Recombinant Interleukin - 2 2 Immunotherapy Ameliorates Inflammation and Promotes the Release of Monoamine Neurotransmitters in the Gut-Brain Axis of Schistosoma mansoni-Infected Mice.

Recombinant interleukin-22 (rIL-22) has been reported as a protective agent in murine models of diseases driven by epithelial injury. Parasites have a circadian rhythm and their sensitivity to a certain drug may vary during the day. Therefore, this work aimed to investigate the effect of rIL-22 administration at different times of the day on the inflammation, oxidative status, and neurotransmitter release in the gut-brain axis of the Schistosoma mansoni-infected mice. Sixty male BALB/c mice aged six weeks weighing 25-30 g were divided into a control group (injected intraperitoneally with PBS), mice infected with 80 ± 10 cercariae of S. mansoni (infected group) then injected intraperitoneally with PBS, and rIL-22 treated groups. rIL-22 was administrated intraperitoneally (400 ng/kg) either at the onset or offset of the light phase for 14 days. IL-22 administration reduced the levels of IL-1ß, tumor necrosis factor-alpha (TNF-α), nuclear factor kappa beta (NF-κß), and enhanced the production of IL-22 and IL-17. The treatment with IL-22 increased glutathione (GSH) and reduced malondialdehyde (MDA) and nitric oxide (NO) levels both in the ileum and brain. The B-cell lymphoma 2 (BCL2) protein level in the ileum was diminished after IL-22 administration. Brain-derived neurotrophic factor (BDNF) and neurotransmitter release (serotonin, 5HT, norepinephrine, NE, dopamine, DA, Glutamate, Glu, and -amino butyric acid, GABA) were improved by rIL-22. In conclusion, rIL-22 showed promising immunotherapy for inflammation, oxidative damage, and neuropathological signs associated with schistosomiasis. The efficacy of IL-22 increased significantly upon its administration at the time of light offset.

Semaglutide Attenuates Anxious and Depressive-Like Behaviors and Reverses the Cognitive Impairment in a Type 2 Diabetes Mellitus Mouse Model Via the Microbiota-Gut-Brain Axis.

Newly conducted research suggests that metabolic disorders, like diabetes and obesity, play a significant role as risk factors for psychiatric disorders. This connection presents a potential avenue for creating novel antidepressant medications by repurposing drugs originally developed to address antidiabetic conditions. Earlier investigations have shown that GLP-1 (Glucagon-like Peptide-1) analogs exhibit neuroprotective qualities in various models of neurological diseases, encompassing conditions such as Alzheimer's disease, Parkinson's disease, and stroke. Moreover, GLP-1 analogs have demonstrated the capability to enhance neurogenesis, a process recognized for its significance in memory formation and the cognitive and emotional aspects of information processing. Nonetheless, whether semaglutide holds efficacy as both an antidepressant and anxiolytic agent remains uncertain. To address this, our study focused on a mouse model of depression linked to type 2 diabetes induced by a High Fat Diet (HFD). In this model, we administered semaglutide (0.05 mg/Kg intraperitoneally) on a weekly basis to evaluate its potential as a therapeutic option for depression and anxiety. Diabetic mice had higher blood glucose, lipidic profile, and insulin resistance. Moreover, mice fed HFD showed higher serum interleukin (IL)-1ß and lipopolysaccharide (LPS) associated with impaired humor and cognition. The analysis of behavioral responses revealed that the administration of semaglutide effectively mitigated depressive- and anxiety-like behaviors, concurrently demonstrating an enhancement in cognitive function. Additionally, semaglutide treatment protected synaptic plasticity and reversed the hippocampal neuroinflammation induced by HFD fed, improving activation of the insulin pathway, demonstrating the protective effects of semaglutide. We also found that semaglutide treatment decreased astrogliosis and microgliosis in the dentate gyrus region of the hippocampus. In addition, semaglutide prevented the DM2-induced impairments of pro-opiomelanocortin (POMC), and G-protein-coupled receptor 43 (GPR43) and simultaneously increased the NeuN + and Glucagon-like Peptide-1 receptor (GLP-1R+) neurons in the hippocampus. Our data also showed that semaglutide increased the serotonin (5-HT) and serotonin transporter (5-HTT) and glutamatergic receptors in the hippocampus. At last, semaglutide changed the gut microbiota profile (increasing Bacterioidetes, Bacteroides acidifaciens, and Blautia coccoides) and decreased leaky gut, improving the gut-brain axis. Taken together, semaglutide has the potential to act as a therapeutic tool for depression and anxiety.

Dietary sulforaphane glucosinolate mitigates depression-like behaviors in mice with hepatic ischemia/reperfusion injury: A role of the gut-liver-brain axis.

Nutrition has been increasingly recognized for its use in mental health. Depression is commonly observed in patients with chronic liver disease (CLD). Building on our recent findings of depression-like behaviors in mice with hepatic ischemia/reperfusion (HI/R) injury, mediated by the gut-liver-brain axis, this study explored the potential influence of dietary sulforaphane glucosinolate (SGS) on these behaviors. Behavioral assessments for depression-like behaviors were conducted 7 days post either sham or HI/R injury surgery. Dietary intake of SGS significantly prevented splenomegaly, systemic inflammation, depression-like behaviors, and downregulation of synaptic proteins in the prefrontal cortex (PFC) of HI/R-injured mice. Through 16S rRNA analysis and untargeted metabolomic analyses, distinct bacterial profiles and metabolites were identified between control + HI/R group and SGS + HI/R group. Correlations were observed between the relative abundance of gut microbiota and both behavioral outcomes and blood metabolites. These findings suggest that SGS intake could mitigate depression-like phenotypes in mice with HI/R injury, potentially through the gut-liver-brain axis. Additionally, SGS, found in crucial vegetables like broccoli, could offer prophylactic nutritional benefits for depression in patients with CLD.

Co-decoction of Lilii bulbus and Radix Rehmannia Recens and its key bioactive ingredient verbascoside inhibit neuroinflammation and intestinal permeability associated with chronic stress-induced depression via the gut microbiota-brain axis.

BACKGROUND: Gut microbiota plays a critical role in the pathogenesis of depression and are a therapeutic target via maintaining the homeostasis of the host through the gut microbiota-brain axis (GMBA). A co-decoction of Lilii bulbus and Radix Rehmannia Recens (LBRD), in which verbascoside is the key active ingredient, improves brain and gastrointestinal function in patients with depression. However, in depression treatment using verbascoside or LBRD, mechanisms underlying the bidirectional communication between the intestine and brain via the GMBA are still unclear. PURPOSE: This study aimed to examine the role of verbascoside in alleviating depression via gut-brain bidirectional communication and to study the possible pathways involved in the GMBA. METHODS: Key molecules and compounds involved in antidepressant action were identified using HPLC and transcriptomic analyses. The antidepressant effects of LBRD and verbascoside were observed in chronic stress induced depression model by behavioural test, neuronal morphology, and synaptic dendrite ultrastructure, and their neuroprotective function was measured in corticosterone (CORT)-stimulated nerve cell injury model. The causal link between the gut microbiota and the LBRD and verbascoside antidepressant efficacy was evaluate via gut microbiota composition analysis and faecal microbiota transplantation (FMT). RESULTS: LBRD and Verbascoside administration ameliorated depression-like behaviours and synaptic damage by reversing gut microbiota disturbance and inhibiting inflammatory responses as the result of impaired intestinal permeability or blood-brain barrier leakiness. Furthermore, verbascoside exerted neuroprotective effects against CORT-induced cytotoxicity in an in vitro depression model. FMT therapy indicated that verbascoside treatment attenuated gut inflammation and central nervous system inflammatory responses, as well as eliminated neurotransmitter and brain-gut peptide deficiencies in the prefrontal cortex by modulating the composition of gut microbiota. Lactobacillus, Parabacteroides, Bifidobacterium, and Ruminococcus might play key roles in the antidepressant effects of LBRD via the GMBA. CONCLUSION: The current study elucidates the multi-component, multi-target, and multi-pathway therapeutic effects of LBRD on depression by remodeling GMBA homeostasis and further verifies the causality between gut microbiota and the antidepressant effects of verbascoside and LBRD.

Lavender essential oil alleviates depressive-like behavior in alcohol-withdrawn rats: Insights from gut metabolites and hippocampal transcriptome analysis.

Lavender, an aromatic plant with a history dating back to ancient Egypt and Greece, is consumed because of its diverse pharmacological properties, including sedation, sleep aid, and antidepressant effects. However, the mechanisms underlying these antidepressant properties remain unclear. In this study, we explored the impact of lavender essential oil (LEO) inhalation on the diversity of gut microbiota, metabolites, and differential gene expression in the hippocampus of alcohol-withdrawn depressive rats. Additionally, we examined alterations in the hippocampal transient receptor potential (TRP) channel-mediated inflammatory regulation within the brain-gut axis of depressive rats. The results demonstrated a significant decrease in sucrose preference, diminished activity in the central zone of the open field test, and prolonged immobility time in the forced swim test in alcohol-withdrawn depressive rats, indicating the amelioration of depressive states following lavender essential oil inhalation. 16 S rDNA sequencing analysis revealed a significant reduction in Bacteroidota and Muribaculaceae in the gut of alcohol-withdrawn depressive rats, whereas lavender essential oil significantly increased the relative abundance of Muribaculaceae and other bacterial species. Metabolomic analysis identified 646 distinct metabolites as highly correlated biomarkers between the model and lavender essential oil groups. Furthermore, lavender essential oil inhalation significantly attenuated hippocampal inflammatory factors IL-2, IL-6, IL-1ß, and TNF-α. This study identified elevated expression of Trpv4 and Calml4 in the hippocampal region of alcohol-withdrawn depressed rats and showed that lavender essential oil inhalation regulated aberrantly expressed genes. Our research suggests that lavender essential oil downregulates Trpv4, modulates inflammatory factors, and alleviates depressive-like behavior in alcohol withdrawal rats.

Dietary emulsifier polysorbate 80 exposure accelerates age-related cognitive decline.

Gut microbial homeostasis is crucial for the health of cognition in elderly. Previous study revealed that polysorbate 80 (P80) as a widely used emulsifier in food industries and pharmaceutical formulations could directly alter the human gut microbiota compositions. However, whether long-term exposure to P80 could accelerate age-related cognitive decline via gut-brain axis is still unknown. Accordingly, in this study, we used the senescence accelerated mouse prone 8 (SAMP8) mouse model to investigate the effects of the emulsifier P80 intake (1 % P80 in drinking water for 12 weeks) on gut microbiota and cognitive function. Our results indicated that P80 intake significantly exacerbated cognitive decline in SAMP8 mice, along with increased brain pathological proteins deposition, disruption of the blood-brain barrier and activation of microglia and neurotoxic astrocytes. Besides, P80 intake could also induce gut microbiota dysbiosis, especially the increased abundance of secondary bile acids producing bacteria, such as Ruminococcaceae, Lachnospiraceae, and Clostridium scindens. Moreover, fecal microbiota transplantation from P80 mice into 16-week-old SAMP8 mice could also exacerbated cognitive decline, microglia activation and intestinal barrier impairment. Intriguingly, the alterations of gut microbial composition significantly affected bile acid metabolism profiles after P80 exposure, with markedly elevated levels of deoxycholic acid (DCA) in serum and brain tissue. Mechanically, DCA could activate microglial and promote senescence-associated secretory phenotype production through adenosine triphosphate-binding cassette transporter A1 (ABCA1) importing lysosomal cholesterol. Altogether, the emulsifier P80 accelerated cognitive decline of aging mice by inducing gut dysbiosis, bile acid metabolism alteration, intestinal barrier and blood brain barrier disruption as well as neuroinflammation. This study provides strong evidence that dietary-induced gut microbiota dysbiosis may be a risk factor for age-related cognitive decline.

Long-term use of etomidate disrupts the intestinal homeostasis and nervous system in mice.

Etomidate (ETO) is used as an anesthetic in surgery, but it is being abused in some populations. The damage caused by long-term intake of ETO to intestinal and brain functions is not yet clear, and it remains to be determined whether the drug affects the central nervous system through the gut-brain axis. This study aimed to investigate the neurotoxic and gastrointestinal effects of ETO at doses of 1 mg/kg and 3 mg/kg in mice over 14 consecutive days. The results showed that long-term injection of ETO led to drug resistance in mice, affecting their innate preference for darkness and possibly inducing dependence on ETO. The levels of 5-hydroxytryptamine in the brain, serum, and colon decreased by 37%, 51%, and 42% respectively, while the levels of γ-aminobutyric acid reduced by 38%, 52%, and 41% respectively. H&E staining revealed that ETO reduced goblet cells in the colon and damaged the intestinal barrier. The expression of tight junction-related genes Claudin4 and ZO-1 was downregulated. The intestinal flora changed, the abundance of Akkermansia and Lactobacillus decreased by 33% and 14%, respectively, while Klebsiella increased by 18%. TUNEL results showed that high-dose ETO increased apoptotic cells in the brain. The expression of Claudin1 in the brain was downregulated. Untargeted metabolomics analysis of the colon and brain indicated that ETO caused abnormalities in glycerophospholipid metabolism. Abnormal lipid metabolism might lead to the production or accumulation of lipotoxic metabolites, causing central nervous system diseases. ETO induced changes in the intestinal flora and metabolism, further affecting the central nervous system through the gut-brain axis. The study unveiled the detrimental effects on the brain and gastrointestinal system resulting from long-term intake of ETO, which holds significant implications for comprehending the adverse impact of ETO abuse on human health.

Diminazene aceturate attenuates systemic inflammation via microbiota gut-5-HT brain-spleen sympathetic axis in male mice.

The sympathetic arm of the inflammatory reflex is the efferent pathway through which the central nervous system (CNS) can control peripheral immune responses. Diminazene aceturate (DIZE) is an antiparasitic drug that has been reported to exert protective effects on various experimental models of inflammation. However, the pathways by which DIZE promotes a protective immunomodulatory effects still need to be well established, and no studies demonstrate the capacity of DIZE to modulate a neural reflex to control inflammation. C57BL/6 male mice received intraperitoneal administration of DIZE (2 mg/Kg) followed by lipopolysaccharide (LPS, 5 mg/Kg, i.p.). Endotoxemic animals showed hyperresponsiveness to inflammatory signals, while those treated with DIZE promoted the activation of the inflammatory reflex to attenuate the inflammatory response during endotoxemia. The unilateral cervical vagotomy did not affect the anti-inflammatory effect of DIZE in the spleen and serum. At the same time, splenic denervation attenuated tumor necrosis factor (TNF) synthesis in the spleen and serum. Using broad-spectrum antibiotics for two weeks showed that LPS modulated the microbiota to induce a pro-inflammatory profile in the intestine and reduced the serum concentration of tryptophan and serotonin (5-HT), while DIZE restored serum tryptophan and increased the hypothalamic 5-HT levels. Furthermore, the treatment with 4-Chloro-DL-phenylalanine (pcpa, an inhibitor of 5-HT synthesis) abolished the anti-inflammatory effects of the DIZE in the spleen. Our results indicate that DIZE promotes microbiota modulation to increase central 5-HT levels and activates the efferent sympathetic arm of the inflammatory reflex to control splenic TNF production in endotoxemic mice.

Changes in gut-brain axis parameters in adult rats of both sexes with different feeding pattern that were early nicotine-exposed.

Nicotine is an endocrine disruptor and imprinting factor during breastfeeding that can cause food intake imbalance in the adulthood. As nicotine affects the intestinal microbiota, altering the composition of the bacterial communities and short-chain fatty acids (SCFAs) synthesis in a sex-dependent manner, we hypothesized that nicotine could program the gut-brain axis, consequently modifying the eating pattern of adult male and female rats in a model of maternal nicotine exposure (MNE) during breastfeeding. Lactating Wistar rat dams received minipumps that release 6 mg/kg/day of nicotine (MNE group) or saline for 14 days. The progeny received standard diet from weaning until euthanasia (26 weeks of age). We measured: in vivo electrical activity of the vagus nerve; c-Fos expression in the nucleus tractus solitarius, gastrointestinal peptides receptors, intestinal brain-derived neurotrophic factor (BDNF), SCFAs and microbiota. MNE females showed hyperphagia despite normal adiposity, while MNE males had unchanged food intake, despite obesity. Adult MNE offspring showed decreased Bacteroidetes and increased Firmicutes, Actinobacteria and Proteobacteria. MNE females had lower fecal acetate while MNE males showed higher vagus nerve activity. In summary nicotine exposure through the milk induces long-term intestinal dysbiosis, which may affect eating patterns of adult offspring in a sex-dependent manner.

Predominant role of gut-vagus-brain neuronal pathway in postoperative nausea and vomiting: evidence from an observational cohort study.

BACKGROUND: Postoperative nausea and vomiting (PONV) as a clinically most common postoperative complication requires multimodal antiemetic medications targeting at a wide range of neurotransmitter pathways. Lacking of neurobiological mechanism makes this 'big little problem' still unresolved. We aim to investigate whether gut-vagus-brain reflex generally considered as one of four typical emetic neuronal pathways might be the primary mediator of PONV. METHODS: Three thousand two hundred twenty-three patients who underwent vagus nerve trunk resection (esophagectomy and gastrectomy) and non-vagotomy surgery (hepatectomy, pulmonary lobectomy and colorectomy) from December 2016 to January 2019 were enrolled. Thirty cases of gastrectomy with selective resection on the gastric branch of vagus nerve were also recruited. Nausea and intensity of vomiting was recorded within 24 h after the operation. RESULTS: PONV occurred in 11.9% of 1187 patients who underwent vagus nerve trunk resection and 28.7% of 2036 non-vagotomy patients respectively. Propensity score matching showed that vagotomy surgeries accounted for 19.9% of the whole PONV incidence, much less than that observed in the non-PONV group (35.1%, P <  0.01). Multivariate logistic regression result revealed that vagotomy was one of underlying factor that significantly involved in PONV (OR = 0.302, 95% CI, 0.237-0.386). Nausea was reported in 5.9% ~ 8.6% vagotomy and 12 ~ 17% non-vagotomy patients. Most vomiting were mild, being approximately 3% in vagotomy and 8 ~ 13% in non-vagotomy patients, while sever vomiting was much less experienced. Furthermore, lower PONV occurrence (10%) was also observed in gastrectomy undergoing selective vagotomy. CONCLUSION: Patients undergoing surgeries with vagotomy developed less PONV, suggesting that vagus nerve dependent gut-brain signaling might mainly contribute to PONV.

Caprylic acid ameliorates rotenone induced inflammation and oxidative stress in the gut-brain axis in Zebrafish.

BACKGROUND: Dysfunction of the gastrointestinal tract (GIT) is one of the most common non-motor symptom of Parkinson's Disease (PD). Pathological processes causing PD were suggested to initiate in the enteric nervous system (ENS) and proceed to the central nervous system (CNS). There are studies showing that low-carbohydrate ketogenic diets can improve motor symptoms of PD. Caprylic acid (C8) is the principal fatty acid component of the medium-chain triglycerides in the ketogenic diets. In this study, we aimed to evaluate the effects of caprylic acid, in neurotoxin exposed zebrafish focusing on the relationship between intestinal and brain oxidative stress and inflammation. METHODS: Adult zebrafish were exposed to rotenone (5 µg/L) (R group) and caprylic acid (20 and 60 mg/mL) (L + HDCA and R + HDCA groups) for 30 days. At the end of 30 days locomotor activities were determined. Levels of lipid peroxidation (LPO), nitric oxide, glutathione and superoxide dismutase and glutathione S-transferase activities were determined by spectrophotometric methods and gene expressions of tnf⍺, il1, il6, il21, ifnÉ£ and bdnf were evaluated by RT-PCR in the brain and intestinal tissues of zebrafish. RESULTS: Caprylic acid ameliorated LPO, NO, SOD and the expressions of tnf⍺, il1, il6, il21, ifnÉ£ and bdnf in brain and intestines. Locomotor activities were only ameliorated in high dose R + HDCA group. CONCLUSIONS: Caprylic acid ameliorated the neurotoxin-induced oxidative stress and inflammation both in the brain and intestines and enhanced locomotor activity in zebrafish.

Loss of vagal integrity disrupts immune components of the microbiota-gut-brain axis and inhibits the effect of Lactobacillus rhamnosus on behavior and the corticosterone stress response.

The vagus nerve is one of the major signalling components between the gut microbiota and brain. However, the exact relationship between gut-brain signaling along the vagus and the effects of gut microbes on brain function and behaviour is unclear. In particular, the relationship between the vagus nerve and immune signaling, that also appears to play a critical role in microbiota-gut-brain communication, has not been delineated. The aim of the present study was to determine the effect of subdiaphragmatic vagotomy on peripheral and central immune changes associated with the anxiolytic actions of L.rhamnosus. Male mice underwent vagotomy or sham surgery, followed by administration of L.rhamnosus for 14 days. L.rhamnosus administration following sham surgery resulted in reduced anxiety-like behaviour, and an attenuation of the hypothalamic-pituitary-adrenal axis (HPA axis), as indicated by reduced plasma corticosterone after acute restraint stress. These effects were associated with an increase in splenic T regulatory cells and a decrease in activated microglia in the hippocampus. The anxiolytic effects, HPA modulation and increase in T regulatory cells were prevented by vagotomy, whereas vagotomy alone led to a significant increase in activated microglia in the hippocampus that was not altered with L.rhamnosus treatment. Thus, both microbe induced and constitutive vagal signaling influences critical immune components of the microbiota-gut-brain axis. These findings suggest that, rather than acting as a direct neural link to the central nervous system, the role of the vagus nerve in gut-microbe to brain signalling is as an integral component of a bi-directional neuroimmunoendocrine pathway.

The therapeutic potential of GLP-1 analogues for stress-related eating and role of GLP-1 in stress, emotion and mood: a review.

Stress and low mood are powerful triggers for compulsive overeating, a maladaptive form of eating leading to negative physical and mental health consequences. Stress-vulnerable individuals, such as people with obesity, are particularly prone to overconsumption of high energy foods and may use it as a coping mechanism for general life stressors. Recent advances in the treatment of obesity and related co-morbidities have focused on the therapeutic potential of anorexigenic gut hormones, such as glucagon-like peptide 1 (GLP-1), which acts both peripherally and centrally to reduce energy intake. Besides its appetite suppressing effect, GLP-1 acts on areas of the brain involved in stress response and emotion regulation. However, the role of GLP-1 in emotion and stress regulation, and whether it is a viable treatment for stress-induced compulsive overeating, has yet to be established. A thorough review of the pre-clinical literature measuring markers of stress, anxiety and mood after GLP-1 exposure points to potential divergent effects based on temporality. Specifically, acute GLP-1 injection consistently stimulates the physiological stress response in rodents whereas long-term exposure indicates anxiolytic and anti-depressive benefits. However, the limited clinical evidence is not as clear cut. While prolonged GLP-1 analogue treatment in people with type 2 diabetes improved measures of mood and general psychological wellbeing, the mechanisms underlying this may be confounded by associated weight loss and improved blood glucose control. There is a paucity of longitudinal clinical literature on mechanistic pathways by which stress influences eating behavior and how centrally-acting gut hormones such as GLP-1, can modify these. (250).