Targeting the Gut-Brain Axis Through Insulin-like Growth Factors: Therapeutic Implications and Future Directions.

Huang-Lian-Jie-Du decoction alleviates diabetic ischemic stroke by modulating gut microbiota-derived short-chain fatty acids.

Gut Microbiota-Derived Short-Chain Fatty Acids and Sleep Disturbances in Pediatric Attention-Deficit/Hyperactivity Disorder: Insights Into Neurobiological Links and Treatment Implications.

Background/Objective: Gut flora plays an important role in host stress response, anxiety, depression and cognitive function through the gut-brain axis. Microbial diversity decreases with age, which in turn affects the function of the nervous system. The role of exercise in the prevention and treatment of age-related diseases and neurodegenerative diseases has received increasing attention. The purpose of this study was to elucidate the regulatory role of intestinal flora, gut-brain axis and nervous system function in the prevention of nervous system function decline in the elderly. Methods: The sample consisted of 16, 52-week-old SPF C57BL/6 male mice that were randomly divided into two groups: a old control group (OC) and an old treadmill exercise group (OE). The mice underwent 16 W moderate intensity incremental load exercise. ELISA was used to detect 5-Hydroxytryptamine (5-HT), gamma-aminobutyric acid (GABA) and Dopamine (DA) in the hippocampus. Serum and hippocampal glutamate and serum Acetylcholine (ACH) were determined by ultraviolet colorimetry. The expression of insulin-like growth factors 1 (IGF1) and brain-derived neurotrophic factor (BDNF) in hippocampus and vascular epithelial growth factor (VEGF) were measured by Western blot. Fecal samples were collected and analyzed by 16S rDNA sequencing. Results: (1) 5-HT and Glu in the hippocampus (P < 0.01), and DA and GABA in the hippocampus were significantly increased (P < 0.05) after aerobic exercise. Serum Glu and serum Ach in aerobic exercise group were significantly higher than those in the control group (P < 0.01). (2) The expression of BDNF, VEGF and IGF1 in the hippocampus of naturally aged mice were significantly increased after aerobic exercise (P < 0.01). (3) The results of Alpha diversity analysis showed that Shannon index, Simpson index and Chao1 in OE group were significantly increased compared with those in OC group (P < 0.01). The relative abundances of Bacteroidetes and Parasicutes were significantly increased, while the relative abundances of Proteobacteria in naturally aged mice were significantly decreased (P < 0.01) after aerobic exercise. Conclusions: The composition of intestinal flora and the expression of central neurotransmitters in elderly mice were significantly improved after 16 weeks of moderate-intensity aerobic exercise with incremental load. The expression of adult hippocampal neurogenesis (AHN)-related proteins in hippocampus: VEGF, IGF1 and BDNF were significantly improved, and neurogenesis was promoted. Intestinal microbiota - gut - brain axis plays an important role in the improvement of hippocampal neurogenesis in elderly mice.

Alcohol use disorder (AUD) is commonly associated with distressing psychological symptoms. Pathologic changes associated with AUD have been described in both the gut microbiome and brain, but the mechanisms underlying gut-brain signaling in individuals with AUD are unknown. This study examined associations among the gut microbiome, brain morphometry, and clinical symptoms in treatment-seeking individuals with AUD. We performed a secondary analysis of data collected during inpatient treatment for AUD in subjects who provided gut microbiome samples and had structural brain magnetic resonance imaging (MRI; n = 16). Shotgun metagenomics sequencing was performed, and the morphometry of brain regions of interest was calculated. Clinical symptom severity was quantified using validated instruments. Gut-brain modules (GBMs) used to infer neuroactive signaling potential from the gut microbiome were generated in addition to microbiome features (e.g., alpha diversity and bacterial taxa abundance). Bivariate correlations were performed between MRI and clinical features, microbiome and clinical features, and MRI and microbiome features. Amygdala volume was significantly associated with alpha diversity and the abundance of several bacteria including taxa classified to Blautia, Ruminococcus, Bacteroides, and Phocaeicola. There were moderate associations between amygdala volume and GBMs, including butyrate synthesis I, glutamate synthesis I, and GABA synthesis I & II, but these relationships were not significant after false discovery rate (FDR) correction. Other bacterial taxa with shared associations to MRI features and clinical symptoms included Escherichia coli and Prevotella copri. We identified gut microbiome features associated with MRI morphometry and AUD-associated symptom severity. Given the small sample size and bivariate associations performed, these results require confirmation in larger samples and controls to provide meaningful clinical inferences. Nevertheless, these results will inform targeted future research on the role of the gut microbiome in gut-brain communication and how signaling may be altered in patients with AUD.

Neurodegenerative diseases associated with aging are often accompanied by cognitive decline and gut microbiota disorder. But the impact of gut microbiota on these cognitive disturbances remains incompletely understood. Short chain fatty acids (SCFAs) are major metabolites produced by gut microbiota during the digestion of dietary fiber, serving as an energy source for gut epithelial cells and/or circulating to other organs, such as the liver and brain, through the bloodstream. SCFAs have been shown to cross the blood-brain barrier and played crucial roles in brain metabolism, with potential implications in mediating Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, the underlying mechanisms that SCFAs might influence psychological functioning, including affective and cognitive processes and their neural basis, have not been fully elucidated. Furthermore, the dietary sources which determine these SCFAs production was not thoroughly evaluated yet. This comprehensive review explores the production of SCFAs by gut microbiota, their transportation through the gut–brain axis, and the potential mechanisms by which they influence age-related neurodegenerative disorders. Also, the review discusses the importance of dietary fiber sources and the challenges associated with harnessing dietary-derived SCFAs as promoters of neurological health in elderly individuals. Overall, this study suggests that gut microbiota-derived SCFAs and/or dietary fibers hold promise as potential targets and strategies for addressing age-related neurodegenerative disorders.

The vagus nerve, a key component of the cross-communication between the gut and the brain, is a major element of homeostasis sensing the "milieu intérieur" and boosting the nervous and endocrine responses to maintain the gastrointestinal health status. This nerve has anti-inflammatory properties regulating the gut through the activation of the hypothalamic-pituitary-adrenal axis and the release of cortisol and through a vagovagal reflex, which has an anti-tumor necrosis factor (TNF) effect called the cholinergic anti-inflammatory pathway. Stimulating this nerve is an interesting tool as a nondrug therapy for the treatment of gastrointestinal diseases in which brain-gut communication is dysfunctional, such as inflammatory bowel disorders and others. This review presents the rationale of vagal gastrointestinal physiology and diseases and the most recent advances in vagus nerve stimulation. It also highlights the main issues to be addressed in the future to improve this bioelectronic therapy for gastrointestinal disorders.

The microbiota–gut–brain axis (MGBA) comprises a complex bidirectional communication network integrating neural, immune, metabolic, and endocrine pathways. Dopamine, traditionally viewed as a central neurotransmitter, also plays essential roles in the gastrointestinal (GI) tract, where it regulates motility, secretion, barrier homeostasis, and mucosal immunity. Growing evidence indicates that the gut microbiota significantly contributes to intestinal dopamine metabolism through specialized enzymatic pathways, particularly tyrosine decarboxylase in Enterococcus species and catechol dehydroxylase in Eggerthella species. These microbial reactions compete with host processes, alter dopaminergic tone, and degrade orally administered levodopa (L-DOPA), providing a mechanistic explanation for the variability in treatment response in Parkinson’s disease (PD). Beyond PD, microbially mediated alterations in dopaminergic signaling have been implicated in mood disorders, neurodevelopmental conditions, metabolic dysfunction, and immune-mediated diseases. This review synthesizes current mechanistic and translational evidence on the dopamine–microbiota interface, outlines microbial pathways shaping dopaminergic activity, and highlights therapeutic opportunities including microbiota modulation, dietary strategies, fecal microbiota transplantation, and targeted inhibitors of microbial dopamine metabolism. Understanding this interface offers a foundation for developing personalized approaches in neurogastroenterology and neuromodulatory therapies.

The role of IL-23/IL-17 axis in ischemic stroke from the perspective of gut-brain axis

The microbiota-gut-brain axis involves complex bidirectional communication through neural, immune, and endocrine pathways. Microbial metabolites, such as short-chain fatty acids, influence gut motility and brain function by interacting with gut receptors and modulating hormone release. Additionally, microbial components such as lipopolysaccharides and cytokines can cross the gut epithelium and the blood-brain barrier, impacting immune responses and cognitive function. Ex vivo models, which preserve gut tissue and neural segments, offer insight into localized gut-brain communication by allowing for detailed study of nerve excitability in response to microbial signals, but they are limited in systemic complexity. Miniaturized in vitro models, including organ-on-chip platforms, enable precise control of the cellular environment and simulate complex microbiota-host interactions. These systems allow for the study of microbial metabolites, immune responses, and neuronal activity, providing valuable insights into gut-brain communication. Despite challenges such as replicating long-term biological processes and integrating immune and hormonal systems, advancements in bioengineered platforms are enhancing the physiological relevance of these models, offering new opportunities for understanding the mechanisms of the microbiota-gut-brain axis. This review aims to describe the ex vivo and miniaturized in vitro models which are used to mimic the in vivo conditions and facilitate more precise studies of gut brain communication.

Polyphenols, as natural compounds abundant in plant-derived foods, have been recognised for their human health benefits. This study evaluates the multifunctional properties of BiombalanceTM (BB), a grape seed extract rich in oligomeric procyanidins, in various in vitro and in vivo models. BB was studied to assess (i) its antimicrobial effects in different bacterial species; (ii) its protective effects against oxidative and inflammatory stress in Caco-2 cells; and (iii) its effects in mice, which were fed a standard diet with or without BB at two different doses (BB1X and BB2X) to understand the impacts of BB on microbiota and gut homeostasis. BB selectively inhibited several bacterial species, including Staphylococcus aureus, Helicobacter pylori, and Blautia coccoides. In addition, BB protected Caco-2 cells against hydrogen peroxide (H2O2)-induced oxidative damage and lipopolysaccharide (LPS)-induced oxidative and inflammatory stress. In vivo, BB supplementation upregulated the expression of antioxidant and homeostasis genes in the colon, ileum, and liver, accompanied by dose-dependent changes in the gut microbiota composition. Functional predictions indicated favourable modulation of microbial metabolic pathways, including those involved in antioxidant capacity and glutamate degradation. Furthermore, BB positively influenced key gut–brain axis mediators, including GLP-1, the GLP-1 receptor, and NPY. These findings highlight the potential of BiombalanceTM to support health and gut–brain communication and to protect against oxidative and inflammatory stress in the gut.

Gut–brain bidirectional determination in regulating the residual feed intake of small-sized meat ducks

The gut–brain axis: Identifying new therapeutic approaches for type 2 diabetes, obesity, and related disorders

Behavior Therapy and Callous-Unemotional Traits: Effects of a Pilot Study Examining Modified Behavioral Contingencies on Child Behavior

Sepsis-associated encephalopathy (SAE) is a critical complication of sepsis, yet the mechanisms linking gut dysbiosis to hippocampal neuroinflammation remain poorly understood. Our previous work identified sepsis-induced hippocampal neuroinflammation; here, we investigated the role of gut microbiota-derived short-chain fatty acids (SCFAs) and NLRP6 inflammasome signaling in this process. Sepsis was induced in C57BL/6 mice via cecal ligation and puncture (CLP). Gut microbiota composition, SCFA levels, intestinal barrier integrity, and NLRP6 inflammasome activity were analyzed. Colon organoids and NLRP6-silenced CT26 cells were employed to validate SCFA-NLRP6 interactions. Hippocampal neuroinflammation (microglial/astrocytic activation, cytokine levels) and cognitive function (Morris Water Maze, Barnes Maze) were assessed post-SCFA treatment. CLP-induced sepsis triggered hippocampal neuroinflammation, characterized by microglial proliferation (IBA-1+), astrocyte activation (GFAP+), and neuronal dysfunction (reduced c-Fos). Septic mice showed gut dysbiosis (increased Firmicutes/Proteobacteria, decreased α-diversity), reduced SCFA levels, and impaired intestinal barrier integrity (decreased ZO-1/occludin expression, p<0.05). SCFA supplementation restored gut microbiota homeostasis (β-diversity: p=0.019 vs. CLP), enhanced intestinal tight junction proteins (ZO-1:1.8-fold increase, p<0.01), and activated NLRP6 inflammasomes in colonic tissues (NLRP6:2.1-fold increase, caspase-1:1.6-fold increase, p<0.01). NLRP6 knockdown abolished SCFA-mediated IL-18 secretion (p<0.001). Behaviorally, SCFAs ameliorated cognitive deficits in septic mice (escape latency: CLP=48s vs. SCFA+CLP=32s, p<0.01) and correlated with hippocampal c-Fos restoration (R2=0.839 for propionate, p=0.01). Sepsis disrupts the gut-brain axis by impairing intestinal barrier integrity and NLRP6 inflammasome function, exacerbating hippocampal neuroinflammation. SCFAs mitigate these effects via NLRP6-dependent mechanisms, highlighting their therapeutic potential for SAE. This study provides the first evidence linking SCFA-mediated NLRP6 activation to neuroprotection in sepsis, offering novel insights for targeting the gut microbiota in critical care.

Functional dyspepsia (FD) is a disorder of gut-brain interaction, and its putative pathophysiology involves dysregulation of gastric motility and central processing of gastric afference. The vagus nerve modulates gastric peristalsis and carries afferent sensory information to brainstem nuclei, specifically the nucleus tractus solitarii (NTS). Here, we combine MRI assessment of gastric kinematics with measures of NTS functional connectivity to the brain in patients with FD and healthy controls (HC), in order to elucidate how gut-brain axis communication is associated with FD pathophysiology. Functional dyspepsia and HC subjects experienced serial gastric MRI and brain fMRI following ingestion of a food-based contrast meal. Gastric function indices estimated from 4D cine MRI data were compared between FD and HC groups using repeated measure ANOVA models, controlling for ingested volume. Brain connectivity of the NTS was contrasted between groups and associated with gastric function indices. Propagation velocity of antral peristalsis was significantly lower in FD compared to HC. The brain network defined by NTS connectivity loaded most strongly onto the Default Mode Network, and more strongly onto the Frontoparietal Network in FD. FD also demonstrated higher NTS connectivity to insula, anterior cingulate and prefrontal cortices, and pre-supplementary motor area. NTS connectivity was linked to propagation velocity in HC, but not FD, whereas peristalsis frequency was linked with NTS connectivity in patients with FD. Our multi-modal MRI approach revealed lower peristaltic propagation velocity linked to altered brainstem-cortical functional connectivity in patients suffering from FD suggesting specific plasticity in gut-brain communication.