|
1
|
Xie S, Deng N, Fang L, Shen J, Tan Z, Cai Y. TMAO is involved in kidney-yang deficiency syndrome diarrhea by mediating the "gut-kidney axis". Heliyon 2024; 10:e35461. [PMID: 39170478 PMCID: PMC11336722 DOI: 10.1016/j.heliyon.2024.e35461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 07/28/2024] [Accepted: 07/29/2024] [Indexed: 08/23/2024] Open
Abstract
BACKGROUND Trimethylamine-N-oxide (TMAO) is a harmful metabolite dependent on the intestinal microbiota and excreted through the kidneys. According to numerous investigations, rich circulation concentrations of TMAO have been linked to kidney and gastrointestinal disorders. Through the "gut-kidney axis" mediated by TMAO, this research attempted to clarify the microbiological causes of kidney-yang deficiency syndrome diarrhea. METHODS Adenine and Folium Sennae were used to create a mouse model of kidney-yang deficiency syndrome diarrhea. 16S rRNA sequencing was used to identify the traits of the intestinal mucosal microbiota. ELISA was used to assess TMAO, transforming growth factor-β1 (TGF-β1), interleukin-1β (IL-1β), and NOD-like receptor thermal protein domain associated protein 3 (NLRP3). Kidney tissue fibrosis was evaluated using Masson's trichrome staining, and immunohistochemical labeling was used to investigate the protein expression of occludin and Zonula Occludens-1(ZO-1) in small intestine tissue. Microbial activity was determined by using fluorescein diacetate (FDA) hydrolysis spectrophotometry. RESULTS TMAO showed a positive correlation with NLRP3, IL-1β and TGF-β1, all of which exhibited substantial increases (P < 0.05). Significant renal fibrosis and decreased ZO-1 and occludin expression in small intestine tissues were detected in the model group. The sequencing results revealed alterations in both α and β diversities of small intestinal mucosal microbiota. Elevated TMAO concentrations were potentially associated with increasing Firmicutes/Bacteroidota (F/B) ratios, Streptococcus, Pseudomonas and unclassified Clostridia UCG 014, but with decreasing Rothia and RB41 abundances. CONCLUSION This study establishes a link between intestinal microbiota dysbiosis and elevated TMAO concentrations. TMAO can activate inflammatory responses and cytokines, contributing to kidney-yang deficiency syndrome diarrhea via the "gut-kidney axis". Moreover, TMAO may coincide with disruptions in the intestinal barrier and renal fibrosis. Dysfunction of the "gut-kidney axis" further elevates TMAO levels, perpetuating a vicious cycle.
Collapse
Affiliation(s)
- Shiqin Xie
- College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Hunan Key Laboratory of Traditional Chinese Medicine Prescription and Syndromes Translational Medicine, Changsha, Hunan, China
| | - Na Deng
- College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Hunan Key Laboratory of Traditional Chinese Medicine Prescription and Syndromes Translational Medicine, Changsha, Hunan, China
| | - Leyao Fang
- College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Hunan Key Laboratory of Traditional Chinese Medicine Prescription and Syndromes Translational Medicine, Changsha, Hunan, China
| | - Junxi Shen
- College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Hunan Key Laboratory of Traditional Chinese Medicine Prescription and Syndromes Translational Medicine, Changsha, Hunan, China
| | - Zhoujin Tan
- College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Hunan Key Laboratory of Traditional Chinese Medicine Prescription and Syndromes Translational Medicine, Changsha, Hunan, China
| | - Ying Cai
- College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Hunan Key Laboratory of Traditional Chinese Medicine Prescription and Syndromes Translational Medicine, Changsha, Hunan, China
| |
Collapse
|
|
2
|
Zhao Q, Chen YY, Xu DQ, Yue SJ, Fu RJ, Yang J, Xing LM, Tang YP. Action Mode of Gut Motility, Fluid and Electrolyte Transport in Chronic Constipation. Front Pharmacol 2021; 12:630249. [PMID: 34385914 PMCID: PMC8353128 DOI: 10.3389/fphar.2021.630249] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 06/28/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic constipation is a common gastrointestinal disorder, with a worldwide incidence of 14–30%. It negatively affects quality of life and is associated with a considerable economic burden. As a disease with multiple etiologies and risk factors, it is important to understand the pathophysiology of chronic constipation. The purpose of this review is to discuss latest findings on the roles of gut motility, fluid, and electrolyte transport that contribute to chronic constipation, and the main drugs available for treating patients. We conducted searches on PubMed and Google Scholar up to 9 February 2021. MeSH keywords “constipation”, “gastrointestinal motility”, “peristalsis”, “electrolytes”, “fluid”, “aquaporins”, and “medicine” were included. The reference lists of searched articles were reviewed to identify further eligible articles. Studies focusing on opioid-induced constipation, evaluation, and clinic management of constipation were excluded. The occurrence of constipation is inherently connected to disorders of gut motility as well as fluid and electrolyte transport, which involve the nervous system, endocrine signaling, the gastrointestinal microbiota, ion channels, and aquaporins. The mechanisms of action and application of the main drugs are summarized; a better understanding of ion channels and aquaporins may be helpful for new drug development. This review aims to provide a scientific basis that can guide future research on the etiology and treatment of constipation.
Collapse
Affiliation(s)
- Qi Zhao
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, Shaanxi University of Chinese Medicine, Xi'an, China
| | - Yan-Yan Chen
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, Shaanxi University of Chinese Medicine, Xi'an, China
| | - Ding-Qiao Xu
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, Shaanxi University of Chinese Medicine, Xi'an, China
| | - Shi-Jun Yue
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, Shaanxi University of Chinese Medicine, Xi'an, China
| | - Rui-Jia Fu
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, Shaanxi University of Chinese Medicine, Xi'an, China
| | - Jie Yang
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, Shaanxi University of Chinese Medicine, Xi'an, China
| | - Li-Ming Xing
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, Shaanxi University of Chinese Medicine, Xi'an, China
| | - Yu-Ping Tang
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, Shaanxi University of Chinese Medicine, Xi'an, China
| |
Collapse
|
|
3
|
Buddington RK, Wong T, Howard SC. Paracellular Filtration Secretion Driven by Mechanical Force Contributes to Small Intestinal Fluid Dynamics. Med Sci (Basel) 2021; 9:medsci9010009. [PMID: 33572202 PMCID: PMC7931054 DOI: 10.3390/medsci9010009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 01/26/2021] [Accepted: 02/02/2021] [Indexed: 02/07/2023] Open
Abstract
Studies of fluid secretion by the small intestine are dominated by the coupling with ATP-dependent generation of ion gradients, whereas the contribution of filtration secretion has been overlooked, possibly by the lack of a known mechanistic basis. We measured apical fluid flow and generation of hydrostatic pressure gradients by epithelia of cultured mouse enterocytes, Caco-2 and T-84 cells, and fibroblasts exposed to mechanical force provided by vigorous aeration and in response to ion gradients, inhibitors of ion channels and transporters and in vitro using intact mouse and rat small intestine. We describe herein a paracellular pathway for unidirectional filtration secretion that is driven by mechanical force, requires tight junctions, is independent of ionic and osmotic gradients, generates persistent hydrostatic pressure gradients, and would contribute to the fluid shifts that occur during digestion and diarrhea. Zinc inhibits the flow of fluid and the paracellular marker fluorescein isothyocyanate conjugated dextran (MW = 4 kD) across epithelia of cultured enterocytes (>95%; p < 0.001) and intact small intestine (>40%; p = 0.03). We propose that mechanical force drives fluid secretion through the tight junction complex via a “one-way check valve” that can be regulated. This pathway of filtration secretion complements chloride-coupled fluid secretion during high-volume fluid flow. The role of filtration secretion in the genesis of diarrhea in intact animals needs further study. Our findings may explain a potential linkage between intestinal motility and intestinal fluid dynamics.
Collapse
Affiliation(s)
- Randal K. Buddington
- School of Health Studies, University of Memphis, Memphis, TN 38152, USA;
- Babies Taking Flight, Memphis, TN 38117, USA
- Correspondence: ; Tel.: +1-662-418-2666
| | - Thomas Wong
- School of Health Studies, University of Memphis, Memphis, TN 38152, USA;
| | - Scott C. Howard
- Department of Acute and Tertiary Care, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA;
| |
Collapse
|
|
4
|
Kurimoto E, Matsuda S, Shimizu Y, Sako Y, Mandai T, Sugimoto T, Sakamoto H, Kimura H. An Approach to Discovering Novel Muscarinic M 1 Receptor Positive Allosteric Modulators with Potent Cognitive Improvement and Minimized Gastrointestinal Dysfunction. J Pharmacol Exp Ther 2018; 364:28-37. [PMID: 29025977 DOI: 10.1124/jpet.117.243774] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Accepted: 10/09/2017] [Indexed: 03/08/2025] Open
Abstract
Activation of muscarinic M1 receptor (M1R) is a promising approach for improving cognitive impairment in Alzheimer's disease. However, an M1R-selective positive allosteric modulator (PAM), benzyl quinolone carboxylic acid (BQCA), at 30 mg/kg, induced diarrhea in wild-type mice, but not in M1R knockout mice. Moreover, BQCA (0.1-1000 nM) augmented electric field stimulation (EFS)-induced ileum contraction in an in vitro Magnus assay. Thus, we decided to establish a drug-screening strategy to discover novel M1 PAMs producing potent cognitive improvement with minimized gastrointestinal (GI) dysfunction. We assessed PAM parameters of various M1 PAMs with ≥100-fold selectivity over other muscarinic receptor subtypes by using in vitro binding and functional analysis. Evaluation of these M1 PAMs in the Magnus assay revealed a significant correlation between percentage of ileum contractions at 1 μM and their α-value, a PAM parameter associated with the binding cooperativity between acetylcholine and M1 PAM. M1 PAMs with lower α-value showed lower impact on EFS-induced ileum contraction. Next, we characterized in vivo profiles of two M1 PAMs: compound A (log α = 1.18) and compound B (log α = 3.30). Compound A, at 30 mg/kg, significantly improved scopolamine-induced cognitive deficits without prominent signs of diarrhea at up to 1000 mg/kg in mice. In contrast, compound B, at 10 mg/kg, showed both significant improvement of scopolamine-induced cognitive deficits and severe diarrhea. Thus, fine adjustment of the α-values could be a key to discovering M1 PAMs yielding potent cognitive improvement with a lower risk of GI effects.
Collapse
Affiliation(s)
- Emi Kurimoto
- CNS Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Japan
| | - Satoru Matsuda
- CNS Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Japan
| | - Yuji Shimizu
- CNS Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Japan
| | - Yuu Sako
- CNS Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Japan
| | - Takao Mandai
- CNS Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Japan
| | - Takahiro Sugimoto
- CNS Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Japan
| | - Hiroki Sakamoto
- CNS Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Japan
| | - Haruhide Kimura
- CNS Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Japan
| |
Collapse
|