The therapeutic benefits of opioids are compromised by the development of analgesic tolerance, which necessitates higher dosing for pain management thereby increasing the liability for drug dependence and addiction. Rodent models indicate opposing roles of the gut microbiota in tolerance: morphine-induced gut dysbiosis exacerbates tolerance, whereas probiotics ameliorate tolerance. Not all individuals develop tolerance, which could be influenced by differences in microbiota, and yet no study design has capitalized upon this natural variation. We leveraged natural behavioral variation in a murine model of voluntary oral morphine self-administration to elucidate the mechanisms by which microbiota influences tolerance. Although all mice shared similar morphine-driven microbiota changes that largely masked informative associations with variability in tolerance, our high-resolution temporal analyses revealed a divergence in the progression of dysbiosis that best explained sustained antinociception. Mice that did not develop tolerance maintained a higher capacity for production of the short-chain fatty acid (SCFA) butyrate known to bolster intestinal barriers and promote neuronal homeostasis. Both fecal microbial transplantation (FMT) from donor mice that did not develop tolerance and dietary butyrate supplementation significantly reduced the development of tolerance independently of suppression of systemic inflammation. These findings could inform immediate therapies to extend the analgesic efficacy of opioids.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with limited effective treatment options. Emerging evidence links enriched environment (EE)-induced eustress to PDAC inhibition. However, the underlying mechanisms remain unclear. In this study, we explored the role of gut microbiota in PDAC-suppressive effects of EE. We demonstrated that depletion of gut microbiota with antibiotics abolished EE-induced tumor suppression, while fecal microbiota transplantation (FMT) from EE mice significantly inhibited tumor growth in both subcutaneous and orthotopic PDAC models housed in standard environment. 16S rRNA sequencing revealed that EE enhanced gut microbiota diversity and selectively enriched probiotic Lactobacillus, particularly L. reuteri. Treatment with L. reuteri significantly suppressed PDAC tumor growth and increased natural killer (NK) cell infiltration into the tumor microenvironment. Depletion of NK cells alleviated the anti-tumor effects of L. reuteri, underscoring the essential role of NK cell-mediated immunity in anti-tumor response. Clinical analysis of PDAC patients showed that higher fecal Lactobacillus abundance correlated with improved progression-free and overall survival, further supporting the therapeutic potential of L. reuteri in PDAC. Overall, this study identifies gut microbiota as a systemic regulator of PDAC under psychological stress. Supplementation of psychobiotic Lactobacillus may offer a novel therapeutic strategy for PDAC.

Autism, a disorder influenced by both genetic and environmental factors, presents significant challenges for prevention and treatment. While maternal-infant gut microbiota has been a focus in autism research, preventive strategies targeting maternal gut microbiota remain underexplored. This study demonstrates that prenatal probiotic intake can effectively prevent maternal separation-induced autistic-like behaviors in offspring without altering the embryonic neurodevelopment in mice. Using specific PCR primers and cross-fostering experiments, we traced the vertical transmission of probiotics, primarily via fecal/vaginal contamination. Early probiotic colonization conferred resilience against stress-induced gut pathogenic microbes and Th17-mediated peripheral inflammation while significantly inhibiting hypermyelination and neuroinflammation linked to systemic inflammation. Microbial metabolites like tyrosol and xanthurenic acid alleviated neuroinflammation and hypermyelination in vitro, though the causal relationship among neuroinflammation, hypermyelination, and autism in vivo requires further validation. These findings underscore the importance of the maternal-infant microbiota transmission window in autism prevention and highlight the clinical potential of prenatal probiotic interventions.

JOURNAL/nrgr/04.03/01300535-202508000-00002/figure1/v/2024-09-30T120553Z/r/image-tiff Traumatic brain injury is a prevalent disorder of the central nervous system. In addition to primary brain parenchymal damage, the enduring biological consequences of traumatic brain injury pose long-term risks for patients with traumatic brain injury; however, the underlying pathogenesis remains unclear, and effective intervention methods are lacking. Intestinal dysfunction is a significant consequence of traumatic brain injury. Being the most densely innervated peripheral tissue in the body, the gut possesses multiple pathways for the establishment of a bidirectional "brain-gut axis" with the central nervous system. The gut harbors a vast microbial community, and alterations of the gut niche contribute to the progression of traumatic brain injury and its unfavorable prognosis through neuronal, hormonal, and immune pathways. A comprehensive understanding of microbiota-mediated peripheral neuroimmunomodulation mechanisms is needed to enhance treatment strategies for traumatic brain injury and its associated complications. We comprehensively reviewed alterations in the gut microecological environment following traumatic brain injury, with a specific focus on the complex biological processes of peripheral nerves, immunity, and microbes triggered by traumatic brain injury, encompassing autonomic dysfunction, neuroendocrine disturbances, peripheral immunosuppression, increased intestinal barrier permeability, compromised responses of sensory nerves to microorganisms, and potential effector nuclei in the central nervous system influenced by gut microbiota. Additionally, we reviewed the mechanisms underlying secondary biological injury and the dynamic pathological responses that occur following injury to enhance our current understanding of how peripheral pathways impact the outcome of patients with traumatic brain injury. This review aimed to propose a conceptual model for future risk assessment of central nervous system-related diseases while elucidating novel insights into the bidirectional effects of the "brain-gut-microbiota axis."

Sleep-disordered breathing (SDB) is characterized by recurrent reductions or interruptions in airflow during sleep, termed hypopneas and apneas, respectively. SDB impairs sleep quality and is linked to substantive health issues including cardiovascular and metabolic disorders, as well as cognitive decline. Recent evidence suggests a link between gut microbiota (GM) composition and sleep apnea. Indeed, GM, a community of microorganisms residing in the gut, has emerged as a potential player in various diseases, and several studies have identified associations between sleep apnea and GM diversity along with shifts in bacterial populations. Additionally, the concept of "leaky gut," a compromised intestinal barrier with potentially increased inflammation, has emerged as another key player in the potential bidirectional relationship between GM and sleep apnea. One of the potential effectors could be extracellular vesicles (EVs) underlying gut-brain communication pathways that are relevant to sleep regulation and function. Thus, therapeutic implications afforded by targeting the GM or exosomes for sleep apnea management have surfaced as promising areas of research. This review explores current understanding of the relationship between GM, exosomes and sleep apnea, highlighting key research dynamics and potential mechanisms. A comprehensive review of the literature was conducted, focusing on studies investigating GM composition, intestinal barrier function and gut-brain communication in relation to sleep apnea.

Bidirectional communications between the gut and the brain play an important role in the regulation of food intake, pain perception, mood, and cognitive function. The involved communication pathways are modulated by signals generated by the gut microbiome. Alterations in these communications have been implicated in several chronic brain and gut disorders, including food addiction, mood disorders, neurodevelopmental and neurodegenerative disorders, and functional and inflammatory bowel disorders. The gut microbiome holds great promise for the development of novel therapies normalizing altered brain-gut interactions.

The current study explored "comfort food" cravings during pregnancy and compared them with a non-pregnant control group, focusing on the types of craved foods, their associated sensory characteristics and emotional valence. With an online questionnaire, participants were asked about their craved foods during pregnancy or in general through open-ended questions, followed by descriptions of the sensory and affective associations of these items using the Check-All-That-Apply (CATA) method. A total of 867 women participated int eh study, distributed across the pregnancy-diet group (197 pregnant women, 288 postpartum women) and control group (382 non-pregnant) took part. While a significant portion of participants in both groups reported cravings for confectionery/sweets, these cravings were less frequent in the pregnancy group (35.9 % vs. 62.0 %, p < 0.001). Non-citrus fruits were more commonly craved during pregnancy than in the control group (29 % vs. 13 %, p < 0.001). The sensory characteristics of cravings showed that both groups favoured 'sweet' and 'salty' foods, but the pregnancy group exhibited a marked preference for foods described as 'cold' (29 % vs. 13 %, p < 0.001), while the control group preferred 'warm', 'creamy', or 'thick' foods. The most frequently selected descriptors for the Emotion-CATA were 'satisfied', 'happy' and 'pleasant' across both groups, although the control group were more likely to associate comfort foods with 'guilty' (19.5 % vs 11.7 %, p < 0.001). These findings suggest potential alterations of chemosomatosensory functions associated with pregnancy and underscore the importance of understanding these cravings. Recognising the role of comfort foods on dietary choices during pregnancy can help us develop dietary strategies that can help mitigate the negative health impacts of comfort food consumption during pregnancy and highlight the importance of emotional and psychological support during this period.

The gastrointestinal tract is a dynamic biomechanical environment where physical forces, cellular processes, and microbial interactions converge to shape the gut health and disease. In this review, we examine the unique mechanical properties of the gut, including peristalsis, viscoelasticity, shear stress, and tissue stiffness, and their roles in modulating host mechanosignaling and microbial behavior under physiological and pathological conditions. We discuss how these mechanical forces regulate gut epithelial integrity, immune responses, and microbial colonization, leading to distinct ecological niches across different intestinal segments. Furthermore, we highlight recent advancements in 3D culture systems and gut-on-a-chip models that accurately recapitulate the complex interplay between biomechanics and gut microbiota. By elucidating the intricate relationship between mechanobiology and gut function, this review underscores the potential for mechanotherapeutic strategies to modulate host-microbe interactions, offering promising avenues for the prevention and treatment of disorders such as inflammatory bowel disease, irritable bowel syndrome, and colorectal cancer.

This review aims to elucidate the neural mechanisms driving colorectal cancer (CRC) growth, metastasis, and therapeutic resistance, summarizing the roles of neurotransmitters, neurotrophic factors, and neural signaling in carcinogenesis. It further explores therapeutic strategies targeting neural dependencies in CRC.

A comprehensive PubMed search was conducted using the keywords colorectal cancer and tumor innervation, focusing on studies published between 2000 and 2024. The review synthesizes evidence across four domains: neurotransmitter-receptor interactions, gut-brain-microbiota axis dynamics, neuroimmune modulation, and neural regulation of cancer stem cells, discussing their collective impact on CRC pathophysiology.

Neural innervation significantly influences CRC progression. For instance, the neurotransmitter serotonin promotes tumor growth and metastasis via paracrine and autocrine stimulation, while neurotrophic mediators like nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) activate oncogenic signaling through receptor tyrosine kinases (RTKs). Downstream pathways, such as Wnt/β-catenin signaling, are modulated by neural inputs, underscoring CRC's neurodevelopmental dependency and highlighting their potential as therapeutic targets.

Neural mechanisms are pivotal in CRC progression, revealing novel therapeutic avenues. Strategies targeting neurotransmitter synthesis, neurotrophic signaling, or neuroimmune crosstalk may disrupt tumorigenic loops while preserving systemic nervous system integrity. Future research must prioritize translating these insights into clinical interventions to improve patient outcomes. Elucidating the intricate interplay between neural mediators and cancer pathogenesis, coupled with developing therapies specifically targeting the neurogenic basis of CRC aggressiveness, represents a critical frontier in oncology.

It has been found that individuals with psychiatric illnesses are predisposed to an elevated risk of cardiovascular diseases (CVDs). Mood swing is a clinically relevant characteristic linked to psychiatric disorders. This study examined the possible relationship between genetically predicted mood swings and CVDs risk. In this mediation Mendelian randomization (MR) study, we compiled data from genome-wide association studies examining mood swings (n = 451,619) and 5 CVDs among Europeans, including coronary artery disease (CAD) (n = 547,261), major coronary heart disease events (MCEs) (n = 361,194), all-cause heart failure (AHF) (n = 218,208), atrial fibrillation (n = 1030,836), and stroke (n = 446,696). The inverse variance weighting method was considered the primary assessment approach in MR analysis, and several sensitivity analyses were performed to evaluate the reliability of the results. Furthermore, the mediating effect of lifestyle factors including smoking, alcohol intake, walking, and waist-hip ratio was explored by using a two-step MR. According to our MR analysis, mood swings were genetically associated with a higher risk of CAD (OR, 2.101; 95% CI, 1.200-3.679; P = .009), AHF (OR, 2.761; 95% CI, 1.312-5.810; P = .007), and MCE (OR, 1.048; 95% CI, 1.022-1.076; P < .001). In the two-step MR analysis, smoking may mediate the causal pathways from mood swings to CAD (27%), MCE (18%), and AHF (26%). Our MR study revealed a potential causal relationship between mood swings and CVDs, smoking may play an important role in it, highlighting the need for regulating mood stability and build a healthy lifestyle to prevent the onset of CVDs. However, due to the limitations of MR, further research is needed to confirm these associations and clarify the underlying mechanisms.

Exposure to COVID-19 has been shown previously to be associated with a higher risk for irritable bowel syndrome (IBS). This study aimed to better explain this relationship using mediation analysis.

This post hoc analysis of a multicenter cohort study includes 623 patients with and without COVID-19 infection. All participants completed the ROME IV criteria, gastrointestinal symptom rating scale (GSRS), and hospital anxiety and depression scale (HADS) over 1 year. Mediation analysis utilized the PROCESS macro and Baron and Kenny's method for parametric and nonparametric mediating variables, respectively.

The impact of COVID-19 on the development of post-COVID-19 IBS is completely mediated by dyspnea at baseline (adjusted OR = 3.561, p = 0.012), severity of acid regurgitation at 1 month [indirect effect, log-odds metric = 0.090, 95% CI (0.006-0.180)], hunger pains at 1 [indirect effect, log-odds metric = 0.094, 95% CI (0.024-0.178)], and 6 months [indirect effect, log-odds metric = 0.074, 95% CI (0.003-0.150)], depression at 6 [indirect effect, log-odds metric = 0.106, 95% CI (0.009-0.225)] and 12 months [indirect effect, log-odds metric = 0.146, 95% CI (0.016-0.311)] as well as borborygmus [indirect effect, log-odds metric = 0.095, 95% CI (0.009-0.203)], abdominal distention [indirect effect, log-odds metric = 0.162, 95% CI (0.047-0.303)], and increased flatus [indirect effect, log-odds metric = 0.110, 95% CI (0.005-0.234)] at 12 months.

Our findings provide evidence for psychological and clinical mediators between COVID-19 and post-COVID-19 IBS, which may be promising targets for interventions tailored for treating or preventing depression. The presence of specific GI symptoms at COVID-19 onset and their persistence should increase awareness of a potential new onset of IBS diagnosis.

The existing body of evidence has highlighted gut microbiota as a versatile regulator of body wellness affecting not only multiple physiological metabolisms but also the function of remote organs. Emerging studies revealed a reciprocal relationship between physical exercise and intestinal microbiota, suggesting that physical exercise could enhance gut health, including regulating intestinal barrier integrity, increasing microbial diversity, and promoting beneficial microbial metabolism. Furthermore, the beneficial outcomes of exercise on the intestine may also promote brain health through the gut-brain axis. Diet is an important factor in boosting exercise performance and also greatly impacts the structure of gut microbiota. Abundant research has reported that diet alongside exercise could exert beneficial effects on metabolism, immune regulation, and the neuropsychiatric system. In this paper, we used a narrative review, primarily searching PubMed, Web of Science, and Elsevier, to review the existing research on how moderate-intensity exercise promotes gut health, and we introduced the effects of exercise on the nervous system through the gut-brain axis. We also proposed dietary strategies targeting the regulation of gut microbiota to provide guidelines for boosting brain health. This review highlights that moderate exercise and a healthy diet promote gut and brain health.

Schizophrenia (SCZ) and Inflammatory Bowel Disease (IBD) represent significant clinical challenges, frequently co-morbid and potentially linked by a genetic correlation. However, the precise mechanism underlying this correlation remains elusive.

we utilized genome-wide association study (GWAS) data for SCZ and IBD to evaluate their genetic correlation. Initially, we performed an overall assessment using Linkage Disequilibrium Score Regression (LDSC), Genetic Covariance Analysis (GNOVA), and High-Dimensional Likelihood (HDL) methods. Subsequently, we conducted a more detailed local analysis using the Local Analysis of Variant Association (LAVA) method. To quantify the genetic overlap between these traits, we employed the Conditional/Joint False Discovery Rate (cond/conjFDR) statistical framework. Finally, by integrating the conjFDR analysis with Multi-Trait GWAS (MTAG), we successfully identified multiple shared genetic loci, shedding light on the genetic intersection between these two traits.

At the genomic level, three independent methods confirmed the overall genetic correlation between SCZ and IBD, including CD and UC. Local genetic correlations were also observed across multiple chromosomal regions. At the single-nucleotide polymorphism (SNP) level, we performed a conjFDR analysis, which indicated a genetic overlap between the two traits. By integrating conjFDR analysis with MTAG, we successfully identified several shared genetic loci, including SLC39A8, BACH2, ZNF365, NOD2, PLCL1, and KIF21B.

The present study provides a novel perspective on the correlation between SCZ and IBD, potentially advancing the understanding of the genetic architecture and mechanisms of co-morbidities in both diseases.

Disorders of gut-brain interaction (DGBI) are characterized by alterations in both central and peripheral gut-brain axis (GBA)-related stimuli, and include esophageal, gastroduodenal, intestinal and anorectal disorders. Despite the fact that several pathophysiologic mechanisms are involved, the mainstay of treatment is neuromodulators, a heterogeneous group of drugs that act on pathways related to central and peripheral pain processing. This expert review by both the AMG (Asociación Mexicana de Gastroenterología) and AMNM (Asociación Mexicana de Neurogastroenterología y Motilidad) summarizes a series of updated clinical recommendations based on an exhaustive review of the literature, regarding the use of neuromodulators for DGBI, and is grouped into six sections: pharmacologic principles, definition, classification, mechanism of action, indications and use in each DGBI subtype, up/downscaling strategies, combination therapy, adverse events, joint use along with psychiatry in the case of comorbidities, and non-pharmacologic neuromodulation. Furthermore, drug selection process tips and dose personalization according to individual groups and sensitivities are provided, and special cases with DGBI-psychiatric comorbidity, as well as overlap with another DGBI, are considered.

Convergent data across species paint a compelling picture of the critical role of the gut and its resident microbiota in several brain functions and disorders. The chemicals mediating communication along these sophisticated highways of the brain-gut-microbiome (BGM) axis include both microbiota metabolites and classical neurotransmitters. Amongst the latter, GABA is fundamental to brain function, mediating most neuronal inhibition. Until recently, GABA's role and specific molecular targets in the periphery within the BGM axis had received limited attention. Yet, GABA is produced by neuronal and non-neuronal elements of the BGM, and recently, GABA-modulating bacteria have been identified as key players in GABAergic gut systems, indicating that GABA-mediated signalling is likely to transcend physiological boundaries and species. We review the available evidence to better understand how GABA facilitates the integration of molecularly and functionally disparate systems to bring about overall homeostasis and how GABA perturbations within the BGM axis can give rise to multi-system medical disorders, thereby magnifying the disease burden and the challenges for patient care. Analysis of transcriptomic databases revealed significant overlaps between GABAAR subunits expressed in the human brain and gut. However, in the gut, there are notable expression profiles for a select number of subunits that have received limited attention to date but could be functionally relevant for BGM axis homeostasis. GABAergic signalling, via different receptor subtypes, directly regulates BGM homeostasis by modulating the excitability of neurons within brain centres responsible for gastrointestinal (GI) function in a sex-dependent manner, potentially revealing mechanisms underlying the greater prevalence of GI disturbances in females. Apart from such top-down regulation of the BGM axis, a diverse group of cell types, including enteric neurons, glia, enteroendocrine cells, immune cells and bacteria, integrate peripheral GABA signals to influence brain functions and potentially contribute to brain disorders. We propose several priorities for this field, including the exploitation of available technologies to functionally dissect components of these GABA pathways within the BGM, with a focus on GI and brain-behaviour-disease. Furthermore, in silico ligand-receptor docking analyses using relevant bacterial metabolomic datasets, coupled with advances in knowledge of GABAAR 3D structures, could uncover new ligands with novel therapeutic potential. Finally, targeted design of dietary interventions is imperative to advancing their therapeutic potential to support GABA homeostasis across the BGM axis.

Digestive diseases have a high incidence worldwide, with various geographic, age, and gender factors influencing the occurrence and development of the diseases. The main etiologic factors involve genetics, environment, lifestyle, and dietary habits. In a low-oxygen environment, however, the body's tissue cells activate hypoxia-inducible factor (HIF), which produces different inflammatory mediators. Hypoxia impacts health at the molecular level by modulating cellular stress responses, metabolic pathways, and immune functions. It also alters gene expression and cellular behavior, thereby affecting gastrointestinal function. Under normal physiological conditions, the gastrointestinal mucus system serves as a crucial protective barrier, defending against mechanical injury, pathogenic invasion, and exposure to harmful chemicals. The integrity and functionality of this barrier are dependent on the synthesis and regulation of mucins and mucus, which are influenced by multiple factors. Additionally, the composition and diversity of the gastric microbiota are shaped by factors such as Helicobacter pylori infection, diet, and lifestyle. A balanced gastric microbiota supports gastrointestinal health and fortifies the mucus barrier. However, hypoxia can disrupt this equilibrium, leading to inflammation, alterations in the mucus layer, and destabilization of the gastric microbiota. Understanding the interplay between hypoxia, the mucus system, and the gastric microbiota is essential for identifying novel therapeutic strategies. Future research should elucidate the mechanisms through which hypoxia influences these systems and develop interventions to mitigate its adverse effects on gastrointestinal health. We examined the impact of hypoxia on the gastrointestinal mucus system and gastric microbiota, highlighting its implications for human health and potential therapeutic approaches.

In this review we discuss mucus, the viscoelastic secretion from goblet or mucous producing cells that covers and protects all non-keratinized wet epithelial surfaces. In addition to the surface of organs directly contacting with the external environment such as the eyes, this layer provides protection to the underlying gastrointestinal, respiratory and female reproductive tracts by trapping pathogens, irritants, environmental fine particles and potentially harmful foreign substances. Mucins, the primary structural components of mucus, form structurally different mucus layers at different sites in a process regulated by a variety of factors. Currently, more and more studies have shown that the mucus barrier is not only closely related to various intestinal mucus diseases, but also involved in the occurrence and development of various airway diseases and mucus-related diseases, thus it may become a new target for the treatment of various related diseases in the future. Since the dysfunction of the mucous layer is closely related to various pathological processes, in-depth understanding of its molecular mechanism and physiological role is of great theoretical and practical significance for disease prevention and treatment. Here, we discuss different aspects of the mucus layer by focusing on its chemical composition, synthetic pathways, and some of the characteristics of the mucus layer in physiological and pathological situations.

Feeding is essential for both host-organism survival and gut-microbiota maintenance. Our research focuses on how kynurenic acid (KYNA), a gut-microbiota metabolite, regulates appetite during fasting. We find that fasting significantly raises KYNA levels in the intestine, which increases short-term food intake by inhibiting vagal afferent nerve in the nodose ganglion (NG) and activating AgRP neurons in arcuate nucleus (ARCAgRP). The orexigenic effects of KYNA are abolished by subdiaphragmatic vagotomy (sdVx), chemogenetic activation/inhibition of glutamatergic NG/ARCAgRP neurons, inhibiting the nucleus of the solitary tract (NTS) to ARCAgRP inputs, or knockdown of GPR35 (a KYNA receptor) in the intestinal vagal afferent nerve. Our data support a model in which KYNA acts through the GPR35 receptor to inhibit vagal afferent signaling and subsequently activate ARCAgRP neurons, which leads to increased food intake. These findings reveal a mechanism by which gut microbiota controls appetite during fasting, highlighting the complex relationship between microbial and host feeding behavior.

We aim to update readers on the latest evidence regarding the role of the gut microbiome in generalized anxiety disorder (GAD), panic disorder (PD), agoraphobia, and social anxiety disorder (SAD). This review summarises the literature on microbiome composition and function in these conditions, provides insights about causality and mechanisms and evaluates current evidence for microbiome-based interventions in anxiety disorders.

Most studies exploring the microbiome in anxiety disorders are small, cross-sectional studies. Nevertheless, some consistent findings emerge. Bacterial taxa such as Eubacterium, Coprococcus and Faecalibacterium may be depleted in GAD. Studies in PD and SAD are scarce and, to our knowledge, there have been no studies conducted in agoraphobia. Probiotics may help reduce anxiety symptoms, although the majority of studies have been in non-clinical cohorts. Large, prospective studies are required to further elucidate the role of the microbiome-gut-brain axis in anxiety disorders. Microbiome-based interventions hold promise, but randomised controlled trials in clinical populations with relevant diagnoses are now warranted and urgently required.

Tryptophan (Trp), an essential amino acid obtained through dietary sources, plays a crucial role in various physiological processes. The metabolism of Trp branches into three principal pathways: the serotonin pathway, the kynurenine pathway, and the indole pathway. The kynurenine and serotonin pathways are host pathways while the indole pathway is solely the result of bacterial metabolism. Trp metabolites extend their influence beyond protein biosynthesis to affect a spectrum of pathophysiological mechanisms including, but not limited to, neuronal function, immune modulation, inflammatory responses, oxidative stress regulation, and maintenance of intestinal health. This review focuses on indole derivatives and their impact on vascular health. Trp-containing dipeptides are highlighted as a targeted nutraceutical approach to modulate Trp metabolism, enhance beneficial metabolite production, and mitigate risk factors for vascular diseases. The importance of optimizing Trp intake and dietary strategies to harness the benefits of Trp-derived metabolites for vascular health is underscored, bringing to light the need for further research to refine these therapeutic approaches.

Mind-body approaches aim to improve gut symptoms and quality of life by targeting the interaction between the central nervous system and the enteric nervous system. These include treatments such as hypnotherapy, mindfulness, meditation, and yoga. Although evidence is building on efficacy of mind-body approaches, we generally lack a thorough understanding of how they work. Despite being presented as separate treatment modalities, mind-body approaches often use overlapping treatment aspects with the same mechanism of action. There is evidence that yoga, meditation, and hypnotherapy may partly draw their benefit from creating an absorbed state of attention combined with suggestions for change. This has implications for clinical application of these treatments in patients with GI disease. We propose studies on mechanisms of mind-body approaches to develop more efficacious and more precise treatments for GI diseases.

The gastrointestinal (GI) tract plays a critical role in nutrient absorption, immune responses, and overall health. Traditional models such as two-dimensional cell cultures have provided valuable insights but fail to replicate the dynamic and complex microenvironment of the human gut. Gut-on-a-chip platforms, which incorporate cells located in the gut into microfluidic devices that simulate peristaltic motion and fluid flow, represent a significant advancement in modeling GI physiology and diseases. This review discusses the evolution of gut-on-a-chip technology, from simple cellular mono-cultures models to more sophisticated systems incorporating bi-cultures and tri-cultures that enable studies of drug metabolism, disease modeling, and gut-microbiome interactions. Although challenges remain, including maintaining long-term cell viability and replicating immune responses, these platforms hold great potential for advancing personalized medicine and improving drug discovery efforts targeting gastrointestinal disorders.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD) are the major contributors to the liver disease burden globally. The rise in these conditions is linked to obesity, type 2 diabetes, metabolic syndrome and increased alcohol consumption. MASLD and ALD share risk factors, pathophysiology and histological features but differ in their thresholds for alcohol use, and the ALD definition does not require the presence of metabolic dysfunction. A recent multi-society consensus overhauled the nomenclature of liver steatosis and introduced the term MetALD to describe patients with metabolic dysfunction who drink more than those with MASLD and less than those with ALD. This new terminology aims to enhance the understanding and management of liver disease but poses challenges, such as the need to accurately measure alcohol consumption in research and clinical practice settings. Recent studies show that MetALD has significant implications for patient management, as it is associated with increased mortality risks and more severe liver outcomes compared to MASLD alone. MetALD patients face increased risks of liver disease progression, cancer and cardiovascular disease. The diagnosis of MetALD involves the adequate quantification of alcohol use through standardised questionnaires and/or biomarkers as well as proper assessment of liver disease stage and progression risk using non-invasive tools including serologic markers, imaging, elastography techniques and genetic testing. Effective management requires addressing both metabolic and alcohol-related factors to improve outcomes. This review intends to provide a comprehensive overview of MetALD, covering pathogenesis, potential diagnostic approaches, management strategies and emerging therapies.

Arecoline, the main alkaloid in areca nut, has shown potential in modulating metabolism and gut microbiota. This study aimed to evaluate its therapeutic effects on glucose and lipid metabolism, inflammation, liver function, and potential mechanisms in a Type 2 diabetes mellitus (T2DM) mouse model.

T2DM was established in mice with a high-fat, high-sugar diet, and streptozotocin injections. Arecoline significantly reduced fasting blood glucose, enhanced glucose tolerance, and increased insulin sensitivity. Serum lipid profiles showed marked decreases in total cholesterol, triglycerides, and LDL-C levels. Systemic inflammation, as measured by serum levels of IL-1β, IL-6, and MCP-1, decreased significantly. Improvements in liver function were observed, as indicated by reductions in ALT and AST levels. Liver transcriptomic analysis revealed modulation of pathways related to glutathione metabolism, MAPK signaling, and cAMP signaling, which were involved in insulin signaling and oxidative stress response. Additionally, arecoline mitigated gut dysbiosis by restoring microbial diversity, altering gut microbiota composition, and regulating key pathways involved in NAD biosynthesis and fatty acid β-oxidation, which were critical for maintaining energy homeostasis.

Arecoline improves glucose metabolism, lipid profiles, and liver function, while modulating gut microbiota and liver metabolic pathways, showing potential as a therapeutic agent for T2DM.

Dysbiosis, which refers to an imbalance in the composition of the gut microbiome, has been associated with a range of metabolic disorders, including type 2 diabetes, obesity, and metabolic syndrome. Although the exact mechanisms connecting gut dysbiosis to these conditions are not fully understood, various lines of evidence strongly suggest a substantial role for the interaction between the gut microbiome, mitochondria, and epigenetics. Current studies suggest that the gut microbiome has the potential to affect mitochondrial function and biogenesis through the production of metabolites. A well-balanced microbiota plays a pivotal role in supporting normal mitochondrial and cellular functions by providing metabolites that are essential for mitochondrial bioenergetics and signaling pathways. Conversely, in the context of illnesses, an unbalanced microbiota can impact mitochondrial function, leading to increased aerobic glycolysis, reduced oxidative phosphorylation and fatty acid oxidation, alterations in mitochondrial membrane permeability, and heightened resistance to cellular apoptosis. Mitochondrial activity can also influence the composition and function of the gut microbiota. Because of the intricate interplay between nuclear and mitochondrial communication, the nuclear epigenome can regulate mitochondrial function, and conversely, mitochondria can produce metabolic signals that initiate epigenetic changes within the nucleus. Given the epigenetic modifications triggered by metabolic signals from mitochondria in response to stress or damage, targeting an imbalanced microbiota through interventions could offer a promising strategy to alleviate the epigenetic alterations arising from disrupted mitochondrial signaling.

Microbial communities are not simply remnants of the past but dynamic entities that continuously evolve under the selective pressures of nature, reflecting the intricate and adaptive processes of evolution. The microbiota residing in the various regions of the human body has numerous roles in different physiological processes such as nutrition, metabolism, immune regulation, etc. In the zeal of achieving empirical insights into the ambit of the gut microbiome, the research over the years led to the revelation of reciprocal interaction between the gut microbiome and the cognitive functioning of the human body. Dysbiosis in the gut microbial composition disturbs the homeostatic cognitive functioning of the human body. This dysbiosis has been associated with various chronic diseases, including brain cancer, such as glioma, glioblastoma, etc. This review explores the mechanistic role of dysbiosis-mediated progression of brain cancers and their subtypes. Moreover, it demonstrates the regulatory role of microbial metabolites produced by the gut microbiota, such as short-chain fatty acids, amino acids, lipids, etc., in the tumour progression. Further, we also provide valuable insights into the microbiota mediating the efficiency of therapeutic regimens, thereby leveraging gut microbiota as potential biomarkers and targets for improved treatment outcomes.

Irritable bowel syndrome is a gastrointestinal disorder due to multiple pathologies. While patients with this condition experience anxiety and depressed mood more frequently than healthy individuals, it is unclear how gastrointestinal dysfunction interacts with such neuropsychiatric symptoms. Data suggest that irritable bowel syndrome patients predominantly display a lower zinc intake, which presumably impairs enterochromaffin cells producing 5-hydroxytryptamine, gut bacteria fermenting short-chain fatty acids, and barrier system in the intestine, with the accompanying constipation, diarrhea, low-grade mucosal inflammation, and visceral pain. Dyshomeostasis of copper and zinc concentrations as well as elevated pro-inflammatory cytokine levels in the blood can disrupt blood-cerebrospinal fluid barrier function, leading to locus coeruleus neuroinflammation and hyperactivation with resultant amygdalar overactivation and dorsolateral prefrontal cortex hypoactivation as found in neuropsychiatric disorders. The dysregulation between the dorsolateral prefrontal cortex and amygdala is likely responsible for visceral pain-related anxiety, depressed mood caused by anticipatory anxiety, and visceral pain catastrophizing due to catastrophic thinking or cognitive distortion. Collectively, these events can result in a spiral of gastrointestinal symptoms and neuropsychiatric signs, prompting the progression of irritable bowel syndrome. Given that the negative feedback mechanism in regulation of the hypothalamic-pituitary-adrenal axis is preserved in a subset of neuropsychiatric cases, dorsolateral prefrontal cortex abnormality accompanied by neuropsychiatric symptoms may be a more significant contributing factor in brain-gut axis malfunction than activation of the hypothalamic corticotropin-releasing hormone system. The proposed mechanistic model could predict novel therapeutic interventions for comorbid irritable bowel syndrome and neuropsychiatric disorders.

Considerable evidence suggests that the gut-brain axis can influence behavior. However, there has been a conspicuous lack of technology to provide targeted wireless activation of the gut-brain axis in conscious freely moving animals. We utilized a miniature fully implantable battery-free device to apply highly controlled optogenetic stimuli to the terminal region of gastrointestinal tract, in conscious freely moving mice. The optical stimulator was implanted and secured on the serosal surface of the distal colon and rectum to characterize the behavioral responses evoked by optogenetic stimulation of axons expressing channelrhodopsin (ChR2) driven by the Trpv1 promoter (Trpv1Cre+ChR2 mice). In freely moving Trpv1Cre+ChR2 mice, trains of blue light pulses to the distal colon and rectum induced increased abdominal grooming and reduced movement. In contrast to stimulation of the gut, trains of stimuli applied to the peritoneal cavity evoked writhing and abdominal contraction. Anterograde labeling from nodose ganglia revealed sparse vagal afferent axons and endings in the proximal and mid colon, with no labeled axons caudal of the mid colon (within 30 mm of the anus). The distal colon and rectum were densely innervated by spinal afferents. The findings demonstrate that wireless optogenetic stimulation of the gut-brain axis can induce specific behavioral patterns in conscious freely moving rodents, using fully implantable battery-free technology.NEW & NOTEWORTHY The findings demonstrate that distinct behavioral changes can be induced by wireless activation of the terminal region of the large intestine (distal colon and rectum) in freely moving rodents, using fully implantable battery-free devices.

With growing recognition of the pivotal role of gut microbiota in human health, probiotics have gained widespread attention for their potential to restore microbial homeostasis. However, a critical challenge persists: limited colonization efficiency among most probiotic strains compromises their therapeutic efficacy. This overview synthesizes ecological principles with cutting-edge microbiome research to elucidate the dynamic interplay between dietary components and probiotic colonization within the intestinal niche. This overview systematically analyzes: (1) stage-specific colonization mechanisms spanning microbial introduction, establishment, and proliferation; (2) nutrient-driven modulation of gut microbiota composition and function; and (3) the dual role of common dietary patterns as both facilitators and disruptors of probiotic persistence. Notably, this overview identifies key dietary strategies, including precision delivery of prebiotic fibers and polyphenol-microbiota crosstalk, that enhance niche adaptation through pH optimization, adhesion potentiation, and competitive exclusion of pathogens. Furthermore, this overview critically evaluates current limitations in probiotic research, particularly strain-specific variability and methodological constraints in simulating host-microbe-diet tripartite interactions. To bridge these gaps, this overview proposes an interdisciplinary framework integrating omics-driven strain selection, engineered delivery systems, and personalized nutrition models. Collectively, this work advances a mechanistic understanding of diet-microbiota interactions while providing actionable insights for developing targeted probiotic therapies and evidence-based dietary interventions to optimize gut ecosystem resilience.

This study evaluated the antidepressant effects of arecoline, a bioactive alkaloid derived from areca nuts, using a mouse model of depression induced by chronic unpredictable mild stress. Arecoline treatment significantly alleviated depression-like behaviors, including anxiety, anhedonia, and despair, as evidenced by behavioral tests. Mechanistically, arecoline restored serotonin and norepinephrine levels in the brain and serum, reduced pro-inflammatory markers such as IL-1β and LPS in both serum and colon, and enhanced hippocampal neuroplasticity through increased BDNF and PSD-95 expression. Moreover, arecoline modulated gut microbiota composition, particularly enriching beneficial species like Bifidobacterium pseudolongum and Ligilactobacillus murinus, and regulated serum metabolites associated with tryptophan metabolism, neurotransmitter synthesis, and oxidative stress. These findings demonstrate that arecoline exerts its antidepressant effects via a multitargeted approach involving the gut-brain axis, neurotransmitter modulation, and neuroplasticity enhancement. This study highlights arecoline as a promising therapeutic candidate for depression, emphasizing its potential to address both central and peripheral mechanisms.

Disruptions in the gut microbiota metabolism may contribute to the pathophysiology of gut-brain interaction disorders, and correction of intestinal dysbiosis is considered a promising therapeutic approach. Menthacarin, a proprietary fixed combination of Mentha x piperita L. and Carum carvi L. essential oils, is used clinically for the treatment of functional dyspepsia and irritable bowel syndrome. Rodent model data indicate that treatment effects of Menthacarin on visceral hypersensitivity could be mediated via the normalization of gut dysbiosis. However, the impact of Menthacarin on human bacterial gut microbiota has not yet been studied.

The aim of the present study was to assess whether Menthacarin affects the composition and metabolic activity of human fecal microbiota.

Fecal slurry samples from 10 healthy volunteers were cultivated for 36 h under anoxic conditions with and without Menthacarin. Relative bacterial abundance at the phylum and genus levels was evaluated using 16S rRNA metagenomic analysis. Short-chain fatty acids (SCFAs) in the supernatants were measured using the LC-MS technology.

Menthacarin induced robust changes in microbial composition at both the phylum and genus levels among the 10 donor microbiomes. The relative abundance of Firmicutes (+13.6 ± 8.6%) and Actinobacteria (+54.9 ± 47.6%) significantly increased, whereas that of Bacteroidetes (-27.7% ± 21.9%) and Proteobacteria (-25.7% ± 12.3%) significantly decreased in the presence of Menthacarin. At the genus level, the most notable changes were significant increases in Bifidobacterium (+105.1 ± 78.4%) and several SCFA-producing genera accompanied by a significant decrease in genera containing members involved in pro-inflammatory processes. In addition, Menthacarin significantly increased the levels of several SCFAs, namely, propionate, butyrate, isobutyrate, valerate, and isovalerate.

Menthacarin alters the microbiota composition and enhances SCFA production in human microbiota samples under in vitro conditions. These effects may contribute to the clinical benefits observed with Menthacarin treatment.

SUMMARYRecent advances in therapeutic probiotics have shown promising results across various health conditions, reflecting a growing understanding of the human microbiome's role in health and disease. However, comprehensive reviews integrating the diverse therapeutic effects of probiotics in human subjects have been limited. By analyzing randomized controlled trials (RCTs) and meta-analyses, this review provides a comprehensive overview of key developments in probiotic interventions targeting gut, liver, skin, vaginal, mental, and oral health. Emerging evidence supports the efficacy of specific probiotic strains and combinations in treating a wide range of disorders, from gastrointestinal (GI) and liver diseases to dermatological conditions, bacterial vaginosis, mental disorders, and oral diseases. We discuss the expanding understanding of microbiome-organ connections underlying probiotic mechanisms of action. While many clinical trials demonstrate significant benefits, we acknowledge areas requiring further large-scale studies to establish definitive efficacy and optimal treatment protocols. The review addresses challenges in standardizing probiotic research methodologies and emphasizes the importance of considering individual variations in microbiome composition and host genetics. Additionally, we explore emerging concepts such as the oral-gut-brain axis and future directions, including high-resolution microbiome profiling, host-microbe interaction studies, organoid models, and artificial intelligence applications in probiotic research. Overall, this review offers a comprehensive update on the current state of therapeutic probiotics across multiple domains of human health, providing insights into future directions and the potential for probiotics to revolutionize preventive and therapeutic medicine.