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Colon impairments and inflammation driven by an altered gut microbiota leads to social behavior deficits rescued by hyaluronic acid and celecoxib.
BACKGROUND: The exact mechanisms linking the gut microbiota and social behavior are still under investigation. We aimed to explore the role of the gut microbiota in shaping social behavior deficits using selectively bred mice possessing dominant (Dom) or submissive (Sub) behavior features. Sub mice exhibit asocial, depressive- and anxiety-like behaviors, as well as systemic inflammation, all of which are shaped by their impaired gut microbiota composition. METHODS: An age-dependent comparative analysis of the gut microbiota composition of Dom and Sub mice was performed using 16S rRNA sequencing, from early infancy to adulthood. Dom and Sub gastrointestinal (GI) tract anatomy, function, and immune profiling analyses were performed using histology, RT-PCR, flow cytometry, cytokine array, and dextran-FITC permeability assays. Short chain fatty acids (SCFA) levels in the colons of Dom and Sub mice were quantified using targeted metabolomics. To support our findings, adult Sub mice were orally treated with hyaluronic acid (HA) (30 mg/kg) or with the non-steroidal anti-inflammatory agent celecoxib (16 mg/kg). RESULTS: We demonstrate that from early infancy the Sub mouse gut microbiota lacks essential bacteria for immune maturation, including Lactobacillus and Bifidobacterium genera. Furthermore, from birth, Sub mice possess a thicker colon mucin layer, and from early adulthood, they exhibit shorter colonic length, altered colon integrity with increased gut permeability, reduced SCFA levels and decreased regulatory T-cells, compared to Dom mice. Therapeutic intervention in adult Sub mice treated with HA, celecoxib, or both agents, rescued Sub mice phenotypes. HA treatment reduced Sub mouse gut permeability, increased colon length, and improved mouse social behavior deficits. Treatment with celecoxib increased sociability, reduced depressive- and anxiety-like behaviors, and increased colon length, and a combined treatment resulted in similar effects as celecoxib administered as a single agent. CONCLUSIONS: Overall, our data suggest that treating colon inflammation and decreasing gut permeability can restore gut physiology and prevent social deficits later in life. These findings provide critical insights into the importance of early life gut microbiota in shaping gut immunity, functionality, and social behavior, and may be beneficial for the development of future therapeutic strategies.
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[The abdominal brain: neuroanatomic perspectives for the abdominal surgeon].
The "abdominal brain" does not only consist of a separate enteric nervous system but also of bidirectional connections to the autonomous nerve system with parasympathicus und sympathicus as well as brain and spinal cord. Novel studies have shown that these connections can quickly transfer information on the ingested nutrients to the brain to conduct the feeling of hunger and more complex behaviour, such as "reward-related learning". However, even emotional experience, in particular, stress, has a strong impact onto the gastrointestinal system. The immune system, motility and barrier function of the gastrointestinal tract are modulated by the intestinal microbiota. Local bacteria may directly influence neuronal communication by released metabolic products and neuropeptides as well as may control inflammatory factors. Intensive research over the last 10 years was able to provide evidence that intestinal microbiota may affect emotional and cognitive aspects of our behaviour and, thus, it might be in the focus of numerous neuropsychiatric diseases, such as depressions and anxiety disorders.The presented review is to provide a short summary of the I): anatomic basics of the so-called gut-brain axis and II): modi of the bidirectional regulation. Through indirect connections to the limbic system, gut-brain axis can substantially influence stress and anxiety but also the pain processing. In addition, the role of microbiota is outlined and future paths are shown, e.g., how the (microbiota-)gut-brain axis may alter emotional experience, pain processing and intestinal function. Such associations are relevant for further development of visceral medicine, and, thus, also for the abdominal surgeon to derive future treatment concepts with interdisciplinary orientation.
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Gut feeling: Exploring the intertwined trilateral nexus of gut microbiota, sex hormones, and mental health.
The complex interplay between the gut microbiota, sex hormones, and mental health is emerging as a pivotal factor in understanding and managing psychiatric disorders. Beyond their traditional roles, sex hormones exert profound effects on various physiological systems including the gut microbiota. Fluctuations in sex hormone levels, notably during the menstrual cycle, influence gut physiology and barrier function, shaping gut microbiota composition and immune responses. Conversely, the gut microbiota actively modulates sex hormone levels via enzymatic processes. This bidirectional relationship underscores the significance of the gut-brain axis in maintaining mental well-being. This review explores the multifaceted interactions between sex hormones, the gut microbiota, and mental health outcomes. We highlight the potential of personalized interventions in treating psychiatric disorders, particularly in vulnerable populations such as premenopausal women and individuals with depressive disorders. By elucidating these complex interactions, we aim to provide insights for future research into targeted interventions, enhancing mental health outcomes.
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The Relationship Between Perinatal Mental Health and Stress: a Review of the Microbiome.
PURPOSE OF REVIEW: Our current understanding of the underlying mechanisms and etiologies of perinatal mood and anxiety disorders (PMADs) is not clearly identified. The relationship of stress-induced adaptations (i.e., the hypothalamic-pituitary-adrenal (HPA) axis, the autonomic nervous system (ANS), the immune system) and the microbiota are potential contributors to psychopathology exhibited in women during pregnancy and postpartum and should be investigated. RECENT FINDINGS: The stress response activates the HPA axis and dysregulates the ANS, leading to the inhibition of the parasympathetic system. Sustained high levels of cortisol, reduced heart variability, and modulated immune responses increase the vulnerability to PMAD. Bidirectional communication between the nervous system and the microbiota is an important factor to alter host homeostasis and development of PMAD. Future research in the relationship between the psychoneuroimmune system, the gut microbiota, and PMAD has the potential to be integrated in clinical practice to improve screening, diagnosis, and treatment.
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Multimodal (Bio)Markers and Risk of Obesity - A Comprehensive Scoping Review.
Obesity has been associated with several chronic diseases, especially noncommunicable ones and related comorbidities. Despite international efforts to decrease the prevalence of obesity, the number of persons struggling with this ailment is not decreasing. An important aspect is obesity prevention, including the early detection of the risk, i.e. whether an individual is likely to develop obesity, to allow for early risk stratification and countermeasure initiation. However, obesity is a complex and multifactorial complication, and many factors appear to play a role, including age, sex, diet, physical activity (PA), psychological and emotional status, genetic make-up, epigenetics, and gut microbiota. One isolated biomarker, therefore, could not enable optimal risk stratification and prognosis for the individual; rather, a combined set or multimodal approach to tackle risk prediction is demanded. Such a multimodal interpretation would integrate biomarkers from various domains, such as more classical markers (insulin, leptin), multiomics (e.g. genetics, epigenomics, transcriptomics, proteomics, and metabolomics), behavioral attributes (dietary, PA, and sleep patterns, and smoking status), psychological traits (mental health status, depression, and eating disorders), and gut-microbiota (composition and diversity) into a combined interpretation, also employing more advanced interpretation tools, such as machine learning and artificial intelligence. In this scoping review, we aimed to summarize the current state of the art in this area, highlighting the progress and novel approaches in combating obesity, and focusing on the feasibility and effectiveness of such biomarkers and their application within clinical trials. In addition, we outline potential future steps and recommendations for future approaches.
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Bioengineered gut bacterium synthesizing levodopa alleviates motor deficits in models of Parkinson's disease.
L-3,4-Dihydroxyphenylalanine (L-DOPA), synthesized from L-tyrosine, is a direct precursor to dopamine. L-DOPA is the gold-standard treatment for Parkinson's disease (PD), given orally alongside decarboxylase inhibitors (e.g., benserazide) to enhance bioavailability. However, its chronic daily pulsatile-like delivery is associated with complications. Herein, we show the construction and in vivo efficacy of a programmable, titratable, genetically engineered E. coli Nissle 1917 system (EcNL-DOPA) that continuously synthesizes L-DOPA from L-tyrosine for systemic distribution. Oral administration of EcNL-DOPA with benserazide maintains therapeutic plasma L-DOPA concentrations and increases brain dopamine levels. EcNL-DOPA improves motor performance and limits depressive-like behaviors without adverse side effects in healthy mice, Parkinsonian mice, and canine models. Simulated physiological models from pharmacokinetic and pharmacodynamic studies in canines demonstrate the translational feasibility of this biotherapeutic system for potential human studies. This work lays the groundwork for EcNL-DOPA as a continuous, non-invasive microbial drug delivery platform for PD and chronic neurological diseases.
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Melatonin Ameliorates Neuropsychiatric Behaviors, Gut Microbiome, and Microbiota-Derived Metabolites in Rats with Chronic Sleep Deprivation.
With the increasing prevalence of sleep deprivation (SD)-related disorders, the effective treatment of sleep disorders has become a critical health research topic. Thus, we hypothesized and investigated the effectiveness of a 3-week melatonin intervention on neuropsychiatric behavioral responses mediated throughout melatonin receptors, gut microbiota, and lipid metabolites in rats with chronic SD. Eighteen 6-week-old Wistar rats were used and divided into the control grup (C, n = 6), SD group (n = 6), and melatonin-supplemented group (SDM, n = 6). During weeks 0 to 6, animals were provided with the AIN-93M diet and free access to water. Four-week chronic SD was conducted from weeks 7 to 10. Exogenous melatonin administration (10 mg/kg BW) was injected intraperitoneally 1 h before the daily administration of SD for 3 weeks in the SDM group. SD rats exhibited anxiety-like behavior, depression-like behavior, and cognitive impairment. Exogenous melatonin administration ameliorated neuropsychiatric behaviors induced by chronic SD. Analysis of fecal metabolites indicated that melatonin may influence brain messaging through the microbiota-gut-brain axis by increasing the production of short-chain fatty acids (SCFA) and decreasing the production of secondary bile acids (SBA). Four-week SD reduced the cerebral cortex expression of MT1, but not in the colon. Chronic SD led to anxiety and depression-like behaviors and cognitive decline, as well as the reduced intestinal level of SCFAs and the enhanced intestinal level of SBAs in rats. In this work, we confirmed our hypothesis that a 3-week melatonin intervention on neuropsychiatric behavioral response mediated throughout melatonin receptors, gut microbiota, and lipid metabolites in rats with chronic SD.
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The Intestinal Microbiota in the Irritable Bowel Syndrome.
The irritable bowel syndrome (IBS) is a chronic abdominal symptom complex occurring in a bowel devoid of discernible relevant pathology. There is growing interest in the role of the intestinal microbiota as a basis for the intestinal and possibly behavioral manifestations of this condition. Molecular-based microbial profiling has revealed compositional changes in the microbiota of at least a subset of IBS patients but the data are often conflicting and no microbial signature for this condition has yet been defined. Animal studies in which a previously stable intestinal microbiota is perturbed, by antibiotics or dietary change, results in alterations in intestinal function reminiscent of that seen in IBS patients. These include visceral sensitivity to painful stimuli, altered motility and intestinal barrier function as well as immune activation, and low-grade inflammation. More recent studies have shown that perturbation of the microbial composition of the gut alters brain chemistry and behavior. In a step toward establishing a causal link between an altar microbiota and gut-brain manifestations of IBS, colonization of germ-free mice with microbiota from IBS patients results in an IBS-like phenotype, including alterations and behavior if the donor exhibited psychiatric comorbidity, such as high levels of anxiety. This model provides an opportunity for exploring the mechanisms underlying host-microbe interactions relevant to the pathogenesis of IBS and for developing novel therapeutic targets.
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Prucalopride, a serotonin type 4 receptor agonist, induces fast anxiolytic/antidepressant effects and concomitant changes in the gut microbiota.
Major Depressive Disorder (MDD) affects around 20% of people globally and is often comorbid with anxiety. This study investigates prucalopride, a serotonin type 4 receptor (5-HT4R) agonist approved for constipation, as a fast-acting anxiolytic/antidepressant using a mouse model of stress, based on corticosterone (CORT) administration. Behavioral effects of prucalopride (0.5 and 1.5 mg/kg/day) were compared to fluoxetine, a common SSRI, over 7 (subchronic) and 28 (chronic) days. Prucalopride showed faster and more significant improvements in emotionality scores than fluoxetine, reversing CORT-induced behavioral changes within 7 days. Gut microbiota analysis revealed CORT-induced changes at the subchronic timepoint. While chronic prucalopride did not alter microbial alpha diversity, it significantly shifted microbial composition (beta-diversity). Notably, prucalopride restored levels of the genus Ruminococcus, which were depleted by CORT. Our findings highlight prucalopride's rapid anxiolytic and antidepressant-like effects and its impact on gut microbiota, supporting the potential of 5-HT4R-targeting molecules as therapeutic options for psychiatric disorders.
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Enteric nervous system and intestinal epithelial regulation of the gut-brain axis.
The gut-brain axis describes a bidirectional interplay within the enteric environment between the intestinal epithelium, the mucosal immune system, and the microbiota with the enteric nervous system. This interplay provides a link between exogenous environmental stimuli such as nutrient sensing, and nervous system function, as well as a mechanism of feedback from cortical and sensory centers of the brain to enteric activities. The intestinal epithelium is one of the human body's largest sources of hormones and neurotransmitters, which have critical effects on neuronal function. The influence of the gut microbiota on these processes appears to be profound; yet to date, it has been insufficiently explored. Disruption of the intestinal microbiota is linked not only to diseases in the gut but also to brain symptomatology, including neurodegenerative and behavioral disorders (Parkinson disease, Alzheimer disease, autism, and anxiety and/or depression). In this review we discuss the cellular wiring of the gut-brain axis, with a particular focus on the epithelial and neuronal interaction, the evidence that has led to our current understanding of the intestinal role in neurologic function, and future directions of research to unravel this important interaction in both health and allergic disease.