Helicobacter pylori Vacuolating Cytotoxin A Causes Anorexia and Anxiety via Hypothalamic Urocortin 1 in Mice

Suzuki, Hajime; Ataka, Koji; Asakawa, Akihiro; Cheng, Kai‐Chun; Ushikai, Miharu; Iwai, Haruki; Yagi, Takakazu; Arai, T.; Yahiro, Kinnosuke; Yamamoto, Kenji; Yokoyama, Yoshito; Kojima, Masayasu; Yada, Toshihiko; Hirayama, Toshiya; Nakamura, Norifumi; Inui, Akio

doi:10.1038/s41598-019-42163-4

Cited by 14 publications

(9 citation statements)

References 54 publications

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“…A few studies have identified some toxic factors released by H. pylori that could pose a threat to the structural integrity of the tight junctions within the blood-brain barrier, potentially causing harm to the central nervous system (CNS). [20,21]. Amongst toxic elements, Vacuolating cytotoxin (VacA toxin), discovered in the hypothalamus after peripheral injection, induces anorexia and anxiety in mice [20].…”

Section: Graphical Abstract Introductionmentioning

confidence: 99%

WITHDRAWN: Helicobacter Pylori-Vacuolating Cytotoxin A Inducing Neurotoxic Neuroinflammation in Human Stomach-Brain Axis

Tran,

Etemadi,

Tran

et al. 2023

Preprint

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Background Several epidemiological research have recommended a potential link between Helicobacter pylori infection and neurodegeneration, including Alzheimer’s and Parkinson’s diseases. However, the current research could not fully provide a comprehensive understanding of this association due to the absence of suitable model systems for studying multi-organ interactions and multiplex effects upon Helicobacter pylori infection. Results Here, we recapitulated a human stomach-brain axis by treating human in vitro cellular models with Helicobacter pylori’s cell-free supernatant (HPCFS). We first confirmed that HPCFS disrupted the tightness of gut and brain barriers via Vacuolating cytotoxin A (VacA) binding to Low-density Lipoprotein receptor 1 (LRP1) receptor, leading to reduced tight junction proteins and transmembrane electrical resistance. Blood-brain barrier-penetrating VacA toxin in HPCFS activated central innate immune cells, evidenced by the increased expression of inflammatory markers, oxidative stress, the release of neurotoxic factors, and inflammatory soluble markers, such as NO, IL-8, IL-18 from microglia as well as H2O2, IL-6, and IL-16 from astrocytes. VacA toxin hindered microglial amyloid-beta phagocytosis of amyloid-beta by microglia through by blocking LRP1, a receptor for amyloid-beta. We found that VacA in HPCFS led to neurodegeneration, evidenced by the presence of phosphorylated tau, phosphorylated alpha-synuclein, synaptic impairment, and neuronal loss. Notably, microglia stimulated with VacA exacerbated neurodegeneration compared to direct HPCFS stimulation. Furthermore, we demonstrated that VacA-mediated neuroinflammation and neurodegeneration were mitigated by LRP1 antagonist or VacA immunodepletion. Conclusions This study demonstrates the efficacy of our human stomach-brain axis model that allows us to untangle the complex association between Helicobacter pylori infection and neurological diseases and discover the mechanism of neurotoxic neuroinflammation systematically and this paves the way for future research and therapeutic interventions. Graphical Abstract

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Section: Graphical Abstract Introductionmentioning

confidence: 99%

WITHDRAWN: Helicobacter Pylori-Vacuolating Cytotoxin A Inducing Neurotoxic Neuroinflammation in Human Stomach-Brain Axis

Tran,

Etemadi,

Tran

et al. 2023

Preprint

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“…Vacuolating cytotoxin A (VacA) is a major cytotoxin produced by Hp in the stomach (Cover et al, 2005). VacA might travels via the peripheral circulation, passes through the bloodbrain barrier (BBB) and affects entire brain including hypothalamus (Suzuki et al, 2019). Helicobacter pylori infection can lead to chronic inflammation (Abadi et al, 2017), and various inflammatory mediators, produced locally in the stomach, such as interleukin (IL) −1β, 6, −8, −10, and −12, tumor necrosis factor (TNF) and interferon (IFN)γ, might reach the circulation and induce neuroinflammation and toxicity (Peek et al, 2010;Alvarez-Arellano et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Effect of Helicobacter pylori-Associated Chronic Gastritis on Autonomous Activity and Sleep Quality in Mice

Liu

Zheng²,

Zhang

et al. 2022

Front. Pharmacol.

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Many reports have shown that patients with Hp-associated chronic gastritis exhibit anxiety and poor sleep quality. However, less is known about the effects and specific manifestations of Hp-associated chronic gastritis on autonomous activity and sleep quality in animals. Here, we investigated the effect of Helicobacter pylori (Hp)-associated chronic gastritis on autonomous activity and sleep quality in mice. To do this, a Hp-associated chronic gastritis mouse model was first established, then analyzed for autonomous activity, relative to controls, for 15 min using an autonomous activity tester. Next, sleep quality of mice was detected by sodium pentobarbital-induced sleep experiment and results compared between groups. The results showed that male mice in the model group exhibited higher activity counts but lower forelimb lift counts, relative to those in the control group, although there were no significant differences (all p > .05). Conversely, female mice in the model group recorded lower activity counts, albeit at no significant difference (p > .05), and significantly lower counts of forelimb lift (p < .05), relative to those in the control group. Notably, male mice in the model group had longer sleep latency and shorter sleep duration than those in the control group, albeit at no significant differences (all p > .05). On the other hand, female mice in the model group recorded significantly longer sleep latency as well as shorter sleep duration compared to those in the control group (all p < .01). We conclude that Hp-associated chronic gastritis exerts certain effects on autonomous activity and sleep quality of mice in a gender-dependent manner. Notably, female mice with Hp-associated chronic gastritis had lower activity and forelimb lift counts, as well as prolonged sleep latency, and shortened sleep duration. These effects were all statistically significant except for activity counts.

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“…In these studies, unexpected results may be produced since H. pylori infection leads to increased expression of IL12 and IFN γ in Mongolian gerbils, which seriously affects the accuracy of experimental results [ 25 – 27 ]. Besides, H. pylori infection may induce extragastric diseases, making it difficult to determine the health status of experimental gerbils [ 28 ]. Though H. pylori detection before replicating the H. pylori -infected model in gerbils is necessary, we found few studies that used H. pylori -free gerbils or detected the natural infection before challenge with H. pylori [ 10 , 11 ].…”

Section: Discussionmentioning

confidence: 99%

Establishment of Noninvasive Methods for the Detection of Helicobacter pylori in Mongolian Gerbils and Application of Main Laboratory Gerbil Populations in China

Zhang

Wang

et al. 2022

BioMed Research International

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Identifying Helicobacter pylori (H. pylori, Hp) infection in animals before and after artificial infection influences the subsequent experiment. We established effective and noninvasive detection methods, including the gastric fluid nested polymerase chain reaction (PCR) method and the 13C-urea breath test, which can detect Hp before modeling Hp infection in Mongolian gerbils. We designed a gas collection equipment for gerbils. Hp nested PCR was also performed on gastric fluid, gastric mucosa, duodenal contents, and faeces of gerbils challenged with Hp. Conventional Hp detection methods, including rapid urease assay and immunohistochemistry, were compared. Moreover, we assessed the natural infection of Hp in 135 gerbils that had never been exposed to Hp artificially from the major laboratory gerbil groups in China. In 10 Hp infected gerbils, the positive detection results were 100%, 100%, 90%, and 10% in gastric fluid, gastric mucosa, duodenal contents, and faeces with nested PCR, respectively. A rapid urease test performed on gastric mucosa showed that all animals were infected with Hp. Immunohistochemical detection and bacteria culture of gastric mucosa samples that were positive by the nested PCR method also confirmed the presence of Hp. 9% (3/35) and 6% (2/31) natural infection rates were found in conventional gerbil groups from the Capital Medical University and Zhejiang Laboratory Animal Center. In conclusion, we established two noninvasive Hp detection methods that can be performed before modelingHp infection, including the gastric fluid nested PCR method and the 13C-urea breath test.

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Helicobacter pylori Vacuolating Cytotoxin A Causes Anorexia and Anxiety via Hypothalamic Urocortin 1 in Mice

Cited by 14 publications

References 54 publications

WITHDRAWN: Helicobacter Pylori-Vacuolating Cytotoxin A Inducing Neurotoxic Neuroinflammation in Human Stomach-Brain Axis

WITHDRAWN: Helicobacter Pylori-Vacuolating Cytotoxin A Inducing Neurotoxic Neuroinflammation in Human Stomach-Brain Axis

Effect of Helicobacter pylori-Associated Chronic Gastritis on Autonomous Activity and Sleep Quality in Mice

Establishment of Noninvasive Methods for the Detection of Helicobacter pylori in Mongolian Gerbils and Application of Main Laboratory Gerbil Populations in China

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