Figure 5 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Localization of EC cells in the small intestine of mice. (A–D) Sections of paraffin-embedded small intestine tissue from uninfected BALB/c mice were processed for immunohistochemistry with rabbit anti-chromogranin A and peroxidase-labelled goat-anti rabbit. The EC cells were identified in all segments of the small intestine. (A) Ileum, (B–D) duodenum. Stars indicate chromogranin A containing-EC cells.
Source publication
Rotavirus (RV) is the major cause of severe gastroenteritis in young children. A virus-encoded enterotoxin, NSP4 is proposed to play a major role in causing RV diarrhoea but how RV can induce emesis, a hallmark of the illness, remains unresolved. In this study we have addressed the hypothesis that RV-induced secretion of serotonin (5-hydroxytryptam...
Citations
... There are several families of 5-HT receptors (HTR), and five of them are expressed in the gut [7]. There is evidence that RV activates serotonin secretion via the enterochromaffin cells of the small intestine and that HTR3 is involved in the RV-derived activation of vomiting and diarrhea [6,8,9]. ...
... The released serotonin activates vagal afferent nerves linked to vomiting brain structures and contributes to diarrhea and intestinal motility. These actions are primarily mediated by the 5-HT 3 receptor [6,8,9]. At the gene expression level, RV promotes downregulation of the gene encoding the serotonin transporter SERT in the ileum of infected mice, without modifying the expression of the gene encoding the rate-limiting enzyme THP1 in the serotonin synthesis pathway [6]. ...
Rotavirus (RV) infection is a major cause of acute gastroenteritis in children under 5 years old, resulting in elevated mortality rates in low-income countries. The efficacy of anti-RV vaccines is limited in underdeveloped countries, emphasizing the need for novel strategies to boost immunity and alleviate RV-induced diarrhea. This study explores the effectiveness of interventions involving extracellular vesicles (EVs) from probiotic and commensal E. coli in mitigating diarrhea and enhancing immunity in a preclinical model of RV infection in suckling rats. On days 8 and 16 of life, variables related to humoral and cellular immunity and intestinal function/architecture were assessed. Both interventions enhanced humoral (serum immunoglobulins) and cellular (splenic natural killer (NK), cytotoxic T (Tc) and positive T-cell receptor γδ (TCRγδ) cells) immunity against viral infections and downregulated the intestinal serotonin receptor-3 (HTR3). However, certain effects were strain-specific. EcoR12 EVs activated intestinal CD68, TLR2 and IL-12 expression, whereas EcN EVs improved intestinal maturation, barrier properties (goblet cell numbers/mucin 2 expression) and absorptive function (villus length). In conclusion, interventions involving probiotic/microbiota EVs may serve as a safe postbiotic strategy to improve clinical symptoms and immune responses during RV infection in the neonatal period. Furthermore, they could be used as adjuvants to enhance the immunogenicity and efficacy of anti-RV vaccines.
... We next sought to visualize the infectivity in the ileum and colon of antibiotic-treated mice. Adults and pups were orally infected for 48 h with 100 diarrhea doses (100 DD ) of murine rotavirus epizootic diarrhea of infant mice as previously described (21,22). To investigate the extent of rotavirus infection, we took advantage of iDISCO tissue clearing, volumetric 3D imaging, and computer analysis which together give significantly more information about the extent of the infection compared to conventional methods (15). ...
... Untreated and antibiotic-treated adult females and 5-7 days old mice pups (sv129 mice) were orally infected with 100 diarrhea doses (100 DD ) EDIM rotavirus in 10 µL of 0.9% NaCl via a pipette, as described previously (21,22). At 48 h p.i., mice were sacrificed, and small intestine and colon were taken for PCR investigation of microbiota, virus shedding, and immunofluorescence staining. ...
Rotavirus is associated with extensive infection of the small intestine, whereas colon is considered to be uninfected. Considering that almost all bacteria in the gut colonize the colon, we hypothesized that the microbiota may act as a physical barrier preventing rotavirus infection in the colon in vivo . To address this hypothesis, we used human and mice colonoids, and biopsies of different intestinal segments of untreated and antibiotic-treated adult and infant mice. Rotavirus quantification was performed by qPCR and volumetric 3D imaging of intestinal segments. By 3D imaging, we observed infection in all the small intestinal segments, most extensively in the ileum, with most limited number of infected cells in colon. Broad-spectrum antibiotic treatment yielded no significant change in infection in either ileum or colon of adults and mice pups, although there is a substantial decrease in microbial load. We also show that rotavirus can successfully infect and replicate in colonoids from both mice and humans. Collectively, our data, including novel 3D imaging of the gut, mouse, and human colonoids, conclude that microbiota does not affect rotavirus infection in colon.
IMPORTANCE
Alterations of the gut microbiome can have significant effects on gastrointestinal homeostasis leading to various diseases and symptoms. Increased understanding of rotavirus infection in relation to the microbiota can provide better understanding on how microbiota can be used for clinical prevention as well as treatment strategies. Our volumetric 3D imaging data show that antibiotic treatment and its consequent reduction of the microbial load does not alter the extent of rotavirus infection of enterocytes in the small intestine and that restriction factors other than bacteria limit the infection of colonocytes.
... [70][71][72] In IBS, inhibition of 5-HTR3 located on intrinsic sensory neurons reduces motor and secretory reflex activity and reduces activation of extrinsic sensory neurons that transmit signals to the CNS, suppressing sensory signals that cause pain and discomfort. [73] In rotavirus-induced diarrhea, 5-HTR3 has been shown to play a role by influencing intestinal motility, sensory neuron activation, cytokine secretion, and inflammatory responses, resulting in a reduced number of diarrhea days and diarrhea mouse counts in 5-HT3 receptor knockout mice compared with wild-type mice. However, vagal signaling to the vomiting center also occurs in the absence of 5-HTR3, indicating a complicated interaction between intestinal 5-HT and neural systems in the gut. ...
As a neurotransmitter, 5-hydroxytryptamine (5-HT) plays a variety of regulatory roles in the brain, including affecting mood, memory, circadian rhythm, and other aspects. However, the brain contains only approximately 10% of the 5-HT in humans. Ninety percent of the 5-HT is produced and stored in the gut. 5-HT in the gut is involved in the regulation of irritable bowel syndrome (IBS), colitis, obesity, and other diseases. Therefore, a comprehensive understanding of the bioactivity of 5-HT is necessary. The gut microbiota has been reported to affect 5-HT synthesis and function, but the exact mechanism remains unclear. This review focuses on the production of 5-HT, its relationship with gut microbiota, its mechanism of action in different disease progression processes, and the biological effects of its derivative 5-hydroxyindoleacetic acid.
... The main depository of serotonin in the body is the mucosa of the gastrointestinal tract [41], although the details of gut serotonin remain unclear [42]. Rotavirus has previously been shown to stimulate human EC cells in the gut, causing serotonin release, which activates vagal afferents and the brain stem emesis center, a reaction cascade associated with emesis [43]. It has been previously reported that the oral administration of K. septempunctata to house musk shrews induced serotonin production in the intestines [44]. ...
Kudoa septempunctata is a myxosporean parasite that infects the trunk muscles of olive flounder (Paralichthys olivaceus) and has been reported to cause foodborne illnesses in humans. However, the molecular mechanisms underlying K. septempunctata spore toxicity remain largely unknown. In this study, the gastroenteropathy of K. septempunctata was examined in human colon adenocarcinoma cells as well as experimental mice inoculated with spores. We found that K. septempunctata decreased transepithelial resistance and disrupted epithelial tight junctions by deleting ZO-1 in Caco-2 monolayers. Additionally, serotonin (5-HT), an emetic neurotransmitter, was increased in K. septempunctata-inoculated cells. In vivo, K. septempunctata spores induced diarrhea in suckling mice (80% in ddY and 70% in ICR mice), with a minimum provocative dose of 2 × 105 K. septempunctata spores. In house musk shrews, K. septempunctata induced emesis within 1 h and induced serotonin secretion in the intestinal epithelium. In conclusion, K. septempunctata may induce diarrhea and emesis by increasing intestinal permeability and serotonin secretion.
... Rotavirus and/or the rotavirus enterotoxin NSP4 (green dots) (8) and norovirus (49) recognize yet unknown receptors on enterochromaffin (EC) cells. These cells then respond by the release of serotonin (5-HT, brown dots), which can activate the enteric nervous system and vagal afferents that project signals to the NTS and AP, structures of the vomiting center (8). Efferent vagal signaling from the vomiting center stimulates a nerve-muscle vomiting reflex in the stomach. ...
... Information can also reach the brain through the blood system, e.g., the interleukin (IL)-1 b, IL-6, and tumor necrosis factor alpha (TNF-a) which can initiate fever (17). Recent studies have identified the NTS and BNST to be activated and deactivated following rotavirus infection (8,12). Even though precise pathways between rotavirus-and norovirus-infected enteric cells and neurons of the NTS and BNST remain unknown, both areas are known to propagate peripheral sensory inputs through different nuclei of the hypothalamus to ultimately control nonfear related stress (28), appetite, and fever (20). ...
... Nausea and vomiting are hallmarks of the sickness symptoms of rotavirus and particularly norovirus, which causes the winter vomiting disease. While being common symptoms, surprisingly little information is available on how these viruses trigger nausea and vomiting (2,4,8,12,43,44). The fact that norovirus can rapidly induce nausea and vomiting in the absence of diarrhea and with an incubation as short as 10 h (13), strongly argues for nervous control of nausea and vomiting. ...
Viral infections have a major impact on physiology and behavior. The clinical symptoms of human rotavirus and norovirus infection are primarily diarrhea, fever, and vomiting, but several other sickness symptoms, such as nausea, loss of appetite, and stress response are never or rarely discussed. These physiological and behavioral changes can be considered as having evolved to reduce the spread of the pathogen and increase the chances of survival of the individual as well as the collective. The mechanisms underlying several sickness symptoms have been shown to be orchestrated by the brain, specifically, the hypothalamus. In this perspective, we have described how the central nervous system contributes to the mechanisms underlying the sickness symptoms and behaviors of these infections. Based on published findings, we propose a mechanistic model depicting the role of the brain in fever, nausea, vomiting, cortisol-induced stress, and loss of appetite.
... In addition, 5-fluorouracil treatment increased the expression of 5-HT3 receptors in nerve fibres in mice [66]. Nausea and vomiting were also induced by several infectious agents, including the rotavirus, cholera toxin, and Campylobacter, and the activation of vagal afferents via 5-HT released from ECL cells has been proposed to be involved in this process [67,68]. However, the mechanism of the oxaliplatin-induced 5-HT release from ECL cells is not known. ...
Nausea and vomiting are common gastrointestinal side effects of oxaliplatin chemotherapy used for the treatment of colorectal cancer. However, the mechanism underlying oxaliplatin-induced nausea and vomiting is unknown. The stomach is involved in the emetic reflex but no study investigated the effects of oxaliplatin treatment on the stomach. In this study, the in vivo effects of oxaliplatin treatment on eating behaviour, stomach content, intrinsic gastric neuronal population, extrinsic innervation to the stomach, levels of mucosal serotonin (5-hydroxytryptamine, 5-HT), and parasympathetic vagal efferent nerve activity were analysed. Chronic systemic oxaliplatin treatment in mice resulted in pica, indicated by increased kaolin consumption and a reduction in body weight. Oxaliplatin treatment significantly increased the stomach weight and content. The total number of myenteric and nitric oxide synthase-immunoreactive neurons as well as the density of sympathetic, parasympathetic, and sensory fibres in the stomach were decreased significantly with oxaliplatin treatment. Oxaliplatin treatment significantly increased the levels in mucosal 5-HT and the number of enterochromaffin-like cells. Chronic oxaliplatin treatment also caused a significant increase in the vagal efferent nerve activity. The findings of this study indicate that oxaliplatin exposure has adverse effects on multiple components of gastric innervation, which could be responsible for pica and gastric dysmotility.
... The damage of absorptive enterocytes (causes malabsorption), intestinal secretion induced by rotavirus nonstructural protein 4, and activation of the enteric nervous system are all mechanisms used by rotavirus to cause diarrhea (Crawford et al., 2017). Furthermore, the release of 5-hydroxytryptamine (also known as serotonin) by rotavirus infection can activate signaling pathways that cause diarrhea and vomiting (Hagbom et al., 2011). ...
... Rotavirus infection can cause vomiting, lethargy, and fever in addition to diarrhea. Vomiting is a common symptom of rotavirus infection (Hagbom et al., 2011). Fever is a typical symptom of rotavirus infection, as is malaise (Brodal, 2004). ...
... Rotavirus can release an enterotoxin, namely rotavirus nonstructural protein 4 (NSP4). This mediator can activate adjacent intestinal enterochromaffin cells for further release of serotonin (Hagbom et al., 2011). Thus the enteric nerves and vagal nerve to the brain are activated and can be involved in symptoms such as diarrhea and vomiting (Spiller, 2008). ...
The gut microbiota undergoes significant alterations in response to viral infections, particularly the novel SARS-CoV-2. As impaired gut microbiota can trigger numerous neurological disorders, we suggest that the long-term neurological symptoms of COVID-19 may be related to intestinal microbiota disorders in these patients. Thus, we have gathered available information on how the virus can affect the microbiota of gastrointestinal systems, both in the acute and the recovery phase of the disease, and described several mechanisms through which this gut dysbiosis can lead to long-term neurological disorders, such as Guillain-Barre syndrome, chronic fatigue, psychiatric disorders such as depression and anxiety, and even neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. These mechanisms may be mediated by inflammatory cytokines, as well as certain chemicals such as gastrointestinal hormones (e.g., CCK), neurotransmitters (e.g., 5-HT), etc. (e.g., short-chain fatty acids), and the autonomic nervous system. In addition to the direct influences of the virus, repurposed medications used for COVID-19 patients can also play a role in gut dysbiosis. In conclusion, although there are many dark spots in our current knowledge of the mechanism of COVID-19-related gut-brain axis disturbance, based on available evidence, we can hypothesize that these two phenomena are more than just a coincidence and highly recommend large-scale epidemiologic studies in the future.
... We know much less about intracellular Ca 2+ signalling during mechanotransduction. Mechanical stimulation in BON-1 cells involves IP 3 receptor-mediated Ca 2+ increase (Hagbom et al., 2011;Kim et al., 2001;Linan-Rico et al., 2016). Additionally, in the KRJ-1 cell line and human EC cells, PKA/cAMP pathways are involved in mechanotransduction (Chin et al., 2012). ...
Enteroendocrine cells (EECs) are specialized sensors of luminal forces and chemicals in the gastrointestinal (GI) epithelium that respond to stimulation with a release of signalling molecules such as serotonin (5‐HT). For mechanosensitive EECs, force activates Piezo2 channels, which generate a very rapidly activating and inactivating (∼10 ms) cationic (Na⁺, K⁺, Ca²⁺) receptor current. Piezo2 receptor currents lead to a large and persistent increase in intracellular calcium (Ca²⁺) that lasts many seconds to sometimes minutes, suggesting signal amplification. However, intracellular calcium dynamics in EEC mechanotransduction remain poorly understood. The aim of this study was to determine the role of Ca²⁺ stores in EEC mechanotransduction. Mechanical stimulation of a human EEC cell model (QGP‐1) resulted in a rapid increase in cytoplasmic Ca²⁺ and a slower decrease in ER stores Ca²⁺, suggesting the involvement of intracellular Ca²⁺ stores. Comparing murine primary colonic EECs with colonocytes showed expression of intercellular Ca²⁺ store receptors, a similar expression of IP3 receptors, but a >30‐fold enriched expression of Ryr3 in EECs. In mechanically stimulated primary EECs, Ca²⁺ responses decreased dramatically by emptying stores and pharmacologically blocking IP3 and RyR1/3 receptors. RyR3 genetic knockdown by siRNA led to a significant decrease in mechanosensitive Ca²⁺ responses and 5‐HT release. In tissue, pressure‐induced increase in the Ussing short circuit current was significantly decreased by ryanodine receptor blockade. Our data show that mechanosensitive EECs use intracellular Ca²⁺ stores to amplify mechanically induced Ca²⁺ entry, with RyR3 receptors selectively expressed in EECs and involved in Ca²⁺ signalling, 5‐HT release and epithelial secretion. image
Key points
A population of enteroendocrine cells (EECs) are specialized mechanosensors of the gastrointestinal (GI) epithelium that respond to mechanical stimulation with the release of important signalling molecules such as serotonin.
Mechanical activation of these EECs leads to an increase in intracellular calcium (Ca²⁺) with a longer duration than the stimulus, suggesting intracellular Ca²⁺ signal amplification.
In this study, we profiled the expression of intracellular Ca²⁺ store receptors and found an enriched expression of the intracellular Ca²⁺ receptor Ryr3, which contributed to the mechanically evoked increases in intracellular calcium, 5‐HT release and epithelial secretion.
Our data suggest that mechanosensitive EECs rely on intracellular Ca²⁺ stores and are selective in their use of Ryr3 for amplification of intracellular Ca²⁺.
This work advances our understanding of EEC mechanotransduction and may provide novel diagnostic and therapeutic targets for GI motility disorders.
... Было выявлено, что вирус ротавируса, обычно ответственный за детский гастроэнтерит (симптомами которого являются рвота и диарея), инфицирует и размножается в энтерохроматофинных клетках, увеличивая внутриклеточный [Ca++] и секрецию 5-гидрокситритамина из энтерохроматофинной клетки. Примечательно, что секреция 5-гидрокситритамина увеличилась через 6 часов после заражения [30], а также иммуногистохимия показала интенсивную активацию ядра одиночного тракта, что наводит на мысль об активации афферентного пути блуждающего нерва. Та же лаборатория также продемонстрировала способность аденовируса 41, вызывающего острый гастроэнтерит с диареей и рвотой, увеличивать высвобождение 5-гидрокситритамина из энтерохроматофинных клеток человека [31]. ...
Coronaviruses, seven of which are known to infect humans, can range from asymptomatic infection to malnutrition and death. Russia has over 12.4 million confirmed cases of COVID-19 at the time of writing, with nearly 334,000 deaths. While all other coronaviruses affect cardiovascular disease, the SARS-CoV-2 virus also has a tropism for the cardiovascular system, gastrointestinal tract, liver, pancreas, kidneys, and nervous system. In this review, we describe the important gastrointestinal manifestations of COVID-19 in children and discuss possible underlying pathophysiological mechanisms for their occurrence.
