCD) or a 72% kcal HFD for 8 weeks. We analyzed the associations between sex and intestinal dysmotility, neuropathy and dysbiosis using motility assays, immunohistochemistry and next-generation sequencing. HFD ingestion caused obesity, glucose intolerance and insulin resistance in male but not female mice. However, HFD ingestion slowed intestinal propulsive motility in both male and female mice. This was associated with decreased inhibitory neuromuscular transmission, loss of myenteric inhibitory motor neurons and axonal swelling and loss of cytoskeletal filaments. HFD induced dysbiosis and changed the abundance of specific bacteria, especially Allobaculum, Bifidobacterium and Lactobacillus, which correlated with dysmotility and neuropathy. Female mice had higher immunoreactivity and numbers of myenteric inhibitory motor neurons, matching larger amplitudes of inhibitory junction potentials. This study suggests that sex influences the development of HFD-induced metabolic syndrome but dysmotility, neuropathy and dysbiosis occur independent of sex and prior to T2D conditions. Gastrointestinal dysmotility, neuropathy and dysbiosis might play a crucial role in the pathophysiology of T2D in humans irrespective of sex.
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Affiliation(s)
- Yvonne Nyavor
- Department of Biological Sciences, University of Idaho, 875 Perimeter Drive, LSS 252, Moscow, ID, 83844, USA
| | - Rachel Estill
- Department of Biological Sciences, University of Idaho, 875 Perimeter Drive, LSS 252, Moscow, ID, 83844, USA
| | - Hannah Edwards
- Department of Biological Sciences, University of Idaho, 875 Perimeter Drive, LSS 252, Moscow, ID, 83844, USA
| | - Hailey Ogden
- Department of Biological Sciences, University of Idaho, 875 Perimeter Drive, LSS 252, Moscow, ID, 83844, USA
| | - Kaila Heideman
- Department of Biological Sciences, University of Idaho, 875 Perimeter Drive, LSS 252, Moscow, ID, 83844, USA
| | - Kiefer Starks
- Department of Biological Sciences, University of Idaho, 875 Perimeter Drive, LSS 252, Moscow, ID, 83844, USA
| | - Christopher Miller
- Department of Biological Sciences, University of Idaho, 875 Perimeter Drive, LSS 252, Moscow, ID, 83844, USA
| | - George May
- Department of Biological Sciences, University of Idaho, 875 Perimeter Drive, LSS 252, Moscow, ID, 83844, USA
| | - Lance Flesch
- Department of Biological Sciences, University of Idaho, 875 Perimeter Drive, LSS 252, Moscow, ID, 83844, USA
| | - John McMillan
- Department of Biological Sciences, University of Idaho, 875 Perimeter Drive, LSS 252, Moscow, ID, 83844, USA
| | - Martin Gericke
- Institute for Anatomy, University of Leipzig, Liebigstraße 13, 04103, Leipzig, Germany
| | - Larry Forney
- Department of Biological Sciences, University of Idaho, 875 Perimeter Drive, LSS 252, Moscow, ID, 83844, USA
| | - Onesmo Balemba
- Department of Biological Sciences, University of Idaho, 875 Perimeter Drive, LSS 252, Moscow, ID, 83844, USA.
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Duchalais E, Machairas N, Kelley SR, Landmann RG, Merchea A, Colibaseanu DT, Mathis KL, Dozois EJ, Larson DW. Does obesity impact postoperative outcomes following robotic-assisted surgery for rectal cancer? Surg Endosc 2018; 32:4886-4892. [PMID: 29987562 DOI: 10.1007/s00464-018-6247-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 05/29/2018] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Obesity has been identified as a risk factor for both conversion and severe postoperative morbidity in patients undergoing laparoscopic rectal resection. Robotic-assisted surgery (RAS) is proposed to overcome some of the technical limitations associated with laparoscopic surgery for rectal cancer. The aim of our study was to determine if obesity remains a risk factor for severe morbidity in patients undergoing robotic-assisted rectal resection. PATIENTS This study was a retrospective review of a prospective database. A total of 183 patients undergoing restorative RAS for rectal cancer between 2007 and 2016 were divided into 2 groups: control (BMI < 30 kg/m2; n = 125) and obese (BMI ≥ 30 kg/m2; n = 58). Clinicopathologic data, 30-day postoperative morbidity, and perioperative outcomes were compared between groups. The main outcome was severe postoperative morbidity defined as any complication graded Clavien-Dindo ≥ 3. RESULTS Control and obese groups had similar clinicopathologic characteristics. Severe complications were observed in 9 (7%) and 4 (7%) patients, respectively (p > 0.99). Obesity did not impact conversion, anastomotic leak rate, length of stay, or readmission but was significantly associated with increased postoperative morbidity (29 vs. 45%; p = 0.04) and especially more postoperative ileus (11 vs. 26%; p = 0.01). Obesity and male gender were the two independent risk factors for postoperative overall morbidity (OR 1.97; 95% CI 1.02-3.94; p = 0.04 and OR 2.23; 95% CI 1.10-4.76; p = 0.03, respectively). CONCLUSION Obesity did not impact severe morbidity or conversion rate following RAS for rectal cancer but remained a risk factor for overall morbidity and especially postoperative ileus.
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Affiliation(s)
- E Duchalais
- Division of Colon and Rectal Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - N Machairas
- Division of Colon and Rectal Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - S R Kelley
- Division of Colon and Rectal Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - R G Landmann
- Division of Colon & Rectal Surgery, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
| | - A Merchea
- Division of Colon & Rectal Surgery, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
| | - D T Colibaseanu
- Division of Colon & Rectal Surgery, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
| | - K L Mathis
- Division of Colon and Rectal Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - E J Dozois
- Division of Colon and Rectal Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - D W Larson
- Division of Colon and Rectal Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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da Rosa CVD, de Campos JM, de Sá Nakanishi AB, Comar JF, Martins IP, Mathias PCDF, Pedrosa MMD, de Godoi VAF, Natali MRM. Food restriction promotes damage reduction in rat models of type 2 diabetes mellitus. PLoS One 2018; 13:e0199479. [PMID: 29924854 PMCID: PMC6010257 DOI: 10.1371/journal.pone.0199479] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 06/07/2018] [Indexed: 12/27/2022] Open
Abstract
There are several animal models of type 2 diabetes mellitus induction but the comparison between models is scarce. Food restriction generates benefits, such as reducing oxidative stress, but there are few studies on its effects on diabetes. The objective of this study is to evaluate the differences in physiological and biochemical parameters between diabetes models and their responses to food restriction. For this, 30 male Wistar rats were distributed in 3 groups (n = 10/group): control (C); diabetes with streptozotocin and cafeteria-style diet (DE); and diabetes with streptozotocin and nicotinamide (DN), all treated for two months (pre-food restriction period). Then, the 3 groups were subdivided into 6, generating the groups CC (control), CCR (control+food restriction), DEC (diabetic+standard diet), DER (diabetic+food restriction), DNC (diabetic+standard diet) and DNR (diabetic+food restriction), treated for an additional two months (food restriction period). The food restriction (FR) used was 50% of the average daily dietary intake of group C. Throughout the treatment, physiological and biochemical parameters were evaluated. At the end of the treatment, serum biochemical parameters, oxidative stress and insulin were evaluated. Both diabetic models produced hyperglycemia, polyphagia, polydipsia, insulin resistance, high fructosamine, hepatic damage and reduced insulin, although only DE presented human diabetes-like alterations, such as dyslipidemia and neuropathy symptoms. Both DEC and DNC diabetic groups presented higher levels of protein carbonyl groups associated to lower antioxidant capacity in the plasma. FR promoted improvement of glycemia in DNR, lipid profile in DER, and insulin resistance and hepatic damage in both diabetes models. FR also reduced the protein carbonyl groups of both DER and DNR diabetic groups, but the antioxidant capacity was improved only in the plasma of DER group. It is concluded that FR is beneficial for diabetes but should be used in conjunction with other therapies.
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Affiliation(s)
| | | | | | | | - Isabela Peixoto Martins
- Department of Biotechnology, Cell Biology and Genetics State University of Maringá, Paraná, Brazil
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Rastelli M, Knauf C, Cani PD. Gut Microbes and Health: A Focus on the Mechanisms Linking Microbes, Obesity, and Related Disorders. Obesity (Silver Spring) 2018; 26:792-800. [PMID: 29687645 PMCID: PMC5947576 DOI: 10.1002/oby.22175] [Citation(s) in RCA: 129] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 01/26/2018] [Accepted: 01/30/2018] [Indexed: 12/12/2022]
Abstract
The past decade has been characterized by tremendous progress in the field of the gut microbiota and its impact on host metabolism. Although numerous studies show a strong relationship between the composition of gut microbiota and specific metabolic disorders associated with obesity, the key mechanisms are still being studied. The present review focuses on specific complex pathways as well as key interactions. For instance, the nervous routes are explored by examining the enteric nervous system, the vagus nerve, and the brain, as well as the endocrine routes (i.e., glucagon-like peptide-1, peptide YY, endocannabinoids) by which gut microbes communicate with the host. Moreover, the key metabolites involved in such specific interactions (e.g., short chain fatty acids, bile acids, neurotransmitters) as well as their targets (i.e., receptors, cell types, and organs) are briefly discussed. Finally, the review highlights the role of metabolic endotoxemia in the onset of metabolic disorders and the implications for alterations in gut microbiota-host interactions and ultimately the onset of diseases.
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Affiliation(s)
- Marialetizia Rastelli
- Metabolism and Nutrition Research Group, Walloon Excellence in Life Sciences and Biotechnology Institute and Louvain Drug Research InstituteUniversité catholique de LouvainBrusselsBelgium
- European Associated Laboratory NeuroMicrobiotaInstitut National de la Santé et de la Recherche MédicaleToulouseFrance
- European Associated Laboratory NeuroMicrobiotaUniversité catholique de LouvainBrusselsBelgium
| | - Claude Knauf
- European Associated Laboratory NeuroMicrobiotaInstitut National de la Santé et de la Recherche MédicaleToulouseFrance
- European Associated Laboratory NeuroMicrobiotaUniversité catholique de LouvainBrusselsBelgium
- Paul Sabatier UniversityToulouseFrance
- Institut de Recherche en Santé Digestive, Institut National de la Santé et de la Recherche Médicale U1220, Institut national de la recherche agronomique, École nationale vétérinaire de ToulouseToulouseFrance
| | - Patrice D. Cani
- Metabolism and Nutrition Research Group, Walloon Excellence in Life Sciences and Biotechnology Institute and Louvain Drug Research InstituteUniversité catholique de LouvainBrusselsBelgium
- European Associated Laboratory NeuroMicrobiotaInstitut National de la Santé et de la Recherche MédicaleToulouseFrance
- European Associated Laboratory NeuroMicrobiotaUniversité catholique de LouvainBrusselsBelgium
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Abot A, Cani PD, Knauf C. Impact of Intestinal Peptides on the Enteric Nervous System: Novel Approaches to Control Glucose Metabolism and Food Intake. Front Endocrinol (Lausanne) 2018; 9:328. [PMID: 29988396 PMCID: PMC6023997 DOI: 10.3389/fendo.2018.00328] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 05/31/2018] [Indexed: 12/13/2022] Open
Abstract
The gut is one of the most important sources of bioactive peptides in the body. In addition to their direct actions in the brain and/or peripheral tissues, the intestinal peptides can also have an impact on enteric nervous neurons. By modifying the endogenousproduction of these peptides, one may expect modify the "local" physiology such as glucose absorption, but also could have a "global" action via the gut-brain axis. Due to the various origins of gut peptides (i.e., nutrients, intestinal wall, gut microbiota) and the heterogeneity of enteric neurons population, the potential physiological parameters control by the interaction between the two partners are multiple. In this review, we will exclusively focus on the role of enteric nervous system as a potential target of gut peptides to control glucose metabolism and food intake. Potential therapeutic strategies based on per os administration of gut peptides to treat type 2 diabetes will be described.
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Affiliation(s)
- Anne Abot
- NeuroMicrobiota, European Associated Laboratory (EAL), INSERM, Université catholique de Louvain (UCL), Toulouse, France
- INSERM U1220 Institut de Recherche en Santé Digestive (IRSD), CHU Purpan, Université Toulouse III Paul Sabatier, Paris, France
| | - Patrice D. Cani
- NeuroMicrobiota, European Associated Laboratory (EAL), INSERM, Université catholique de Louvain (UCL), Toulouse, France
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute (LDRI), WELBIO (Walloon Excellence in Life Sciences and BIOtechnology), Université catholique de Louvain (UCL), Brussels, Belgium
| | - Claude Knauf
- NeuroMicrobiota, European Associated Laboratory (EAL), INSERM, Université catholique de Louvain (UCL), Toulouse, France
- INSERM U1220 Institut de Recherche en Santé Digestive (IRSD), CHU Purpan, Université Toulouse III Paul Sabatier, Paris, France
- *Correspondence: Claude Knauf,
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Bauzá-Thorbrügge M, M Galmés-Pascual B, Sbert-Roig M, J García-Palmer F, Gianotti M, M Proenza A, Lladó I. Antioxidant peroxiredoxin 3 expression is regulated by 17beta-estradiol in rat white adipose tissue. J Steroid Biochem Mol Biol 2017; 172:9-19. [PMID: 28529127 DOI: 10.1016/j.jsbmb.2017.05.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 04/26/2017] [Accepted: 05/16/2017] [Indexed: 11/18/2022]
Abstract
Peroxiredoxin 3 (PRX3) plays a role as a regulator of the adipocyte mitochondrial function due to its antioxidant activity. We have previously reported the existence of a sexual dimorphism in the mitochondrial oxidative stress status of many rat tissues such as white (WAT) and brown (BAT) adipose tissues. The aim was to elucidate whether sex hormones may play a role in PRX3 expression in the adipose tissues of rats. In in vivo experiments, male and female standard diet fed rats, high fat diet (HFD) fed rats and rosiglitazone-supplemented HFD (HDF+Rsg) fed rats, as well as ovariectomized (OVX) and 17beta-estradiol-supplemented OVX (OVX+E2) female rats were used. 3T3-L1 adipocytes and brown adipocyte primary culture were used to study the roles of both E2 and testosterone in in vitro experiments. PRX3 levels were greater in the WAT of female rats than in males. This sexual dimorphism disappeared by HFD feeding but was magnified with Rsg supplementation. PRX3 sexual dimorphism was not observed in BAT, and neither HFD nor ovariectomy modified PRX3 levels. Rsg increased Prx3 expression in the BAT of both sexes. In vitro studies supported the results obtained in vivo and confirmed the contribution of E2 to sex differences in WAT Prx3 expression. Finally, we reported an E2 upregulation of both PRX3 and thioredoxin 2 (TRX2) in WAT but not in BAT that could play a key role in the sex dimorphism reported in the antioxidant defence of WAT in order to palliate the detrimental effect of the oxidative stress.
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Affiliation(s)
- Marco Bauzá-Thorbrügge
- Grup Metabolisme Energètic i Nutrició, Departament de Biologia Fonamental i Ciències de la Salut, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Palma de Mallorca, Spain; Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma de Mallorca, Spain
| | - Bel M Galmés-Pascual
- Grup Metabolisme Energètic i Nutrició, Departament de Biologia Fonamental i Ciències de la Salut, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Palma de Mallorca, Spain; Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma de Mallorca, Spain
| | - Miquel Sbert-Roig
- Grup Metabolisme Energètic i Nutrició, Departament de Biologia Fonamental i Ciències de la Salut, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Palma de Mallorca, Spain; Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma de Mallorca, Spain
| | - Francisco J García-Palmer
- Grup Metabolisme Energètic i Nutrició, Departament de Biologia Fonamental i Ciències de la Salut, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Palma de Mallorca, Spain; Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma de Mallorca, Spain; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y la Nutrición (CIBERobn, CB06/03/0043), Instituto de Salud Carlos III, Spain
| | - Magdalena Gianotti
- Grup Metabolisme Energètic i Nutrició, Departament de Biologia Fonamental i Ciències de la Salut, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Palma de Mallorca, Spain; Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma de Mallorca, Spain; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y la Nutrición (CIBERobn, CB06/03/0043), Instituto de Salud Carlos III, Spain.
| | - Ana M Proenza
- Grup Metabolisme Energètic i Nutrició, Departament de Biologia Fonamental i Ciències de la Salut, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Palma de Mallorca, Spain; Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma de Mallorca, Spain; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y la Nutrición (CIBERobn, CB06/03/0043), Instituto de Salud Carlos III, Spain
| | - Isabel Lladó
- Grup Metabolisme Energètic i Nutrició, Departament de Biologia Fonamental i Ciències de la Salut, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Palma de Mallorca, Spain; Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma de Mallorca, Spain; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y la Nutrición (CIBERobn, CB06/03/0043), Instituto de Salud Carlos III, Spain
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Reichardt F, Chassaing B, Nezami BG, Li G, Tabatabavakili S, Mwangi S, Uppal K, Liang B, Vijay-Kumar M, Jones D, Gewirtz AT, Srinivasan S. Western diet induces colonic nitrergic myenteric neuropathy and dysmotility in mice via saturated fatty acid- and lipopolysaccharide-induced TLR4 signalling. J Physiol 2017; 595:1831-1846. [PMID: 28000223 PMCID: PMC5330876 DOI: 10.1113/jp273269] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Accepted: 12/01/2016] [Indexed: 01/01/2023] Open
Abstract
KEY POINTS A high-fat diet (60% kcal from fat) is associated with motility disorders inducing constipation and loss of nitrergic myenteric neurons in the proximal colon. Gut microbiota dysbiosis, which occurs in response to HFD, contributes to endotoxaemia. High levels of lipopolysaccharide lead to apoptosis in cultured myenteric neurons that express Toll-like receptor 4 (TLR4). Consumption of a Western diet (WD) (35% kcal from fat) for 6 weeks leads to gut microbiota dysbiosis associated with altered bacterial metabolites and increased levels of plasma free fatty acids. These disorders precede the nitrergic myenteric cell loss observed in the proximal colon. Mice lacking TLR4 did not exhibit WD-induced myenteric cell loss and dysmotility. Lipopolysaccharide-induced in vitro enteric neurodegeneration requires the presence of palmitate and may be a result of enhanced NO production. The present study highlights the critical role of plasma saturated free fatty acids that are abundant in the WD with respect to driving enteric neuropathy and colonic dysmotility. ABSTRACT The consumption of a high-fat diet (HFD) is associated with myenteric neurodegeneration, which in turn is associated with delayed colonic transit and constipation. We examined the hypothesis that an inherent increase in plasma free fatty acids (FFA) in the HFD together with an HFD-induced alteration in gut microbiota contributes to the pathophysiology of these disorders. C57BL/6 mice were fed a Western diet (WD) (35% kcal from fat enriched in palmitate) or a purified regular diet (16.9% kcal from fat) for 3, 6, 9 and 12 weeks. Gut microbiota dysbiosis was investigated by fecal lipopolysaccharide (LPS) measurement and metabolomics (linear trap quadrupole-Fourier transform mass spectrometer) analysis. Plasma FFA and LPS levels were assessed, in addition to colonic and ileal nitrergic myenteric neuron quantifications and motility. Compared to regular diet-fed control mice, WD-fed mice gained significantly more weight without blood glucose alteration. Dysbiosis was exhibited after 6 weeks of feeding, as reflected by increased fecal LPS and bacterial metabolites and concomitant higher plasma FFA. The numbers of nitrergic myenteric neurons were reduced in the proximal colon after 9 and 12 weeks of WD and this was also associated with delayed colonic transit. WD-fed Toll-like receptor 4 (TLR4)-/- mice did not exhibit myenteric cell loss or dysmotility. Finally, LPS (0.5-2 ng·ml-1 ) and palmitate (20 and 30 μm) acted synergistically to induce neuronal cell death in vitro, which was prevented by the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester. In conclusion, WD-feeding results in increased levels of FFA and microbiota that, even in absence of hyperglycaemia or overt endotoxaemia, synergistically induce TLR4-mediated neurodegeneration and dysmotility.
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Affiliation(s)
- François Reichardt
- Department of Digestive Diseases, Emory University School of Medicine, Atlanta & Atlanta VA Medical Center, Decatur, GA, USA
| | - Benoit Chassaing
- Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, GA, USA
| | - Behtash Ghazi Nezami
- Department of Digestive Diseases, Emory University School of Medicine, Atlanta & Atlanta VA Medical Center, Decatur, GA, USA
| | - Ge Li
- Department of Digestive Diseases, Emory University School of Medicine, Atlanta & Atlanta VA Medical Center, Decatur, GA, USA
| | - Sahar Tabatabavakili
- Department of Digestive Diseases, Emory University School of Medicine, Atlanta & Atlanta VA Medical Center, Decatur, GA, USA
| | - Simon Mwangi
- Department of Digestive Diseases, Emory University School of Medicine, Atlanta & Atlanta VA Medical Center, Decatur, GA, USA
| | - Karan Uppal
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University, GA, USA
| | - Bill Liang
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University, GA, USA
| | - Matam Vijay-Kumar
- Department of Nutritional Sciences & Medicine, Pennsylvania State University, University Park, PA, USA
| | - Dean Jones
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University, GA, USA
| | - Andrew T Gewirtz
- Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, GA, USA
| | - Shanthi Srinivasan
- Department of Digestive Diseases, Emory University School of Medicine, Atlanta & Atlanta VA Medical Center, Decatur, GA, USA
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