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The role of the gut–microbiota–brain axis via the subdiaphragmatic vagus nerve in chronic inflammatory pain and comorbid spatial working memory impairment in complete Freund's adjuvant mice
... It is a primary channel through which the gut microbiota exerts its influence on the CNS Yang et al., 2023). Notably, SDV can effectively disrupt the impact of gut microbes on the CNS and cognitive functions Yue et al., 2023). These findings highlight the significant function of VN fibers in facilitating communication between the gut microbiota and the brain (Margolis et al., 2021). ...
Transcutaneous vagus nerve stimulation (tVNS) is an emerging non-invasive technique designed to stimulate branches of the vagus nerve distributed over the body surface. Studies suggest a correlation between the brain-gut-microbiota (BGM) axis and the pathogenesis of Alzheimer’s disease (AD). The BGM axis represents a complex bidirectional communication system, with the vagus nerve being a crucial component. Therefore, non-invasive electrical stimulation of the vagus nerve might have the potential to modify—most of the time probably in a non-physiological way—the signal transmission within the BGM axis, potentially influencing the progression or symptoms of AD. This review explores the interaction between percutaneous vagus nerve stimulation and the BGM axis, emphasizing its potential effects on AD. It examines various aspects, such as specific brain regions, gut microbiota composition, maintenance of intestinal environmental homeostasis, inflammatory responses, brain plasticity, and hypothalamic–pituitary–adrenal (HPA) axis regulation. The review suggests that tVNS could serve as an effective strategy to modulate the BGM axis and potentially intervene in the progression or treatment of Alzheimer’s disease in the future.
Cognitive impairment is a common comorbidity of chronic pain, significantly disrupting patients’ quality of life. Despite this comorbidity being clinically recognized, the underlying neuropathological mechanisms remain unclear. Recent preclinical studies have focused on the fundamental mechanisms underlying the coexistence of chronic pain and cognitive decline. Pain chronification is accompanied by structural and functional changes in the neural substrate of cognition. Based on the developments in electrophysiology and optogenetics/chemogenetics, we summarized the relevant neural circuits involved in pain-induced cognitive impairment, as well as changes in connectivity and function in brain regions. We then present the cellular and molecular alternations related to pain-induced cognitive impairment in preclinical studies, mainly including modifications in neuronal excitability and structure, synaptic plasticity, glial cells and cytokines, neurotransmitters and other neurochemicals, and the gut-brain axis. Finally, we also discussed the potential treatment strategies and future research directions.
Background
Patients with chronic pain frequently suffer from anxiety symptoms. It has been well established that gut microbiota is associated with the pathogenesis of pain and anxiety. However, it is unknown whether the gut microbiota, particularly the specific bacteria, play a role in the comorbidity of chronic pain and anxiety.Methods
Chronic inflammatory pain was induced in mice by a single injection of complete Freund’s adjuvant (CFA). Mice were then separated into anxiety-susceptible and anxiety-resilient phenotypes by hierarchical clustering analysis of behaviors. Fecal samples were collected to perform 16S rRNA gene sequencing. Chronic diazepam intervention served as a therapeutic strategy and its effect on the composition of gut microbiota was also determined.Resultsα-Diversity and β-diversity both showed significant differences among the groups. A total of 12 gut bacteria were both altered after CFA injection and reversed by chronic diazepam treatment. More importantly, the pain hypersensitivity and anxiety-like behaviors were relieved by chronic diazepam treatment. Interestingly, we also found that Desulfovibrio was increased in anxiety-resilient group compared to control and anxiety-susceptible groups.Conclusion
Abnormal composition of gut microbiota plays an essential role in chronic pain as well as in anxiety. Besides, the increased level of Desulfovibrio in anxiety-resilient mice indicated its therapeutic effects on the comorbidity of pain and anxiety. Collectively, targeting gut microbiota, especially increasing the Desulfovibrio level, might be effective in the alleviation of chronic pain-anxiety comorbidity.
Chronic inflammatory pain is manifested in many diseases. The potential use of molecular hydrogen (H2) as a new therapy for neurological disorders has been demonstrated. Recent studies prove its analgesic properties in animals with neuropathic pain, but the possible antinociceptive, antidepressant, and/or anxiolytic actions of H2 during persistent inflammatory pain have not been investigated. Therefore, using male mice with chronic inflammatory pain incited by the subplantar injection of complete Freud’s adjuvant (CFA), we assessed the actions of hydrogen-rich water (HRW) systemically administered on: (1) the nociceptive responses and affective disorders associated and (2) the oxidative (4-hydroxy-2-nonenal; 4-HNE), inflammatory (phosphorylated-NF-kB inhibitor alpha; p-IKBα), and apoptotic (Bcl-2-like protein 4; BAX) changes provoked by CFA in the paws and amygdala. The role of the antioxidant system in the analgesia induced by HRW systemically and locally administered was also determined. Our results revealed that the intraperitoneal administration of HRW, besides reducing inflammatory pain, also inhibited the depressive- and anxiolytic-like behaviors associated and the over expression of 4-HNE, p-IKBα, and BAX in paws and amygdala. The contribution of the nuclear factor erythroid 2-related factor 2/heme oxygenase 1 and NAD(P)H: quinone oxidoreductase 1 pathway in the analgesic activities of HRW, systemically or locally administered, was also shown. These data revealed the analgesic, antidepressant, and anxiolytic actions of HRW. The protective, anti-inflammatory, and antioxidant qualities of this treatment during inflammatory pain were also demonstrated. Therefore, this study proposes the usage of HRW as a potential therapy for chronic inflammatory pain and linked comorbidities.
The neuroimmune mechanism underlying neuropathic pain has been extensively studied. Tumor necrosis factor-alpha (TNF-α), a key pro-inflammatory cytokine that drives cytokine storm and stimulates a cascade of other cytokines in pain-related pathways, induces and modulates neuropathic pain by facilitating peripheral (primary afferents) and central (spinal cord) sensitization. Functionally, TNF-α controls the balance between cell survival and death by inducing an inflammatory response and two programmed cell death mechanisms (apoptosis and necroptosis). Necroptosis, a novel form of programmed cell death, is receiving increasing attraction and may trigger neuroinflammation to promote neuropathic pain. Chronic pain is often accompanied by adverse pain-associated emotional reactions and cognitive disorders. Overproduction of TNF-α in supraspinal structures such as the anterior cingulate cortex (ACC) and hippocampus plays an important role in pain-associated emotional disorders and memory deficits and also participates in the modulation of pain transduction. At present, studies reporting on the role of the TNF-α–necroptosis pathway in pain-related disorders are lacking. This review indicates the important research prospects of this pathway in pain modulation based on its role in anxiety, depression and memory deficits associated with other neurodegenerative diseases. In addition, we have summarized studies related to the underlying mechanisms of neuropathic pain mediated by TNF-α and discussed the role of the TNF-α–necroptosis pathway in detail, which may represent an avenue for future therapeutic intervention.
The regenerative potential of mammalian peripheral nervous system neurons after injury is critically limited by their slow axonal regenerative rate¹. Regenerative ability is influenced by both injury-dependent and injury-independent mechanisms². Among the latter, environmental factors such as exercise and environmental enrichment have been shown to affect signalling pathways that promote axonal regeneration³. Several of these pathways, including modifications in gene transcription and protein synthesis, mitochondrial metabolism and the release of neurotrophins, can be activated by intermittent fasting (IF)4,5. However, whether IF influences the axonal regenerative ability remains to be investigated. Here we show that IF promotes axonal regeneration after sciatic nerve crush in mice through an unexpected mechanism that relies on the gram-positive gut microbiome and an increase in the gut bacteria-derived metabolite indole-3-propionic acid (IPA) in the serum. IPA production by Clostridium sporogenes is required for efficient axonal regeneration, and delivery of IPA after sciatic injury significantly enhances axonal regeneration, accelerating the recovery of sensory function. Mechanistically, RNA sequencing analysis from sciatic dorsal root ganglia suggested a role for neutrophil chemotaxis in the IPA-dependent regenerative phenotype, which was confirmed by inhibition of neutrophil chemotaxis. Our results demonstrate the ability of a microbiome-derived metabolite, such as IPA, to facilitate regeneration and functional recovery of sensory axons through an immune-mediated mechanism.
The intestinal flora plays an important role in the development of many human and animal diseases. Microbiome association studies revealed the potential regulatory function of intestinal bacteria in many liver diseases, such as autoimmune hepatitis, viral hepatitis and alcoholic hepatitis. However, the key intestinal bacterial strains that affect pathological liver injury and the underlying functional mechanisms remain unclear. We found that the gut microbiota from gentamycin (Gen)-treated mice significantly alleviated concanavalin A (ConA)-induced liver injury compared to vancomycin (Van)-treated mice by inhibiting CD95 expression on the surface of hepatocytes and reducing CD95/CD95L-mediated hepatocyte apoptosis. Through the combination of microbiota sequencing and correlation analysis, we isolated 5 strains with the highest relative abundance, Bacteroides acidifaciens (BA), Parabacteroides distasonis (PD), Bacteroides thetaiotaomicron (BT), Bacteroides dorei (BD) and Bacteroides uniformis (BU), from the feces of Gen-treated mice. Only BA played a protective role against ConA-induced liver injury. Further studies demonstrated that BA-reconstituted mice had reduced CD95/CD95L signaling, which was required for the decrease in the L-glutathione/glutathione (GSSG/GSH) ratio observed in the liver. BA-reconstituted mice were also more resistant to alcoholic liver injury. Our work showed that a specific murine intestinal bacterial strain, BA, ameliorated liver injury by reducing hepatocyte apoptosis in a CD95-dependent manner. Determination of the function of BA may provide an opportunity for its future use as a treatment for liver disease.
The persistence of negative affect in pain leads to co-morbid symptoms such as anhedonia and depression—major health issues in the United States. The neuronal circuitry and contribution of specific cellular populations underlying these behavioral adaptations remains unknown. A common characteristic of negative affect is a decrease in motivation to initiate and complete goal-directed behavior, known as anhedonia. We report that in rodents, inflammatory pain decreased the activity of ventral tegmental area (VTA) dopamine (DA) neurons, which are critical mediators of motivational states. Pain increased rostromedial tegmental nucleus inhibitory tone onto VTA DA neurons, making them less excitable. Furthermore, the decreased activity of DA neurons was associated with reduced motivation for natural rewards, consistent with anhedonia-like behavior. Selective activation of VTA DA neurons was sufficient to restore baseline motivation and hedonic responses to natural rewards. These findings reveal pain-induced adaptations within VTA DA neurons that underlie anhedonia-like behavior.
In recent years, studies investigating the role of the gut microbiota in health and diseases have increased enormously – making it essential to deepen and question the research methodology employed. Fecal microbiota transplantation (FMT) in rodent studies (either from human or animal donors) allows us to better understand the causal role of the intestinal microbiota across multiple fields. However, this technique lacks standardization and requires careful experimental design in order to obtain optimal results. By comparing several studies in which rodents are the final recipients of FMT, we summarize the common practices employed. In this review, we document the limitations of this method and highlight different parameters to be considered while designing FMT Studies. Standardizing this method is challenging, as it differs according to the research topic, but avoiding common pitfalls is feasible. Several methodological questions remain unanswered to this day and we offer a discussion on issues to be explored in future studies.
Social interactions among animals mediate essential behaviours, including mating, nurturing, and defence1,2. The gut microbiota contribute to social activity in mice3,4, but the gut–brain connections that regulate this complex behaviour and its underlying neural basis are unclear5,6. Here we show that the microbiome modulates neuronal activity in specific brain regions of male mice to regulate canonical stress responses and social behaviours. Social deviation in germ-free and antibiotic-treated mice is associated with elevated levels of the stress hormone corticosterone, which is primarily produced by activation of the hypothalamus–pituitary–adrenal (HPA) axis. Adrenalectomy, antagonism of glucocorticoid receptors, or pharmacological inhibition of corticosterone synthesis effectively corrects social deficits following microbiome depletion. Genetic ablation of glucocorticoid receptors in specific brain regions or chemogenetic inactivation of neurons in the paraventricular nucleus of the hypothalamus that produce corticotrophin-releasing hormone (CRH) reverse social impairments in antibiotic-treated mice. Conversely, specific activation of CRH-expressing neurons in the paraventricular nucleus induces social deficits in mice with a normal microbiome. Via microbiome profiling and in vivo selection, we identify a bacterial species, Enterococcus faecalis, that promotes social activity and reduces corticosterone levels in mice following social stress. These studies suggest that specific gut bacteria can restrain the activation of the HPA axis, and show that the microbiome can affect social behaviours through discrete neuronal circuits that mediate stress responses in the brain.
Chronic stress manifests as depressive- and anxiety-like behavior while recurrent stress elicits disproportionate behavioral impairments linked to stress-induced immunological priming. The gut-brain-microbiota-axis is a promising therapeutic target for stress-induced behavioral impairments as it simultaneously modulates peripheral and brain immunological landscapes. In this study, a combination of probiotics and prebiotics, known as a synbiotic, promoted behavioral resilience to chronic and recurrent stress by normalizing gut microbiota populations and promoting regulatory T cell (Treg) expansion through modulation of ileal innate lymphoid cell (ILC)3 activity, an impact reflecting behavioral responses better than limbic brain region neuroinflammation. Supporting this conclusion, a multivariate machine learning model correlatively predicted a cross-tissue immunological signature of stress-induced behavioral impairment where the ileal Treg/T helper17 cell ratio associated to hippocampal chemotactic chemokine and prefrontal cortex IL-1β production in the context of stress-induced behavioral deficits. In conclusion, stress-induced behavioral impairments depend on the gut-brain-microbiota-axis and through ileal immune regulation, synbiotics attenuate the associated depressive- and anxiety-like behavior.
Osteoarthritis (OA) is a leading cause of disability among older adults worldwide. Treatment aims are to alleviate inflammatory pain and improve physical function through non-pharmacological and pharmacological interventions. Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended as first-line therapy. However, selection is challenged by patient age, comorbidities and polypharmacy, and by the drug’s benefit/risk balance, all of which together influence the risk of cardiovascular (CV), gastrointestinal (GI) and renal adverse events (AEs). While the efficacy profile of the various NSAIDs is delineated, the differences in their safety profile are not straightforward. This narrative review provides practical indications by a multidisciplinary Italian expert panel for general practitioners and specialists managing OA patients with chronic inflammatory pain; the goal is to maximize therapy efficacy while reducing untoward effects caused by inappropriate NSAID use. The discussion on the best approach to NSAIDs spanned the following topics: (1) patient evaluation: investigate pain origin, duration and components together with possible risk factors for CV, GI and renal AEs; (2) non-pharmacological interventions: the physiatrist provides a person-centered, holistic approach accounting for all patient aspects; (3) pharmacological interventions: patient profile and drugs’ pharmacological properties affect NSAID selection, which drugs to be used in combination or to be avoided, formulation and therapy duration; (4) the pharmacologist’s, general practitioner’s and pain therapist’s points of view; (5) NSAID safety: the individual baseline risk and the drug’s safety profile are major determinants of CV, GI and renal risk; consider possible drug–drug interactions; (6) periodical re-evaluation of treatment response and adherence, using scales to assess pain and function.
Traumatic brain injury (TBI) is the largest non-genetic, non-aging related risk factor for Alzheimer’s disease (AD). We report here that TBI induces tau acetylation (ac-tau) at sites acetylated also in human AD brain. This is mediated by S-nitrosylated-GAPDH, which simultaneously inactivates Sirtuin1 deacetylase and activates p300/CBP acetyltransferase, increasing neuronal ac-tau. Subsequent tau mislocalization causes neurodegeneration and neurobehavioral impairment, and ac-tau accumulates in the blood. Blocking GAPDH S-nitrosylation, inhibiting p300/CBP, or stimulating Sirtuin1 all protect mice from neurodegeneration, neurobehavioral impairment, and blood and brain accumulation of ac-tau after TBI. Ac-tau is thus a therapeutic target and potential blood biomarker of TBI that may represent pathologic convergence between TBI and AD. Increased ac-tau in human AD brain is further augmented in AD patients with history of TBI, and patients receiving the p300/CBP inhibitors salsalate or diflunisal exhibit decreased incidence of AD and clinically diagnosed TBI.
Pain is the most common symptom reported by patients with rheumatoid arthritis (RA) even after the resolution of chronic joint inflammation. It is believed that RA-associated pain is not solely due to inflammation, but could also be attributed to aberrant modifications to the central nervous system. The P2X4 receptor (P2X4R) is an ATP-activated purinergic receptor that plays a significant role in the transmission of information in the nervous system and pain. The involvement of P2X4R during the pathogenesis of chronic inflammatory pain and neuropathic pain is well-established. The attenuation of this receptor alleviates disease pathogenesis and related symptoms, including hyperalgesia and allodynia. Although some studies have revealed the contribution of P2X4R in promoting joint inflammation in RA, how it implicates pain associated with RA at peripheral and central nervous systems is still lacking. In this review, the possible contributions of P2X4R in the nervous system and how it implicates pain transmission and responses were examined.
The functional diversity of the mammalian intestinal microbiome far exceeds that of the host organism, and microbial genes contribute substantially to the well-being of the host. However, beneficial gut organisms can also be pathogenic when present in the gut or other locations in the body. Among dominant beneficial bacteria are several species of Bacteroides, which metabolize polysaccharides and oligosaccharides, providing nutrition and vitamins to the host and other intestinal microbial residents. These topics and the specific organismal and molecular interactions that are known to be responsible for the beneficial and detrimental effects of Bacteroides species in humans comprise the focus of this review. The complexity of these interactions will be revealed.
Chronic neuropathic pain is frequently accompanied by memory impairment, yet the underlying mechanisms remain unclear. Here we showed that mice displayed memory impairment starting at 14 days and lasting for at least 21 days after chronic constriction injury (CCI) of unilateral sciatic nerve in mice. Systemic administration of the pan histone deacetylase (HDAC) inhibitor sodium butyrate attenuated this memory impairment. More specifically, we found that hippocampus HDAC3 was involved in this process because the levels of its mRNA and protein increased significantly in the hippocampus at 14 and 21 days after CCI, but not sham surgery. Systemic administration of the selective HDAC3 antagonist RGPF966 attenuated CCI-induced memory impairment, improved hippocampal long-term potentiation impairment and rescued reductions of dendritic spine density and synaptic plasticity-associated protein in the hippocampus. Additionally, HDAC3 overexpression in the hippocampus led to memory impairment without affecting basal nociceptive responses in naive mice. Our findings suggest that HDAC3 contributes to memory impairment after CCI by impairing synaptic plasticity in hippocampus. HDAC3 might serve as a potential molecular target for therapeutic treatment of memory impairment under neuropathic pain conditions.
Abstract Neuropathic pain (NP) is a sustained and nonreversible condition characterized by long-term devastating physical and psychological damage. Therefore, it is urgent to identify an effective treatment for NP. Unfortunately, the precise pathogenesis of NP has not been elucidated. Currently, the microbiota-gut-brain axis has drawn increasing attention, and the emerging role of gut microbiota is investigated in numerous diseases including NP. Gut microbiota is considered as a pivotal regulator in immune, neural, endocrine, and metabolic signaling pathways, which participates in forming a complex network to affect the development of NP directly or indirectly. In this review, we conclude the current understanding of preclinical and clinical findings regarding the role of gut microbiota in NP and provide a novel therapeutic method for pain relief by medication and dietary interventions.
Background
The brain–gut–microbiota axis plays a role in the pathogenesis of stress-related disorders such as depression. In this study, we examined the effects of fecal microbiota transplantation (FMT) in mice with antibiotic-treated microbiota depletion.
Methods
The fecal microbiota was obtained from mice subjected to chronic social defeat stress (CSDS) and control (no CSDS) mice. FMT from these two groups was performed to antibiotic-treated mice. 16S rRNA analysis was performed to examine the composition of gut microbiota. Furthermore, the effects of subdiaphragmatic vagotomy in depression-like phenotypes after ingestion of microbes were examined.
Results
The ingestion of fecal microbiota from CSDS-susceptible mice resulted in an anhedonia-like phenotype, higher plasma levels of interleukin-6 (IL-6), and decreased expression of synaptic proteins in the prefrontal cortex (PFC) in antibiotic-treated mice but not in water-treated mice. 16S rRNA analysis suggested that two microbes (Lactobacillus intestinalis and Lactobacillus reuteri) may be responsible for the anhedonia-like phenotype in antibiotic-treated mice after FMT. Ingestion of these two microbes for 14 days led to depression- and anhedonia-like phenotypes, higher plasma IL-6 levels, and decreased expression of synaptic proteins in the PFC of antibiotic-treated mice. Interestingly, subdiaphragmatic vagotomy significantly blocked the development of behavioral abnormalities, elevation of plasma IL-6 levels, and downregulation of synaptic proteins in the PFC after ingestion of these two microbes.
Conclusions
These findings suggest that microbiota depletion using an antibiotic cocktail is essential for the development of FMT-induced behavioral changes and that the vagus nerve plays a key role in behavioral abnormalities in antibiotic-treated mice after the ingestion of L. intestinalis and L. reuteri. Therefore, it is likely that the brain–gut–microbiota axis participates in the pathogenesis of depression via the vagus nerve.
The vagus nerve plays a role in the cross talk between the brain and gut microbiota, which could be involved in depression. The subdiaphragmatic vagus nerve serves as a major modulatory pathway between the brain and gut microbiota. Here, we investigated the effects of subdiaphragmatic vagotomy (SDV) on the depression-like phenotype and the abnormal composition of gut microbiota in mice after lipopolysaccharide (LPS) administration. LPS caused a depression-like phenotype, inflammation, increase in spleen weight, and downregulation of synaptic proteins in the medial prefrontal cortex (mPFC) in the sham-operated mice. In contrast, LPS did not produce a depression-like phenotype and downregulated synaptic proteins in the mPFC after SDV. The spleen weight and plasma levels of pro-inflammatory cytokines in the SDV + LPS group were lower than those of the sham + LPS group. Interestingly, there were positive correlations between the plasma levels of pro-inflammatory cytokines and spleen weight, suggesting a relationship between inflammatory events and spleen weight. Furthermore, LPS led to significant alterations in gut microbiota diversity in sham-operated mice, but not SDV-operated mice. In an unweighted UniFrac PCoA, the dots representing the sham + LPS group were located far away from the dots representing the other three groups. Our results suggest that LPS produces a depression-like phenotype, increases spleen weight, triggers inflammation, downregulates synaptic proteins in the mPFC, and leads to abnormal composition of gut microbiota via the subdiaphragmatic vagus nerve. It is likely that the vagus nerve plays a crucial role in the brain–gut–microbiota axis.
Alistipes is a relatively new genus of bacteria isolated primarily from medical clinical samples, although at a low rate compared to other genus members of the Bacteroidetes phylum, which are highly relevant in dysbiosis and disease. According to the taxonomy database at The National Center for Biotechnology Information, the genus consists of 13 species: Alistipes finegoldii, Alistipes putredinis, Alistipes onderdonkii, Alistipes shahii, Alistipes indistinctus, Alistipes senegalensis, Alistipes timonensis, Alistipes obesi, Alistipes ihumii, Alistipes inops, Alistipes megaguti, Alistipes provencensis, and Alistipes massiliensis. Alistipes communis and A. dispar, and the subspecies A. Onderdonkii subspecies vulgaris (vs. onderdonkii subsp.) are the newest strains featured outside that list. Although typically isolated from the human gut microbiome various species of this genus have been isolated from patients suffering from appendicitis, and abdominal and rectal abscess. It is possible that as Alistipes spp. emerge, their identification in clinical samples may be underrepresented as novel MS-TOF methods may not be fully capable to discriminate distinct species as separate since it will require the upgrading of MS-TOF identification databases. In terms of pathogenicity, there is contrasting evidence indicating that Alistipes may have protective effects against some diseases, including liver fibrosis, colitis, cancer immunotherapy, and cardiovascular disease. In contrast, other studies indicate Alistipes is pathogenic in colorectal cancer and is associated with mental signs of depression. Gut dysbiosis seems to play a role in determining the compositional abundance of Alistipes in the feces (e.g., in non-alcoholic steatohepatitis, hepatic encephalopathy, and liver fibrosis). Since Alistipes is a relatively recent sub-branch genus of the Bacteroidetes phylum, and since Bacteroidetes are commonly associated with chronic intestinal inflammation, this narrative review illustrates emerging immunological and mechanistic implications by which Alistipes spp. correlate with human health.
The human gut microbiota is an important component in the pathogenesis of Crohn’s disease (CD), promoting host–microbe imbalances and disturbing intestinal and immune homeostasis. We aimed to assess the potential clinical usefulness of the colonic tissue microbiome for obtaining biomarkers for upper gastrointestinal (UGI) tract involvement in CD. We analyzed colonic tissue samples from 26 CD patients (13 with and 13 without UGI involvement at diagnosis) from the Inflammatory Bowel Disease Multi-Omics Database. QIIME1, DiTaxa, linear discriminant analysis effect size (LEfSe), and PICRUSt2 methods were used to examine microbial dysbiosis. Linear support vector machine (SVM) and random forest classifier (RF) algorithms were used to identify the UGI tract involvement-associated biomarkers. There were no statistically significant differences in community richness, phylogenetic diversity, and phylogenetic distance between the two groups of CD patients. DiTaxa analysis predicted significant association of the species Ruminococcus torques with UGI involvement, which was confirmed by the LEfSe analysis (P = 0.025). For the feature ranking method in both linear SVM and RF models, the species R. torques and age at diagnosis contributed to the combined models. The L-methionine biosynthesis III (P = 0.038) and palmitate biosynthesis II (P = 0.050) were under-represented in CD with UGI involvement. These findings suggest that R. torques might serve as a novel potential biomarker for UGI involvement in CD and its correlations, in addition to a range of bacterial species. The mechanisms of interaction between hosts and R. torques should be further investigated.
This paper examines the development of and some logistical and methodological issues surrounding the use of animal models of chronic pain. The first section addresses the emergent move towards mechanism-based and disease-related animal models of chronic pain that has accelerated since the late 1980s following publication of Bennett and Xie’s (Pain 33:87–107, 1998) paper on chronic constriction injury of the sciatic nerve and Stein et al.’s (Pharmacol Biochem Behav 31:445–451, 1988) paper on unilateral hind paw inflammation with complete Freund’s adjuvant. The discussion covers vast areas of chronic pain models developed over the past 50 years, starting with the numerous neuropathic, inflammatory and central pain models, as well as the growing number of models developed to study various forms of chronic pain from chronic back pain to visceral pain. It also examines the advantages and disadvantages of tonic pain models, mechanism-based and disease-related models of chronic pain, including issues related to the novel discovery of injury- or disease-related pathophysiological processes, the expansion of testing repertoires, and the successes and failures in the translation of analgesic development from animal preclinical models to human chronic pain conditions. The second section addresses experimental design considerations in the implementation of one of the 3Rs for the use of animal models of chronic pain; that is methods employed to reduce the number of animals used. The discussion covers various issues including the advantages and disadvantages of repeated dose designs and within-group drug testing, including incremental dosing schedules, and crossover designs. It also examines concerns surrounding the stability of symptoms and measures, including varying durations of multiple symptoms and the potential development of nociceptive sensitization, as well as possible use-dependent alterations in drug sensitivity and time-dependent changes in pain processes in specific animal models.
The relationship between gut microbiota and neurological diseases, including chronic pain, has received increasing attention. The gut microbiome is a crucial modulator of visceral pain, whereas recent evidence suggests that gut microbiota may also play a critical role in many other types of chronic pain, including inflammatory pain, headache, neuropathic pain, and opioid tolerance. We present a narrative review of the current understanding on the role of gut microbiota in pain regulation and discuss the possibility of targeting gut microbiota for the management of chronic pain. Numerous signalling molecules derived from gut microbiota, such as by-products of microbiota, metabolites, neurotransmitters, and neuromodulators, act on their receptors and remarkably regulate the peripheral and central sensitisation, which in turn mediate the development of chronic pain. Gut microbiota-derived mediators serve as critical modulators for the induction of peripheral sensitisation, directly or indirectly regulating the excitability of primary nociceptive neurones. In the central nervous system, gut microbiota-derived mediators may regulate neuroinflammation, which involves the activation of cells in the blood-brain barrier, microglia, and infiltrating immune cells, to modulate induction and maintenance of central sensitisation. Thus, we propose that gut microbiota regulates pain in the peripheral and central nervous system, and targeting gut microbiota by diet and pharmabiotic intervention may represent a new therapeutic strategy for the management of chronic pain.
Comorbid depressive symptoms (CDS) in chronic pain are a common health problem, but the neural circuit mechanisms underlying these symptoms remain unclear. Here we identify a novel pathway involving 5-hydroxytryptamine (5-HT) projections from the dorsal raphe nucleus (5-HTDRN) to somatostatin (SOM)-expressing and non-SOM interneurons in the central nucleus of the amygdala (CeA). The SOMCeA neurons project directly to the lateral habenula, an area known involved in depression. Inhibition of the 5-HTDRN→SOMCeA pathway produced depression-like behavior in a male mouse model of chronic pain. Activation of this pathway using pharmacological or optogenetic approaches reduced depression-like behavior in these mice. Human functional magnetic resonance imaging data showed that compared to healthy controls, functional connectivity between the CeA-containing centromedial amygdala and the DRN was reduced in patients with CDS but not in patients in chronic pain without depression. These findings indicate that a novel 5-HTDRN→SOMCeA→lateral habenula pathway may mediate at least some aspects of CDS.
Background
With the establishment of the heart-gut axis concept, accumulating studies suggest that the gut microbiome plays an important role in the pathogenesis of cardiovascular diseases. Yet, little evidence has been reported in characterizing the gut microbiota shift in atrial fibrillation.
Methods
We include the result of the global alterations that occur in the intestinal microbiota in a cohort of 50 patients with atrial fibrillation and 50 matched controls based on a strategy of metagenomic and metabolomic analyses.
Results
The alterations include a dramatic elevation in microbial diversity and a specific perturbation of gut microbiota composition. Overgrowth of Ruminococcus, Streptococcus, and Enterococcus, as well as reduction of Faecalibacterium, Alistipes, Oscillibacter, and Bilophila were detected in patients with atrial fibrillation. A gut microbial function imbalance and correlated metabolic pattern changes were observed with atrial fibrillation in both fecal and serum samples. The differential gut microbiome signatures could be used to identify patients with atrial fibrillation.
Conclusions
Our findings characterize the disordered gut microbiota and microbial metabolite profiles in atrial fibrillation. Further research could determine whether intervention strategies targeting intestinal microbiome composition might be useful to counteract the progression of atrial fibrillation.
Background
Chronic pain is a major clinical problem with limited treatment options. Previous studies have demonstrated that activation of adenosine monophosphate-activated protein kinase (AMPK) can attenuate neuropathic pain. Inflammation/immune response at the site of complete Freund’s adjuvant (CFA) injection is known to be a critical trigger of the pathological changes that produce inflammatory pain. However, whether activation of AMPK produces an analgesic effect through inhibiting the proinflammatory cytokines, including interleukin-1β (IL-1β), in inflammatory pain remains unknown.
Methods
Inflammatory pain was induced in mice injected with CFA. The effects of AICAR (5-aminoimidazole-4-carboxyamide ribonucleoside, an AMPK activator), Compound C (an AMPK inhibitor), and IL-1ra (an IL-1 receptor antagonist) were tested at day 4 after CFA injection. Inflammatory pain was assessed with von Frey filaments and hot plate. Immunoblotting, hematoxylin and eosin (H&E) staining, and immunofluorescence were used to assess inflammation-induced biochemical changes.
Results
The AMPK activator AICAR produced an analgesic effect and inhibited the level of proinflammatory cytokine IL-1β in the inflamed skin in mice. Moreover, activation of AMPK suppressed CFA-induced NF-κB p65 translocation from the cytosol to the nucleus in activated macrophages (CD68⁺ and CX3CR1⁺) of inflamed skin tissues. Subcutaneous injection of IL-1ra attenuated CFA-induced inflammatory pain. The AMPK inhibitor Compound C and AMPKα shRNA reversed the analgesic effect of AICAR and the effects of AICAR on IL-1β and NF-κB activation in inflamed skin tissues.
Conclusions
Our study provides new information that AMPK activation produces the analgesic effect by inhibiting NF-κB activation and reducing the expression of IL-1β in inflammatory pain.
Background
Preemptive administration of analgesic drugs reduces perceived pain and prolongs duration of antinociceptive action. Whereas several lines of evidence suggest that endomorphins, the endogenous mu-opioid agonists, attenuate acute and chronic pain at the spinal level, their preemptive analgesic effects remain to be determined. In this study, we evaluated the anti-allodynic activities of endomorphins and explored their mechanisms of action after preemptive administration in a mouse model of inflammatory pain.
Methods
The anti-allodynic activities of preemptive intrathecal administration of endomorphin-1 and endomorphin-2 were investigated in complete Freund’s adjuvant (CFA)-induced inflammatory pain model and paw incision-induced postoperative pain model. The modulating effects of endomorphins on the expression of p38 mitogen-activated protein kinase (p38 MAPK) and inflammatory mediators in dorsal root ganglion (DRG) of CFA-treated mice were assayed by real-time reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, or immunofluorescence staining.
Results
Preemptive intrathecal injection of endomorphins dose-dependently attenuated CFA-induced mechanical allodynia via the mu-opioid receptor and significantly reversed paw incision-induced allodynia. In addition, CFA-caused increase of phosphorylated p38 MAPK in DRG was dramatically reduced by preemptive administration of endomorphins. Repeated intrathecal application of the specific p38 MAPK inhibitor SB203580 reduced CFA-induced mechanical allodynia as well. Further RT-PCR assay showed that endomorphins regulated the mRNA expression of inflammatory cytokines in DRGs induced by peripheral inflammation.
Conclusions
Our findings reveal a novel mechanism by which preemptive treatment of endomorphins attenuates inflammatory pain through regulating the production of inflammatory cytokines in DRG neurons via inhibition of p38 MAPK phosphorylation.
Diet and exercise are conventional methods for controlling body weight and are linked to alterations in gut microbiota. However, the associations of diet, exercise, and gut microbiota in the control of obesity remain largely unknown. In the present study, using 16S rRNA amplicon sequencing and fecal microbiota transplantation (FMT), normal fat diet (NFD), exercise and their combination resulted in improved metabolic profiles in comparison to sedentary lifestyle with high fat diet (HFD). Moreover, diet exerted more influence than exercise in shaping the gut microbiota. HFD-fed mice receiving FMT from NFD-exercised donors not only showed remarkably reduced food efficacy, but also mitigated metabolic profiles (p < 0.05). The transmissible beneficial effects of FMT were associated with bacterial genera Helicobacter, Odoribacter and AF12 and overrepresentation of oxidative phosphorylation and glycolysis genes. Our findings demonstrate that the beneficial effects of diet and exercise are transmissible via FMT, suggesting a potential therapeutic treatment for obesity.
The microbiota, the gut, and the brain communicate through the microbiota-gut-brain axis in a bidirectional way that involves the autonomic nervous system. The vagus nerve (VN), the principal component of the parasympathetic nervous system, is a mixed nerve composed of 80% afferent and 20% efferent fibers. The VN, because of its role in interoceptive awareness, is able to sense the microbiota metabolites through its afferents, to transfer this gut information to the central nervous system where it is integrated in the central autonomic network, and then to generate an adapted or inappropriate response. A cholinergic anti-inflammatory pathway has been described through VN's fibers, which is able to dampen peripheral inflammation and to decrease intestinal permeability, thus very probably modulating microbiota composition. Stress inhibits the VN and has deleterious effects on the gastrointestinal tract and on the microbiota, and is involved in the pathophysiology of gastrointestinal disorders such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) which are both characterized by a dysbiosis. A low vagal tone has been described in IBD and IBS patients thus favoring peripheral inflammation. Targeting the VN, for example through VN stimulation which has anti-inflammatory properties, would be of interest to restore homeostasis in the microbiota-gut-brain axis.
Contemporary techniques including the use of germ-free models and next generation sequencing have deepened our understanding of the gut microbiota dynamics and its influence on host physiology. There is accumulating evidence that the gut microbiota can communicate to the CNS and is involved in the development of metabolic and behavioral disorders.
Vagal afferent terminals are positioned beneath the gut epithelium where they can receive, directly or indirectly, signals produced by the gut microbiota, to affect host behavior, including feeding behavior.
Supplementation with L. Rhamnosus in mice notably causes a decrease in anxiety and these effects are abolished by vagotomy. Additionally, chronic treatment with bacterial byproduct lipopolysaccharide (LPS) blunts vagally-mediated post-ingestive feedback and is associated with increased food intake. Inflammation in the nodose ganglion (NG), the location of vagal afferent neurons’ cell bodies, may be a key triggering factor of microbiota-driven vagal alteration. Interestingly, several models show that vagal damage leads to an increase in immune cell (microglia) activation in the NG and remodeling of the vagal pathway. Similarly, diet-driven microbiota dysbiosis is associated with NG microglia activation and decreased vagal outputs to the CNS. Crucially, preventing dysbiosis and microglia activation in high-fat diet fed rodents normalizes vagal innervation and energy intake, highlighting the importance of microbiota/vagal communication in controlling feeding behavior.
As of today, new consideration of potential roles for glial influence on vagal communication and new methods of vagal afferent ablation open opportunities to increase our understanding of how the gut microbiota influence its host’s health and behavior.
Fermentation of undigested proteins in human gastrointestinal tract (gut) by the resident microbiota, a process called bacterial putrefaction, can sometimes disrupt the gut homeostasis. In this process, essential amino acids (e.g., histidine, tryptophan, etc.) that are required by the host may be utilized by the gut microbes. In addition, some of the products of putrefaction, like ammonia, putrescine, cresol, indole, phenol, etc., have been implicated in the disease pathogenesis of colorectal cancer (CRC). We have investigated bacterial putrefaction pathways that are known to be associated with such metabolites. Results of the comprehensive in silico analysis of the selected putrefaction pathways across bacterial genomes revealed presence of these pathways in limited bacterial groups. Majority of these bacteria are commonly found in human gut. These include Bacillus, Clostridium, Enterobacter, Escherichia, Fusobacterium, Salmonella, etc. Interestingly, while pathogens utilize almost all the analyzed pathways, commensals prefer putrescine and H2S production pathways for metabolizing the undigested proteins. Further, comparison of the putrefaction pathways in the gut microbiomes of healthy, carcinoma and adenoma datasets indicate higher abundances of putrefying bacteria in the carcinoma stage of CRC. The insights obtained from the present study indicate utilization of possible microbiome-based therapies to minimize the adverse effects of gut microbiome in enteric diseases.
Our results provide novel evidence linking faecal microbiota composition to the occurrence of abdominal pain and its frequency, duration and intensity in the general population.
Chemotherapy-induced pain is a dose-limiting condition that affects 30% of patients undergoing chemotherapy. We found that gut microbiota promotes the development of chemotherapy-induced mechanical hyperalgesia. Oxaliplatin-induced mechanical hyperalgesia was reduced in germ-free mice and in mice pretreated with antibiotics. Restoring the microbiota of germ-free mice abrogated this protection. These effects appear to be mediated, in part, by TLR4 expressed on hematopoietic cells, including macrophages.
Background
The gut microbiota (GM) and brain are strongly associated, which significantly affects neuronal development and disorders. GM-derived metabolites modulate neuronal function and influence many cascades in age-related neurodegenerative disorders (NDDs). Because of the dual role of GM in neuroprotection and neurodegeneration, understanding the balance between beneficial and harmful bacteria is crucial for applying this approach to clinical therapies.
Aim
of the review
This review briefly discusses the role of the gut-brain relationship in promoting brain and cognitive function. Although a healthy gut environment is helpful for brain function, gut dysbiosis can disrupt the brain's environment and create a vicious cycle of degenerative cascades. The ways in which the GM population can affect brain function and the development of neurodegeneration are also discussed. In the treatment and management of NDDs, the beneficial effects of methods targeting GM populations and their derivatives, including probiotics, prebiotics, and fecal microbial transplantation (FMT) are also highlighted.
Key scientific concept of the review
In this review, we aimed to provide a deeper understanding of the mechanisms of the gut microbe-brain relationship and their twin roles in neurodegeneration progression and therapeutic applications. Here, we attempted to highlight the different pathways connecting the brain and gut, together with the role of GM in neuroprotection and neuronal development. Furthermore, potential roles of GM metabolites in the pathogenesis of brain disorders and in strategies for its treatment are also investigated. By analyzing existing in vitro and clinical studies, this review attempts to identify new and promising therapeutic strategies for central nervous system (CNS) disorders. As the connection between the gut microbe-brain relationship and responses to NDD treatments is less studied, this review will provide new insights into the global mechanisms of GM modulation in disease progression, and identify potential future perspectives for developing new therapies to treat NDDs.
Multiple sclerosis (MS) is the most common demyelinating disease that attacks the central nervous system. Dietary intake of cuprizone (CPZ) produces demyelination resembling that of patients with MS. Given the role of the vagus nerve in gut–microbiota–brain axis in development of MS, we performed this study to investigate whether subdiaphragmatic vagotomy (SDV) affects demyelination in CPZ-treated mice. SDV significantly ameliorated demyelination and microglial activation in the brain compared with sham-operated CPZ-treated mice. Furthermore, 16S ribosomal RNA analysis revealed that SDV significantly improved the abnormal gut microbiota composition of CPZ-treated mice. An untargeted metabolomic analysis demonstrated that SDV significantly improved abnormal blood levels of metabolites in CPZ-treated mice compared with sham-operated CPZ-treated mice. Notably, there were correlations between demyelination or microglial activation in the brain and the relative abundance of several microbiome populations, suggesting a link between gut microbiota and the brain. There were also correlations between demyelination or microglial activation in the brain and blood levels of metabolites. Together, these data suggest that CPZ produces demyelination in the brain through the gut–microbiota–brain axis via the subdiaphragmatic vagus nerve.
The microbiota-gut-brain axis or simple gut-brain axis (GBA) is a complex and interactive bidirectional communication network linking the gut to the brain. Alterations in the composition of the gut microbiome have been linked to GBA dysfunction, central nervous system (CNS) inflammation, and dopaminergic degeneration, as those occurring in Parkinson’s disease (PD). Besides inflammation, the activation of brain microglia is known to play a central role in the damage of dopaminergic neurons. Inflammation is attributed to the toxic effect of aggregated α-synuclein, in the brain of PD patients. It has been suggested that the α-synuclein misfolding might begin in the gut and spread "prion-like", via the vagus nerve into the lower brainstem and ultimately to the midbrain, known as the Braak hypothesis. In this review, we discuss how the microbiota-gut-brain axis and environmental influences interact with the immune system to promote a pro-inflammatory state that is involved in the initiation and progression of misfolded α-synuclein proteins and the beginning of the early non-motor symptoms of PD. Furthermore, we describe a speculative bidirectional model that explains how the enteric glia is involved in the initiation and spreading of inflammation, epithelial barrier disruption, and α-synuclein misfolding, finally reaching the central nervous system and contributing to neuroinflammatory processes involved with the initial non-motor symptoms of PD.
The α7 subtype of the nicotinic acetylcholine receptor (α7 nAChR: coded by Chrna7) is known to regulate the cholinergic ascending anti-inflammatory pathway. We previously reported that Chrna7 knock-out (KO) mice show depression-like behaviors through abnormal composition of gut microbiota and systemic inflammation. Given the role of subdiaphragmatic vagus nerve in gut–microbiota–brain axis, we investigated whether subdiaphragmatic vagotomy (SDV) could affect depression-like behaviors, abnormal composition of gut microbiota, and microbes-derived metabolites in Chrna7 KO mice. SDV blocked depression-like behaviors and reduced expression of synaptic proteins in the medial prefrontal cortex (mPFC) of Chrna7 KO mice. LEfSe (linear discriminant analysis effect size) analysis revealed that the species Lactobacillus sp. BL302, the species Lactobacillus hominis, and the species Lactobacillus reuteri, were identified as potential microbial markers in the KO + SDV group. There were several genus and species altered among the three groups [wild-type (WT) + sham group, KO + sham group, KO + SDV group]. Furthermore, there were several plasma metabolites altered among the three groups. Moreover, there were correlations between relative abundance of several microbiome and behavioral data (or synaptic proteins). Network analysis showed correlations between relative abundance of several microbiome and plasma metabolites (or behavioral data). These data suggest that Chrna7 KO mice produce depression-like behaviors and reduced expression of synaptic proteins in the mPFC through gut–microbiota–brain axis via subdiaphragmatic vagus nerve.
Mounting evidence points to a role for the gut microbiome in a wide range of central nervous system diseases and disorders including depression, multiple sclerosis, Alzheimer's disease, Parkinson's disease, and autism spectrum disorder. Moreover, immune system involvement has also been implicated in these diseases, specifically with inflammation being central to their pathogenesis. In addition to the reported changes in gut microbiome composition and altered immune states in many neurological diseases, how the microbiome and the immune system interact to influence disease onset and progression has recently garnered much attention. This chapter provides a review of the literature related to gut microbiome influences on neuro-immune interactions with a particular focus on neurological diseases. Gut microbiome-derived mediators, including short-chain fatty acids and other metabolites, lipopolysaccharide, and neurotransmitters, and their impact on neuro-immune interactions as well as routes by which these interactions may occur are also discussed.
Gut microbiota has implications in Central Nervous System (CNS) disorders. Our study systematically identified preclinical studies aimed to investigate the possible gut microbiota contribution in neuropathy and neuropathic pain. The systematic review is reported in accordance with PRISMA checklist and guidelines outlined updated to 2020. We included research articles reporting neuropathy-related behavioral evaluations and/or neurological scores coupled to gut microbiota analysis performed by high-throughput technologies in the last ten years. Two investigators performed a search through 3 electronic bibliographic databases for full-text articles (PubMed, Scopus, and EMBASE) and three registries (Prospero, SyRF, and bioRxiv), cross-references, and linear searches. We assessed the methodological quality via the CAMARADES checklist and appraised the heterogeneous body of evidence by narrative synthesis. In total, there were 19 eligible studies. The most of these reports showed significant changes in gut microbiota setting in neuropathy conditions. The major gut microbiome remodeling was through fecal microbiome transplantation. Mechanistic proof of the gut-CNS communication was achieved by measuring inflammatory mediators, metabolic products, or neurotransmitters. As a limitation, we found considerable heterogeneity across eligible studies.
We conclude that the current understanding of preclinical findings suggested an association between neuropathy and/or neuropathic pain and gut microbiota modifications. Our analysis provides the basis for further studies targeting microbiota for managing symptoms of neuropathy or other neuroinflammation-based CNS disorders. The systematic review protocol was registered on the international database Prospero under the registration number (# 257628).
A high fat and cholesterol diet (HFCD) can modulate the gut microbiota, which is closely related with hypercholesterolemia. This study aimed to explore the anti-hypercholesterolemia effect of oryzanol, and investigate whether the function of oryzanol is associated with the gut microbiota and related metabolites. 16S rRNA and ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry were applied for the gut microbiota and untargeted metabolomics, respectively. The results showed that HFCD significantly upregulated body fat accumulation and serum lipids, including triglyceride, total cholesterol, low density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-c), and ratio of LDL-c/HDL-c, which induced hypercholesterolemia. Oryzanol supplementation decreased body fat accumulation and serum lipids, especially the LDL-c concentration and LDL-c/HDL-c ratio. In addition, the abundances of Desulfovibrio, Colidextribacter, norank_f__Oscillospiraceae, unclassified_f__Erysipelotrichaceae, unclassified_f__Oscillospiraceae, norank_f__Peptococcaceae, Oscillibacter, Bilophila and Harryflintia were increased and the abundance of norank_f__Muribaculaceae was decreased in HFCD-induced hyperlipidemia hamsters. Metabolites were changed after HFCD treatment and 9 differential metabolites belonged to bile acids and 8 differential metabolites belonged to amino acids. Those genera and metabolites were significantly associated with serum lipids. HFCD also disrupted the intestinal barrier. Oryzanol supplementation reversed the changes of the gut microbiota and metabolites, and intestinal barrier injury was also partly relieved. This suggests that oryzanol supplementation modulating the gut microbiota contributes to its anti-hyperlipidemia function, especially anti-hypercholesterolemia.
The spleen, an important tissue for the immune system, acts as a filter for blood within the immune system. Accumulating evidence suggests that the spleen affects a number of brain functions in health and diseases via immune modulation. Systemic inflammation or chronic social defeat stress (CSDS) can cause splenomegaly in rodents. Interestingly, the new antidepressant arketamine could normalize splenomegaly and depression-like behaviors in CSDS-susceptible mice. A recent study strongly supports the direct connection pathway between the brain and spleen, whereby the spleen can regulate the humoral immune defense by the two brain regions, such as corticotropin-related neurons in the paraventricular nucleus (PVN) and the central nucleus of the amygdala (CeA). Furthermore, afferent and efferent vagus nerve signaling may contribute to brain and spleen communication. In this article, we review recent findings of the brain–spleen axis in health and diseases.
Depression is the most common mental disorder and a leading cause of disability worldwide. Despite abundant research, the precise mechanisms underlying the pathophysiology of depression remain elusive. Accumulating evidence from preclinical and clinical studies suggests that alterations in the gut microbiota, microbe-derived short-chain fatty acids, D-amino acids and metabolites play a key role in the pathophysiology of depression via the brain–gut–microbiota axis, including the neural and immune systems. Notably, the brain–gut–microbiota axis might play a crucial role in susceptibility versus resilience in rodents exposed to stress. Vagotomy is reported to block depression-like phenotypes in rodents after fecal microbiota transplantation of “depression-related” microbiome, suggesting that the vagus nerve influences depression through the brain–gut–microbiota axis. In this article, we review recent findings regarding the brain–gut–microbiota axis in depression and discuss its potential as a therapeutic target for depression.
Multiple sclerosis (MS) is the most common demyelinating disease that attacks the central nervous system. We recently reported that the new antidepressant (R)-ketamine could ameliorate the disease progression in experimental autoimmune encephalomyelitis model of MS. Cuprizone (CPZ) has been used to produce demyelination which resembles demyelination in MS patients. This study was undertaken to investigate whether (R)-ketamine could affect demyelination in CPZ-treated mice and remyelination after CPZ withdrawal. Repeated treatment with (R)-ketamine (10 mg/kg/day, twice a weekly, for 6 weeks) significantly ameliorated demyelination and activated microglia in the brain compared with saline-treated mice. Furthermore, pretreatment with ANA-12 (TrkB antagonist) significantly blocked the beneficial effects of (R)-ketamine on the demyelination and activated microglia in the brain of CPZ-treated mice. The 16S rRNA analysis showed that (R)-ketamine significantly improved abnormal composition of gut–microbiota and decreased levels of lactic acid of CPZ-treated mice. In addition, there were significant correlations between demyelination (or microglial activation) in the brain and the relative abundance of several microbiome, suggesting a link between gut microbiota and brain. Interestingly, (R)-ketamine could facilitate remyelination in the brain after CPZ withdrawal. In conclusion, the study suggests that (R)-ketamine could ameliorate demyelination in the brain of CPZ-treated mice through TrkB activation, and that gut–microbiota–microglia crosstalk may play a role in the demyelination of CPZ-treated mice. Therefore, it is likely that (R)-ketamine could be a new therapeutic drug for MS.
Depression is a prevalent, life-threatening, and highly recurrent psychiatric illness. Several studies have shown that depression is associated with endogenous metabolites and the gut microbiota. However, it is unclear whether metabolites in different gut tissues play a role in the pathogenesis of depression and whether the gut microbiota has an impact on depression. Here, we investigated the metabolic signatures in the jejunum, ileum, and colorectum using metabolomics and explored the influence of the gut microbiota on both the development of chronic variable stress (CVS)-induced depression rat model and variations in gut tissue metabolites using a gnotobiotic rat model. The results showed that CVS induced disturbances in gut metabolites (29 differential metabolites) and had different effects on the different segments. When CVS rats were treated with antibiotics, depression-like ethological disorders disappeared, and the decreased catecholamine levels almost normalized. The depression recovery was attributed to the influence of antibiotics on the gut microbiota, especially inhibiting Clostridiaceae (F1), Candidatus arthromitus (G2), Lactobacillus (G6), and elevating Pseudomonadaceae (F6). Moreover, 16 of 29 varied metabolites in CVS rats were reversed with antibiotic treatment. Among them, 12 increased metabolites were decreased, suggesting a trigger for depression. However, four decreased metabolites were increased, indicating a potential therapeutic effect on depression. Based on the Pearson's correlation analysis, hypoxanthine, 3-hydroxypristanic acid, threonic acid, and L-carnitine were strongly associated with F6, F1, G2, and G6, which are involved in the development and prevention of depression. These findings provide a possibility for further exploration of the pathogenesis and prevention of depression.
Chronic pain exerts an enormous personal and economic burden, affecting more than 30% of people worldwide according to some studies. Unlike acute pain, which carries survival value, chronic pain might be best considered to be a disease, with treatment (eg, to be active despite the pain) and psychological (eg, pain acceptance and optimism as goals) implications. Pain can be categorised as nociceptive (from tissue injury), neuropathic (from nerve injury), or nociplastic (from a sensitised nervous system), all of which affect work-up and treatment decisions at every level; however, in practice there is considerable overlap in the different types of pain mechanisms within and between patients, so many experts consider pain classification as a continuum. The biopsychosocial model of pain presents physical symptoms as the denouement of a dynamic interaction between biological, psychological, and social factors. Although it is widely known that pain can cause psychological distress and sleep problems, many medical practitioners do not realise that these associations are bidirectional. While predisposing factors and consequences of chronic pain are well known, the flipside is that factors promoting resilience, such as emotional support systems and good health, can promote healing and reduce pain chronification. Quality of life indicators and neuroplastic changes might also be reversible with adequate pain management. Clinical trials and guidelines typically recommend a personalised multimodal, interdisciplinary treatment approach, which might include pharmacotherapy, psychotherapy, integrative treatments, and invasive procedures.
The α7 subtype of the nicotinic acetylcholine receptor (α7 nAChR: coded by Chrna7) regulates the cholinergic ascending anti-inflammatory pathway involved in depression. We previously reported that Chrna7 knock-out (KO) mice show depression-like phenotypes through systemic inflammation. In this study, we investigated whether fecal microbiota transplantation (FMT) from Chrna7 KO mice causes depression-like phenotypes in mice treated with an antibiotic cocktail (ABX). Chrna7 KO mice with depression-like phenotypes show an abnormal gut microbiota composition, although the alpha diversity and beta diversity were not altered. FMT from Chrna7 KO mice caused depression-like phenotypes, systemic inflammation, and downregulation of synaptic proteins in the prefrontal cortex (PFC) in the ABX-treated mice compared to FMT from the control mice. The boxplots representing the FMT group from the KO mice were distanced from those representing the FMT group from the control mice in an unweighted UniFrac distance analysis. We found differences in abundance for several bacteria in the FMT group from the KO mice at the taxonomic level when compared with the other group. Interestingly, subdiaphragmatic vagotomy significantly blocked the development of depression-like phenotypes in the ABX-treated mice after FMT from Chrna7 KO mice. These data suggest that FMT from Chrna7 KO mice produce depression-like phenotypes in ABX-treated mice via the subdiaphragmatic vagus nerve. The brain–gut–microbiota axis association with the subdiaphragmatic vagus nerve plays an important role in the development of depression.
Background:
Gut microbiota, a consortium of diverse microorganisms residing in the gastrointestinal tract, has emerged as a key player in neuroinflammatory responses, supporting the functional relevance of the "gut-brain axis." Chronic-constriction injury of the sciatic nerve (CCI) is a commonly used animal model of neuropathic pain with a major input from T cell-mediated immune responses. In this article, we sought to examine whether gut microbiota influences CCI neuropathic pain, and, if so, whether T-cell immune responses are implicated.
Methods:
We used a mixture of wide-spectrum oral antibiotics to perturbate gut microbiota in mice and then performed CCI in these animals. Nociceptive behaviors, including mechanical allodynia and thermal hyperalgesia, were examined before and after CCI. Additionally, we characterized the spinal cord infiltrating T cells by examining interferon (IFN)-γ, interleukin (IL)-17, and Foxp3. Using a Foxp3-GFP-DTR "knock-in" mouse model that allows punctual depletion of regulatory T cells, we interrogated the role of these cells in mediating the effects of gut microbiota in the context of CCI neuropathic pain.
Results:
We found that oral antibiotics induced gut microbiota changes and attenuated the development of CCI neuropathic pain, as demonstrated by dampened mechanical allodynia and thermal hyperalgesia. Percentages of IFN-γ-producing Th1 cells and Foxp3+ regulatory T cells were significantly different between animals that received oral antibiotics (Th1 mean = 1.0, 95% confidence interval [CI], 0.9-1.2; Foxp3 mean = 8.1, 95% CI, 6.8-9.3) and those that received regular water (Th1 mean = 8.4, 95% CI, 7.8-9.0, P < .01 oral antibiotics versus water, Cohen's d = 18.8; Foxp 3 mean = 2.8, 95% CI, 2.2-3.3, P < .01 oral antibiotics versus water, Cohen's d = 6.2). These T cells characterized a skewing from a proinflammatory to an anti-inflammatory immune profile induced by gut microbiota changes. Moreover, we depleted Foxp3+ regulatory T cells and found that their depletion reversed the protection of neuropathic pain mediated by gut microbiota changes, along with a dramatic increase of IFN-γ-producing Th1 cell infiltration in the spinal cord (before depletion mean = 2.8%, 95% CI, 2.2-3.5; after depletion mean = 9.1%, 95% CI, 7.2-11.0, p < .01 before versus after, Cohen's d = 5.0).
Conclusions:
Gut microbiota plays a critical role in CCI neuropathic pain. This role is mediated, in part, through modulating proinflammatory and anti-inflammatory T cells.
Patients with rheumatoid arthritis experience chronic pain, depression and fatigue, even when inflammation of the joints is well controlled. To study the relationship between arthritis, depression, and sustained pain when articular inflammation is no longer observed, we tested the hypothesis that brain TNF drives post-inflammation depression-like behavior and persistent pain in experimental arthritis. The murine model of antigen-induced arthritis (AIA) was used to evaluate the effects of knee inflammation on sustained pain and depression-like behavior. We measured joint pain using an automated dynamic plantar algesiometer and depression-like behavior with the tail suspension test. Cytokines were measured by Luminex assay and ELISA. TNF in the brain was blocked by intracerebroventricular injection of anti-TNF antibodies. Histological damage and elevated levels of cytokines were observed in the knee 24h after antigen treatment, but not at 13 days. Reduced pain thresholds were seen 24h and 13 days after treatment. Depression-like behavior was observed on day 13. Treatment with the antidepressant imipramine reduced both depression-like behavior and persistent pain. However, blocking joint pain with the analgesic dipyrone did not alter depression-like behavior. Elevated levels of TNF, CCL2, and CXCL-1 were observed in the hippocampus 24h after treatment, with TNF remaining elevated at day 13. Intracerebroventricular infusion of an anti-TNF antibody blocked depression-like behavior and reduced persistent pain. We have demonstrated that depression-like behavior and pain is sustained in AIA mice after the resolution of inflammation. These changes are associated with elevated levels of TNF in the hippocampus and are dependent upon brain TNF. The findings reveal an important mechanistic link between the expression of chronic pain and depression in experimental arthritis. Furthermore, they suggest treating depression in rheumatoid arthritis may positively impact other debilitating features of this condition.
Patients with temporomandibular disorders (TMDs) often experience persistent facial pain. However, the treatment of TMD pain is still inadequate. In recent years, the disturbance of gut microbiota has been shown to play an important role in the pathogenesis of different neurological diseases including chronic pain. In the present study, we investigated the involvement of gut microbiota in the development of temporomandibular joint (TMJ) inflammation. Intra-temporomandibular joint injection of complete Freund's adjuvant (CFA) was employed to induce TMJ inflammation. Resveratrol (RSV), a natural bioactive compound with anti-inflammatory property, was used to treat the CFA-induced TMJ inflammation. We observed that CFA injection not only induces persistent joint pain, but also causes the reduction of short-chain fatty acids (SCFAs, including acetic acid, propionic acid and butyric acid) in the gut as well as decreases relevant gut bacteria Bacteroidetes and Lachnospiraceae. Interestingly, systemic administration of RSV (i.p.) dose-dependently inhibits CFA-induced TMJ inflammation, reverses CFA-caused reduction of SCFAs and these gut bacteria. Moreover, CFA injection causes blood-brain barrier (BBB) leakage, activates microglia and enhances tumor necrosis factor alpha (TNFα) release in the spinal trigeminal nucleus caudalis (Sp5C). The RSV treatment restores the BBB integrity, inhibits microglial activation and decreases the release of TNFα in the Sp5C. Furthermore, fecal microbiota transplantation with feces from RSV-treated mice significantly diminishes the CFA-induced TMJ inflammation. Taken together, our results suggest that gut microbiome perturbation is critical for the development of TMJ inflammation and that recovering gut microbiome to normal levels could be a new therapeutic approach for treating such pain.
The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson’s disease, and Alzheimer’s disease. Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field. Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.
The previous decade has seen a rapid increase in microglial studies on pain, with a unique focus on microgliosis in the spinal cord after nerve injury and neuropathic pain. Numerous signaling molecules are altered in microglia and contribute to the pathogenesis of pain. Here, we discuss how microglial signaling regulates spinal cord synaptic plasticity in acute and chronic pain conditions with different degrees and variations of microgliosis. We highlight that microglial mediators such as pro- and anti-inflammatory cytokines are powerful neuromodulators that regulate synaptic transmission and pain via neuron-glial interactions. We also reveal an emerging role of microglia in the resolution of pain, in part via specialized pro-resolving mediators including resolvins, protectins, and maresins. We also discuss a possible role of microglia in chronic itch.
Background
Intestinal microbiota and their metabolites (e.g. short-chain fatty acids (SCFAs)) may influence nonalcoholic fatty liver disease (NAFLD).
Objective
The objective of this article is to analyze gut bacterial diversity together with fecal SCFA concentrations and immunophenotyping of peripheral blood in histology-proven NAFLD patients.
Methods
Thirty-two NAFLD patients (14 nonalcoholic fatty liver (NAFL), 18 nonalcoholic steatohepatitis (NASH)) and 27 healthy controls (HCs)) were included in this study. Bacterial communities in feces were profiled by 16S ribosomal RNA gene sequencing of the V3–V4 region. Fecal SCFA levels were analyzed by high-performance liquid chromatography. Fluorescence-activated cell sorting analysis was performed of peripheral blood mononuclear cells.
Results
NASH patients were characterized by higher abundance of Fusobacteria and Fusobacteriaceae compared to NAFL and HCs. Conforming to our finding that NAFLD patients had higher fecal acetate and propionate levels, taxonomical differences of fecal bacteria were dominated by SCFA-producing bacteria. Higher fecal propionate and acetate levels were associated with lower resting regulatory T-cells (rTregs) (CD4+CD45RA+CD25++) as well as higher Th17/rTreg ratio in peripheral blood as immunological characteristics of NASH patients.
Conclusions
NASH patients are characterized by a different gut microbiome composition with higher fecal SCFA levels and higher abundance of SCFA-producing bacteria in NAFLD. These changes are associated with immunological features of disease progression. Our data suggest an important role of the intestinal microbiome and immunomodulatory bacterial metabolites in human NAFLD.