Abdominal pain in constipation-predominant irritable bowel syndrome (IBS-C) and functional constipation (FC) remains a difficult clinical challenge due to unclear pathophysiological mechanisms and limited pain-targeted treatments. This review critically evaluates the evidence on the underlying pain mechanisms in IBS-C and/or FC and explores management strategies, their limitations, and future directions.

Most research on constipation-related pain is based on IBS-C patients or animal models, with limited studies focusing on FC. Visceral hypersensitivity, serotonin dysregulation, gut-brain axis dysfunction, and central/peripheral nervous system alterations are implicated in IBS-C pain, while FC pain is less studied and may be primarily linked to colonic distension and motility dysfunction. Management strategies include 5-HT4 agonists, GC-C agonists, chloride channel activators, psychological therapies, probiotics and complementary medicine. Despite available treatment options, managing abdominal pain in IBS-C and FC remains challenging due to heterogeneous pathophysiology and limited targeted therapies. While some interventions provide symptomatic relief, there is no universally effective treatment for abdominal pain across all patients. Future research should focus on identifying pain-specific biomarkers, refining diagnostic criteria, and integrating multi-omics data and neuroimaging techniques to better distinguish pain mechanisms in IBS-C versus FC and develop more precise, patient-centered interventions.

The gut microbiota plays a pivotal role in gastrointestinal inflammation and immune response since changes in microbiota may result in abnormal neurotransmitter expression, inducing changes in gastrointestinal sensory-motor function and leading to symptom onset in irritable bowel syndrome (IBS) patients. The Bifidobacterium adolescentis species has a documented immunomodulatory effect through its ability to produce γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the mammalian central nervous system, which is reduced in IBS patients. This is a multicentric, randomized, double-blind, placebo-controlled, parallel-arm trial aimed at evaluating the effectiveness of Bifidobacterium adolescentis PRL2019 in children with IBS. IBS children diagnosed according to Rome IV criteria were enrolled and randomized into two groups to receive one stick containing 20 × 109 colony-forming unit of Bifidobacterium adolescentis PRL2019 (Gabapral, Pontenure, Italy) or an equivalent placebo once a day, in a 1:1 ratio, for 12 weeks. Clinical evaluation of symptoms was performed every four weeks using validated scores. Bowel habit characteristics were assessed using the Bristol Stool Chart (BSC). Seventy-two subjects (mean age 12.2 ± 1.8 years, 30 males) were enrolled and randomized into two groups, each of thirty-six patients. No significant differences were observed between the two groups regarding demographic characteristics, distribution of IBS subtypes, or baseline measures of IBS severity and BSC. The proportion of patients achieving complete remission was significantly higher in the BA Group (19/36; 52.8%) than in the Placebo Group (7/36; 19.4%, p = 0.003, odds ratio [OR] 0.216, 95% confidence interval [CI] 0.075-0.619). Both groups obtained a reduction in Total IBS Symptom Severity Scale (IBS SSS), Pain Intensity Score (PIS), Pain Frequency Score (PFS), and Life Interference Score (LIS) from T0 to T12. However, upon intergroup comparison, only in the BA group did the IBS-SSS (p = 0.001), PIS (p = 0.001), LIS (p = 0.015), and PFS (p = 0.005) significantly improve between T0 and T12. BSC showed a greater representation of normal stools (type 3-4) at the end of treatment in the BA group compared with baseline (25% vs. 58.3%, p = 0.004), especially in patients who presented an IBS-constipation subtype at T0 (44.5% vs. 19.4%, p = 0.02). In our study, Bifidobacterium adolescentis PRL2019 reduces the severity and frequency of symptoms in children with IBS, positively affecting bowel habits in children with the IBS-constipation subtype.

The prenatal and early-life periods pose a crucial neurodevelopmental window whereby disruptions to the intestinal microbiota and the developing brain may have adverse impacts. As antibiotics affect the human intestinal microbiome, it follows that early-life antibiotic exposure may be associated with later-life psychiatric or neurocognitive outcomes.

To explore the association between early-life (in utero and early childhood (age 0-2 years)) antibiotic exposure and the subsequent risk of psychiatric and neurocognitive outcomes.

A search was conducted using Medline, PsychINFO and Excerpta Medica databases on 20 November 2023. Risk of bias was assessed using the Newcastle-Ottawa scale, and certainty was assessed using the grading of recommendations, assessment, development and evaluation (GRADE) certainty assessment.

Thirty studies were included (n = 7 047 853 participants). Associations were observed between in utero antibiotic exposure and later development of autism spectrum disorder (ASD) (odds ratio 1.09, 95% CI: 1.02-1.16) and attention-deficit hyperactivity disorder (ADHD) (odds ratio 1.19, 95% CI: 1.11-1.27) and early-childhood exposure and later development of ASD (odds ratio 1.19, 95% CI: 1.01-1.40), ADHD (odds ratio 1.33, 95% CI: 1.20-1.48) and major depressive disorder (MDD) (odds ratio 1.29, 95% CI: 1.04-1.60). However, studies that used sibling control groups showed no significant association between early-life exposure and ASD or ADHD. No studies in MDD used sibling controls. Using the GRADE certainty assessment, all meta-analyses but one were rated very low certainty, largely owing to methodological and statistical heterogeneity.

While there was weak evidence for associations between antibiotic use in early-life and later neurodevelopmental outcomes, these were attenuated in sibling-controlled subgroup analyses. Thus, associations may be explained by genetic and familial confounding, and studies failing to utilise sibling-control groups must be interpreted with caution. PROSPERO ID: CRD42022304128.

Over the past 2 decades, the microbiome has received increasing attention for the role that it plays in health and disease. Historically, the gut microbiome was of particular interest to pain scientists studying nociplastic visceral pain conditions given the anatomical juxtaposition of these microorganisms and the neuroimmune networks that drive pain in such diseases. More recently, microbiomes both inside and across the surface of the body have been recognized for driving sensory symptoms in a broader set of diseases. Microbiomes have never been a more popular topic in pain research, but to date, there has not been a systematic review of the preclinical microbiome pain literature. In this article, we identified all animal studies in which both the microbiome was manipulated and pain behaviors were measured. Our analysis included 303 unique experiments across 97 articles. Microbiome manipulation methods and behavioral outcomes were recorded for each experiment so that field-wide trends could be quantified and reported. This review specifically details the animal species, injury models, behavior measures, and microbiome manipulations used in preclinical pain research. From this analysis, we were also able to conclude how manipulations of the microbiome alter pain thresholds in naïve animals and persistent pain intensity and duration in cutaneous and visceral pain models. This review summarizes by identifying existing gaps in the literature and providing recommendations for how to best plan, implement, and interpret data collected in preclinical microbiome pain experiments.

Pain and psychological stress are intricately linked, with sex differences evident in disorders associated with both systems. Glutamatergic signalling in the central nervous system is influenced by gonadal hormones via the hypothalamic-pituitary-adrenal axis and is central in pain research. Emerging evidence supports an important role for the gut microbiota in influencing pain signalling. Here, the functional activity of excitatory amino acid transporters (EAATs) in the anterior cingulate cortex (ACC) and lumbosacral spinal cord of male and female Wistar-Kyoto rats, an animal model of comorbid visceral hypersensitivity and enhanced stress responsivity, was investigated across the oestrous cycle. Correlations between the gut microbiota and changes in the functional activity of the central glutamatergic system were also investigated. EAAT function in the lumbosacral spinal cord was similar between males and females across the oestrous cycle. EAAT function was higher in the ACC of dioestrus females compared to proestrus and oestrus females. In males, aspartate uptake in the ACC positively correlated with Bacteroides, while aspartate uptake in the spinal cord positively correlated with the relative abundance of Lachnospiraceae NK4A136. Positive associations with aspartate uptake in the spinal cord were also observed for Alistipes and Bifidobacterium during oestrus, and Eubacterium coprostanoligenes during proestrus. Clostridium sensu stricto1 was negatively associated with aspartate uptake in the ACC in males and dioestrus females. These data indicate that glutamate metabolism in the ACC is oestrous stage-dependent and that short-chain fatty acid-producing bacteria are positively correlated with aspartate uptake in males and during specific oestrous stages in females.

Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction affecting 5% of the population. The cardinal symptoms are abdominal pain and altered stool form or frequency.

Diagnosis and management of IBS. We searched the literature for diagnostic accuracy studies, randomized controlled trials, and meta-analyses. A positive diagnosis of IBS, alongside testing to exclude celiac disease, is recommended. Exhaustive investigation has a low yield. Patients should be offered traditional dietary advice. If response is incomplete, specialist dietetic guidance should be considered. Probiotics may be beneficial, but quality of evidence is poor. First-line treatment of constipation is with laxatives, with secretagogues used where these are ineffective. Anti-diarrheal drugs should be used first-line for diarrhea, with second-line drugs including 5-hydroxytryptamine-3 antagonists, eluxadoline, or rifaximin, where available. First-line treatment of abdominal pain should be with antispasmodics, with gut-brain neuromodulators prescribed second-line. Low-dose tricyclic antidepressants, such as amitriptyline, are preferred. Brain-gut behavioral therapies are effective and have evidence for efficacy in patients refractory to standard therapies.

Despite substantial advances, there remains scope for improvement in terms of both the diagnosis and management of IBS. Reinforcement of positive diagnostic strategies for the condition and novel treatment paradigms are required.

Research over the past two decades has established a remarkable ability of the gut microbiota to modulate brain activity and behaviour. Conversely, signals from the brain can influence the composition and function of the gut microbiota. This bidirectional communication across the gut microbiota-brain axis, involving multiple biochemical and cellular mediators, is recognized as a major brain-body network that integrates cues from the environment and the body's internal state. Central to this network is the gut sensory system, formed by intimate connections between chemosensory epithelial cells and sensory nerve fibres, that conveys interoceptive signals to the central nervous system. In this Review, we provide a broad overview of the pathways that connect the gut and the brain, and explore the complex dialogue between microorganisms and neurons at this emerging intestinal neuroepithelial interface. We highlight relevant microbial factors, endocrine cells and neural mechanisms that govern gut microbiota-brain interactions and their implications for gastrointestinal and neuropsychiatric health.

Although antibiotics remain the mainstay of urinary tract infection treatment, many affected women can be caught in a vicious cycle in which antibiotics given to eradicate one infection predispose them to develop another. This effect is primarily mediated by disturbances in the gut microbiome that both directly enrich for uropathogenic overgrowth and induce systemic alterations in inflammation, tissue permeability, and metabolism that also decrease host resistance to infection recurrences. Here, we discuss nonantibiotic approaches to manipulating the gut microbiome to reverse the systemic consequences of antibiotics, including cranberry supplementation and other dietary approaches, probiotic administration, and fecal microbiota transplantation.

Chronic pain is highly prevalent and burdensome, affecting millions of people worldwide. Although it emerges at any point in life, it often manifests in adolescence. Given that adolescence is a unique developmental period, additional strains associated with persistent and often idiopathic pain lead to significant long-term consequences. While there is no singular cause for the chronification of pain, epigenetic modifications that lead to neural reorganization may underpin central sensitization and subsequent manifestation of pain hypersensitivity. Epigenetic processes are particularly active during the prenatal and early postnatal years. We demonstrate how exposure to various traumas, such as intimate partner violence while in utero or adverse childhood experiences, can significantly influence epigenetic regulation within the brain and in turn modify pain-related processes. We provide compelling evidence that the burden of chronic pain is likely initiated early in life, often being transmitted from mother to offspring. We also highlight two promising prophylactic strategies, oxytocin administration and probiotic use, that have the potential to attenuate the epigenetic consequences of early adversity. Overall, we advance understanding of the causal relationship between trauma and adolescent chronic pain by highlighting epigenetic mechanisms that underlie this transmission of risk, ultimately informing how to prevent this rising epidemic.

Nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as a significant health issue. Emerging research has focused on the role of the gut microbiota in NAFLD, emphasizing the gut-liver axis. This study aimed to identify key research trends and guide future investigations in this evolving area.

This bibliometric study utilized Scopus to analyze global research on the link between the gut microbiota and NAFLD. The method involved a search strategy focusing on relevant keywords in article titles, refined by including only peer-reviewed journal articles. The data analysis included bibliometric indicators such as publication counts and trends, which were visualized using VOSviewer software version 1.6.20 for network and co-occurrence analysis, highlighting key research clusters and emerging topics.

Among the 479 publications on the gut microbiota and NAFLD, the majority were original articles (n = 338; 70.56%), followed by reviews (n = 119; 24.84%). The annual publication count increased from 1 in 2010 to 118 in 2022, with a significant growth phase starting in 2017 (R2 = 0.9025, p < 0.001). The research was globally distributed and dominated by China (n = 231; 48.23%) and the United States (n = 90; 18.79%). The University of California, San Diego, led institutional contributions (n = 18; 3.76%). Funding was prominent, with 62.8% of the articles supported, especially by the National Natural Science Foundation of China (n = 118; 24.63%). The average citation count was 43.23, with an h-index of 70 and a citation range of 0 to 1058 per article. Research hotspots shifted their focus post-2020 toward the impact of high-fat diets on NAFLD incidence.

This study has effectively mapped the growing body of research on the gut microbiota-NAFLD relationship, revealing a significant increase in publications since 2017. There is significant interest in gut microbiota and NAFLD research, mainly led by China and the United States, with diverse areas of focus. Recently, the field has moved toward exploring the interconnections among diet, lifestyle, and the gut-liver axis. We hypothesize that with advanced technologies, new opportunities for personalized medicine and a holistic understanding of NAFLD will emerge.

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder with gut microbiota imbalance playing a significant role. There are increasing numbers of research studies exploring treatment options involving probiotics, prebiotics, synbiotics, and fecal microbiota transplantation (FMT), but it is still uncertain which treatment option is superior. The research was conducted on various databases and unpublished trial data (up to February 2023). Randomized controlled trials (RCTs) were screened for adult patients with IBS comparing interventions with placebo. Probiotics, prebiotics, synbiotics, and FMT were assessed for their impact using mean difference and Bayesian network meta-analysis. Out of 6528 articles, 54 were included for probiotics, 7 for prebiotics/synbiotics, and 6 for FMT. Probiotics showed improvement in IBS symptoms, particularly with Bifidobacterium and Lactobacillus strains. Prebiotics and synbiotics did not show significant improvement. Network meta-analysis indicated the favorable effects of probiotics (OR = 0.53, 95% CI, 0.48 to 0.59) and FMT (OR = 0.46, 95% CI, 0.33 to 0.64) on IBS, with no serious adverse events reported. In short, probiotics and FMT are effective for managing IBS, with Bifidobacterium and Lactobacillus being dominant strains. However, the most effective probiotic combination or strain remains unclear, while prebiotics and synbiotics did not show significant improvement.

Recent studies have highlighted the impact of disrupted maternal gut microbiota on the colonization of offspring gut microbiota, with implications for offspring developmental trajectories. The extent to which offspring inherit the characteristics of altered maternal gut microbiota remains elusive. In this study, we employed a mouse model where maternal gut microbiota disruption was induced using non-absorbable antibiotics. Systematic chronological analyses of dam fecal samples, offspring luminal content, and offspring gut tissue samples revealed a notable congruence between offspring gut microbiota profiles and those of the perturbed maternal gut microbiota, highlighting the profound influence of maternal microbiota on early-life colonization of offspring gut microbiota. Nonetheless, certain dominant bacterial genera in maternal microbiota did not transfer to the offspring, indicating a bacterial taxonomy-dependent mechanism in the inheritance of maternal gut microbiota. Our results embody the vertical transmission dynamics of disrupted maternal gut microbiota in an animal model, where the gut microbiota of an offspring closely mirrors the gut microbiota of its mother.

Pain is estimated to affect more than 20% of the global population, imposing incalculable health and economic burdens. Effective pain management is crucial for individuals suffering from pain. However, the current methods for pain assessment and treatment fall short of clinical needs. Benefiting from advances in neuroscience and biotechnology, the neuronal circuits and molecular mechanisms critically involved in pain modulation have been elucidated. These research achievements have incited progress in identifying new diagnostic and therapeutic targets. In this review, we first introduce fundamental knowledge about pain, setting the stage for the subsequent contents. The review next delves into the molecular mechanisms underlying pain disorders, including gene mutation, epigenetic modification, posttranslational modification, inflammasome, signaling pathways and microbiota. To better present a comprehensive view of pain research, two prominent issues, sexual dimorphism and pain comorbidities, are discussed in detail based on current findings. The status quo of pain evaluation and manipulation is summarized. A series of improved and innovative pain management strategies, such as gene therapy, monoclonal antibody, brain-computer interface and microbial intervention, are making strides towards clinical application. We highlight existing limitations and future directions for enhancing the quality of preclinical and clinical research. Efforts to decipher the complexities of pain pathology will be instrumental in translating scientific discoveries into clinical practice, thereby improving pain management from bench to bedside.

Gut physiology is the epicenter of a web of internal communication systems (i.e., neural, immune, hormonal) mediated by cell-cell contacts, soluble factors, and external influences, such as the microbiome, diet, and the physical environment. Together these provide the signals that shape enteric homeostasis and, when they go awry, lead to disease. Faced with the seemingly paradoxical tasks of nutrient uptake (digestion) and retarding pathogen invasion (host defense), the gut integrates interactions between a variety of cells and signaling molecules to keep the host nourished and protected from pathogens. When the system fails, the outcome can be acute or chronic disease, often labeled as "idiopathic" in nature (e.g., irritable bowel syndrome, inflammatory bowel disease). Here we underscore the importance of a holistic approach to gut physiology, placing an emphasis on intercellular connectedness, using enteric neuroimmunophysiology as the paradigm. The goal of this opinion piece is to acknowledge the pace of change brought to our field via single-cell and -omic methodologies and other techniques such as cell lineage tracing, transgenic animal models, methods for culturing patient tissue, and advanced imaging. We identify gaps in the field and hope to inspire and challenge colleagues to take up the mantle and advance awareness of the subtleties, intricacies, and nuances of intestinal physiology in health and disease by defining communication pathways between gut resident cells, those recruited from the circulation, and "external" influences such as the central nervous system and the gut microbiota.

Persistent post-surgical pain (PPSP) is defined as pain which continues after a surgical operation in a significant form for at least three months (and is not related to pre-existing painful conditions). PPSP is a common, under-recognised, and important clinical problem which affects millions of patients worldwide. Preventative measures which are currently available include the selection of a minimally invasive surgical technique and an aggressive multimodal perioperative analgesic regimen. More recently, a role for the gut microbiota in pain modulation has become increasingly apparent. This study aims to investigate any relationship between the gut microbiota and PPSP. A prospective observational study of 68 female adult patients undergoing surgery for management of breast cancer was carried out. Stool samples from 45 of these patients were obtained to analyse the composition of the gut microbiota. Measures of pain and state-trait anxiety were also taken to investigate further dimensions in any relationship between the gut microbiota and PPSP. At 12 weeks postoperatively, 21 patients (51.2%) did not have any pain and 20 patients (48.8%) reported feeling pain that persisted at that time. Analysis of the gut microbiota revealed significantly lower alpha diversity (using three measures) in those patients reporting severe pain at the 60 min post-operative and the 12 weeks post-operative timepoints. A cluster of taxa represented by Bifidobacterium longum, and Faecalibacterium prausnitzii was closely associated with those individuals reporting no pain at 12 weeks postoperatively, while Megamonas hypermegale, Bacteroides pectinophilus, Ruminococcus bromii, and Roseburia hominis clustered relatively closely in the group of patients fulfilling the criteria for persistent post-operative pain. We report for the first time specific associations between the gut microbiota composition and the presence or absence of PPSP. This may provide further insights into mechanisms behind the role of the gut microbiota in the development of PPSP and could inform future treatment strategies.

Sexual dimorphism of visceral pain has been documented in clinics and experimental animal models. Aside from hormones, emerging evidence suggests the sex-differential intrinsic neural regulation of pain generation and maintenance. According to the International Association for the Study of Pain (IASP) and the American College of Gastroenterology (ACG), up to 25% of the population have visceral pain at any one time, and in the United States 10-15 percent of adults suffer from irritable bowel syndrome (IBS). Here we examine the preclinical and clinical evidence of sex differences in visceral pain focusing on IBS, other forms of bowel dysfunction and IBS-associated comorbidities. We summarize preclinical animal models that provide a means to investigate the underlying molecular mechanisms in the sexual dimorphism of visceral pain. Neurons and nonneuronal cells (glia and immune cells) in the peripheral and central nervous systems, and the communication of gut microbiota and neural systems all contribute to sex-dependent nociception and nociplasticity in visceral painful signal processing. Emotion is another factor in pain perception and appears to have sexual dimorphism.

Abdominal pain is a major symptom of diseases that are associated with microbial dysbiosis, including irritable bowel syndrome and inflammatory bowel disease. Germ-free mice are more prone to abdominal pain than conventionally housed mice, and reconstitution of the microbiota in germ-free mice reduces abdominal pain sensitivity. However, the mechanisms underlying microbial modulation of pain remain elusive. We hypothesized that disruption of the intestinal microbiota modulates the excitability of peripheral nociceptive neurons.

In vivo and in vitro assays of visceral sensation were performed on mice treated with the nonabsorbable antibiotic vancomycin (50 μg/mL in drinking water) for 7 days and water-treated control mice. Bacterial dysbiosis was verified by 16s rRNA analysis of stool microbial composition.

Treatment of mice with vancomycin led to an increased sensitivity to colonic distension in vivo and in vitro and hyperexcitability of dorsal root ganglion (DRG) neurons in vitro, compared with controls. Interestingly, hyperexcitability of DRG neurons was not restricted to those that innervated the gut, suggesting a widespread effect of gut dysbiosis on peripheral pain circuits. Consistent with this, mice treated with vancomycin were more sensitive than control mice to thermal stimuli applied to hind paws. Incubation of DRG neurons from naive mice in serum from vancomycin-treated mice increased DRG neuron excitability, suggesting that microbial dysbiosis alters circulating mediators that influence nociception. The cysteine protease inhibitor E64 (30 nmol/L) and the protease-activated receptor 2 (PAR-2) antagonist GB-83 (10 μmol/L) each blocked the increase in DRG neuron excitability in response to serum from vancomycin-treated mice, as did the knockout of PAR-2 in NaV1.8-expressing neurons. Stool supernatant, but not colonic supernatant, from mice treated with vancomycin increased DRG neuron excitability via cysteine protease activation of PAR-2.

Together, these data suggest that gut microbial dysbiosis alters pain sensitivity and identify cysteine proteases as a potential mediator of this effect.

Gastro-oesophageal reflux disease (GORD) is a chronic condition characterised by visceral pain in the distal oesophagus. The current first-line treatment for GORD is proton pump inhibitors (PPIs), however, PPIs are ineffective in a large cohort of patients and long-term use may have adverse effects. Emerging evidence suggests that nerve fibre number and location are likely to play interrelated roles in nociception in the oesophagus of GORD patients. Simultaneously, alterations in cells of the oesophageal mucosa, namely epithelial cells, mast cells, dendritic cells, and T lymphocytes, have been a focus of GORD research for several years. The oesophagus of GORD patients exhibits both macro- and micro-inflammation as a response to chronic acidic reflux at the epithelium. In other conditions of the GI tract, such as IBS and IBD, well-characterised bidirectional processes between immune cells and mucosal nerve fibres contribute to pathogenesis and symptom generation. Sensory alterations in these conditions such as nerve fibre outgrowth and hypersensitivity can be driven by inflammatory processes, which promote visceral pain signalling. This review will examine what is currently known of the molecular pathways linking inflammation and sensory perception leading to the development of GORD symptoms and explore potentially relevant mechanisms in other GI regions which may indicate new areas in GORD research.

Autism spectrum disorders (ASDs) are recognized as central neurodevelopmental disorders diagnosed by impairments in social interactions, communication and repetitive behaviours. The recognition of ASD as a central nervous system (CNS)-mediated neurobehavioural disorder has led most of the research in ASD to be focused on the CNS. However, gastrointestinal function is also likely to be affected owing to the neural mechanistic nature of ASD and the nervous system in the gastrointestinal tract (enteric nervous system). Thus, it is unsurprising that gastrointestinal disorders, particularly constipation, diarrhoea and abdominal pain, are highly comorbid in individuals with ASD. Gastrointestinal problems have also been repeatedly associated with increased severity of the core symptoms diagnostic of ASD and other centrally mediated comorbid conditions, including psychiatric issues, irritability, rigid-compulsive behaviours and aggression. Despite the high prevalence of gastrointestinal dysfunction in ASD and its associated behavioural comorbidities, the specific links between these two conditions have not been clearly delineated, and current data linking ASD to gastrointestinal dysfunction have not been extensively reviewed. This Review outlines the established and emerging clinical and preclinical evidence that emphasizes the gut as a novel mechanistic and potential therapeutic target for individuals with ASD.

Pain is the most common symptom experienced by patients with sickle cell disease (SCD) throughout their lives and is the main cause of hospitalization. Despite the progress that has been made towards understanding the disease pathophysiology, major gaps remain in the knowledge of SCD pain, the transition to chronic pain, and effective pain management. Recent evidence has demonstrated a vital role of gut microbiota in pathophysiological features of SCD. However, the role of gut microbiota in SCD pain is yet to be explored. We sought to evaluate the compositional differences in the gut microbiota of transgenic mice with SCD and nonsickle control mice and investigate the role of gut microbiota in SCD pain by using antibiotic-mediated gut microbiota depletion and fecal material transplantation (FMT). The antibiotic-mediated gut microbiota depletion did not affect evoked pain but significantly attenuated ongoing spontaneous pain in mice with SCD. Fecal material transplantation from mice with SCD to wild-type mice resulted in tactile allodynia (0.95 ± 0.17 g vs 0.08 ± 0.02 g, von Frey test, P < 0.001), heat hyperalgesia (15.10 ± 0.79 seconds vs 8.68 ± 1.17 seconds, radiant heat, P < 0.01), cold allodynia (2.75 ± 0.26 seconds vs 1.68 ± 0.08 seconds, dry ice test, P < 0.01), and anxiety-like behaviors (Elevated Plus Maze Test, Open Field Test). On the contrary, reshaping gut microbiota of mice with SCD with FMT from WT mice resulted in reduced tactile allodynia (0.05 ± 0.01 g vs 0.25 ± 0.03 g, P < 0.001), heat hyperalgesia (5.89 ± 0.67 seconds vs 12.25 ± 0.76 seconds, P < 0.001), and anxiety-like behaviors. These findings provide insights into the relationship between gut microbiota dysbiosis and pain in SCD, highlighting the importance of gut microbial communities that may serve as potential targets for novel pain interventions.

Irritable bowel syndrome (IBS) is a prolonged bowel illness that is generally stress-related and is characterized by a variety of gastrointestinal problems, the most prominent of which is chronic visceral abdominal discomfort. As a result, IBS typically impacts sufferers' standard of living, and it is typically associated with depression and anxiety symptoms. IBS medication is based mostly on symptom alleviation. However, no effective medicines have been discovered too far. As a result, it is essential to discover novel anti-IBS medications.

The purpose of this brief review is to describe the existing research on nutraceutical supplements in irritable bowel syndrome management, including probiotics, prebiotics, symbiotics, herbal products, and dietary fibers.

This review covered the relevant papers from the previous twenty years that were available in different journals such as Science Direct, Elsevier, NCBI, and Web of Science that were related to the role and function of nutraceuticals in Irritable Bowel Syndrome.

Nutraceutical substances have a variety of modes of action, including restoring the healthy microbiome, improving the function of the gastrointestinal barrier, immunomodulatory, antiinflammatory, and antinociceptive properties. According to the literature, these substances not only can improve irritable bowel syndrome symptomatology but also have an excellent long-term safety profile.

Irritable bowel syndrome is a prolonged bowel illness with a lot of gastrointestinal problems. The nutraceuticals treatment works as an anti-IBS intervention and enhances patient compliance with minimum side effects since patients take it better than pharmaceutical treatments.

The International Rome Committee defines Disorders of Gut-Brain Interactions (DGBI) based upon distinct combinations of chronic and/or recurrent unexplained gastrointestinal symptoms. Yet patients often experience overlapping DGBI. Patients with DGBI frequently also suffer from extraintestinal symptoms, including fatigue, sleep disturbances, anxiety, and depression. Patients with overlapping DGBI typically experience more severe GI symptoms and increased psychosocial burden. Concerning the pathophysiology, DGBI are associated with disruptions in gut motility, function of the brain and enteric neurons, immune function, and genetic markers, with recent findings revealing gut microbiome alterations linked to these mechanisms of DGBI. Emerging evidence summarized in this review suggests that the microbiome influences various established disease mechanisms of different DGBI groups. Overall, changes in the gastrointestinal microbiome do not seem to be linked to a specific DGBI subgroup but may play a key role in the manifestation of different DGBI and, subsequently, overlap of DGBI. Understanding these shared mechanisms and the role of the gastrointestinal microbiome, particularly for overlapping DGBI, might aid in developing more precise diagnostic criteria and treatment strategies while developing personalized interventions that target specific mechanisms to improve patient outcomes.

Pain perception involves current stimulation in peripheral nociceptive nerves and the subsequent stimulation of postsynaptic excitatory neurons in the spinal cord. Importantly, in chronic pain, the neural activity of both peripheral nociceptors and postsynaptic neurons in the central nervous system is influenced by several inflammatory mediators produced by the immune system. Growing evidence has indicated that the commensal microbiota plays an active role in regulating pain perception by either acting directly on nociceptors or indirectly through the modulation of the inflammatory activity on immune cells. This symbiotic relationship is mediated by soluble bacterial mediators or intrinsic structural components of bacteria that act on eukaryotic cells, including neurons, microglia, astrocytes, macrophages, T cells, enterochromaffin cells, and enteric glial cells. The molecular mechanisms involve bacterial molecules that act directly on neurons, affecting their excitability, or indirectly on non-neuronal cells, inducing changes in the production of proinflammatory or anti-inflammatory mediators. Importantly, Parkinson disease, a neurodegenerative and inflammatory disorder that affects mainly the dopaminergic neurons implicated in the control of voluntary movements, involves not only a motor decline but also nonmotor symptomatology, including chronic pain. Of note, several recent studies have shown that Parkinson disease involves a dysbiosis in the composition of the gut microbiota. In this review, we first summarize, integrate, and classify the molecular mechanisms implicated in the microbiota-mediated regulation of chronic pain. Second, we analyze the changes on the commensal microbiota associated to Parkinson disease and propose how these changes affect the development of chronic pain in this pathology. SIGNIFICANCE STATEMENT: The microbiota regulates chronic pain through the action of bacterial signals into two main locations: the peripheral nociceptors and the postsynaptic excitatory neurons in the spinal cord. The dysbiosis associated to Parkinson disease reveals increased representation of commensals that potentially exacerbate chronic pain and reduced levels of bacteria with beneficial effects on pain. This review encourages further research to better understand the signals involved in bacteria-bacteria and bacteria-host communication to get the clues for the development of probiotics with therapeutic potential.

The link between gut microbiota and chronic painful conditions has recently gained attention. Nutrition, as a common intervention in daily life and medical practice, is closely related to microbiota and pain. However, no published bibliometric reports have analyzed the scientific literature concerning the link.

We used bibliometrics to identify the characteristics of the global scientific output over the past 20 years. We also aimed to capture and describe how nutrition can modulate the abovementioned link. Relevant papers were searched in the Web of Science database. All necessary publication and citation data were acquired and exported to Bibliometrix for further analyses. The keywords mentioned were illustrated using visualization maps. In total, 1551 papers shed light on the relationship from 2003 to 2022. However, only 122 papers discussed how nutritional interventions can modulate this link. The citations and attention were concentrated on the gut microbiota, pain, and probiotics in terms of the pain-gut relationship. Nutritional status has gained attention in motor themes of a thematic map.

This bibliometric analysis was applied to identify the scientific literature linking gut microbiota, chronic painful conditions, and nutrition, revealing the popular research topics and authors, scientific institutions, countries, and journals in this field. This study enriches the evidence moving boundaries of microbiota medicine as a clinical medicine.

Several studies have shown that the gut microbiota influences behavior and, in turn, changes in the immune system associated with symptoms of depression or anxiety disorder may be mirrored by corresponding changes in the gut microbiota. Although the composition/function of the intestinal microbiota appears to affect the central nervous system (CNS) activities through multiple mechanisms, accurate epidemiological evidence that clearly explains the connection between the CNS pathology and the intestinal dysbiosis is not yet available. The enteric nervous system (ENS) is a separate branch of the autonomic nervous system (ANS) and the largest part of the peripheral nervous system (PNS). It is composed of a vast and complex network of neurons which communicate via several neuromodulators and neurotransmitters, like those found in the CNS. Interestingly, despite its tight connections to both the PNS and ANS, the ENS is also capable of some independent activities. This concept, together with the suggested role played by intestinal microorganisms and the metabolome in the onset and progression of CNS neurological (neurodegenerative, autoimmune) and psychopathological (depression, anxiety disorders, autism) diseases, explains the large number of investigations exploring the functional role and the physiopathological implications of the gut microbiota/brain axis.

The gut-brain axis (GBA) is the umbrella term to include all bidirectional communication between the brain and gastrointestinal (GI) tract in the mammalian body. Evidence from over two centuries describes a significant role of GI microbiome in health and disease states of the host organism. Short-chain fatty acids (SCFAs), mainly acetate, butyrate, and propionate that are the physiological forms of acetic acid, butyric acid, and propionic acid respectively, are GI bacteria derived metabolites. SCFAs have been reported to influence cellular function in multiple neurodegenerative diseases (NDDs). In addition, the inflammation modulating properties of SCFAs make them suitable therapeutic candidates in neuroinflammatory conditions. This review provides a historical background of the GBA and current knowledge of the GI microbiome and role of individual SCFAs in central nervous system (CNS) disorders. Recently, a few reports have also identified the effects of GI metabolites in the case of viral infections. Among these viruses, the flaviviridae family is associated with neuroinflammation and deterioration of CNS functions. In this context, we additionally introduce SCFA based mechanisms in different viral pathogenesis to understand the former's potential as agents against flaviviral disease.

Irritable bowel syndrome (IBS) is a persistent set of symptoms that reduces one's goodness of life. The treatment of these people is usually focused on reducing the symptoms caused by the condition. This article examines the function of probiotics in alleviating symptoms in IBS patients. The goal of studying the impact of probiotics on IBS patients is to research the changes they cause to the gut microbiota, which may be beneficial in preventing and treating such diseases over time. This article also discusses the pathophysiology, diagnostic standards, therapeutic modalities, probiotic sources, and therapeutic relevance for IBS patients.

Celiac disease (CeD) is a common immune-mediated disease triggered by the ingestion of gluten in genetically predisposed individuals. CeD is unique in that the trigger (gluten), necessary genes (HLA-DQ2 and DQ8), and the autoantigen (tissue transglutaminase) have been identified, allowing additional environmental co-factors, like the intestinal microbiota, to be studied through relevant in vivo models. Murine models for CeD have come a long way in the past decade and there are now in vitro and in vivo tools available that mimic certain aspects of clinical disease. These models, many of which express the CeD risk genes, have recently been used to study the mechanisms through which the microbiota play a role in CeD pathogenesis through a gnotobiotic approach. Historically, the generation of gnotobiology technology in mid-20th century allowed for the study of immunity and physiology under a complete absence of microbes (axenic) or known colonized status (gnotobiotic). This enabled understanding of mechanisms by which certain bacteria contribute to health and disease. With this perspective, here, we will discuss the various murine models currently being used to study CeD. We will then describe how utilizing axenic and gnotobiotic CeD models has increased our understanding of how microbes influence relevant steps of CeD pathogenesis, and explain key methodology involved in axenic and gnotobiotic modeling.

Long-term exposure to adverse life events that provoke acute or chronic psychological stress (hereinafter "stress") can negatively affect physical health and even increase susceptibility to psychological illnesses, such as anxiety and depression. As a part of the hypothalamic-pituitary-adrenal axis, corticotropin-releasing factor (CRF) released from the hypothalamus is primarily responsible for the stress response. Typically, CRF disrupts the gastrointestinal system and leads to gut microbiota dysbiosis, thereby increasing risk of functional gastrointestinal diseases, such as irritable bowel syndrome. Furthermore, CRF increases oxidative damage to the colon and triggers immune responses involving mast cells, neutrophils, and monocytes. CRF even affects the differentiation of intestinal stem cells (ISCs), causing enterochromaffin cells to secrete excessive amounts of 5-hydroxytryptamine (5-HT). Therefore, stress is often accompanied by damage to the intestinal epithelial barrier function, followed by increased intestinal permeability and bacterial translocation. There are multi-network interactions between the gut microbiota and stress, and gut microbiota may relieve the effects of stress on the body. Dietary intake of probiotics can provide energy for ISCs through glycolysis, thereby alleviating the disruption to homeostasis caused by stress, and it significantly bolsters the intestinal barrier, alleviates intestinal inflammation, and maintains endocrine homeostasis. Gut microbiota also directly affect the synthesis of hormones and neurotransmitters, such as CRF, 5-HT, dopamine, and norepinephrine. Moreover, the Mediterranean diet enhances the stress resistance to some extent by regulating the intestinal flora. This article reviews recent research on how stress damages the gut and microbiota, how the gut microbiota can improve gut health by modulating injury due to stress, and how the diet relieves stress injury by interfering with intestinal microflora. This review gives insight into the potential role of the gut and its microbiota in relieving the effects of stress via the gut-brain axis.

Compositional changes in the microbiota (dysbiosis) may be a basis for Irritable Bowel Syndrome (IBS), but biomarkers are currently unavailable to direct microbiota-directed therapy. We therefore examined whether changes in fecal β-defensin could be a marker of dysbiosis in a murine model. Experimental dysbiosis was induced using four interventions relevant to IBS: a mix of antimicrobials, westernized diets (high-fat/high-sugar and high salt diets), or mild restraint stress. Fecal mouse β-defensin-3 and 16S rRNA-based microbiome profiles were assessed at baseline and during and following these interventions. Each intervention, except for mild restraint stress, altered compositional and diversity profiles of the microbiota. Exposure to antimicrobials or a high-fat/high-sugar diet, but not mild restraint stress, resulted in decreased fecal β-defensin-3 compared to baseline. In contrast, exposure to the high salt diet increased β-defensin-3 compared to baseline. Mice exposed to the mix of antimicrobials showed the largest compositional changes and the most significant correlations between β-defensin-3 levels and bacterial diversity. The high salt diet was also associated with significant correlations between changes in β-defensin-3 and bacterial diversity, and this was not accompanied by discernible inflammatory changes in the host. Thus, dietary change or antimicrobial exposure, both recognized factors in IBS exacerbations, induced marked dysbiosis that was accompanied by changes in fecal β-defensin-3 levels. We propose that serial monitoring of fecal β-defensins may serve as a marker of dysbiosis and help identify those IBS patients who may benefit from microbiota-directed therapeutic interventions.

Abdominal pain is common in patients with gastrointestinal disorders, but its pathophysiology is unclear, in part due to poor understanding of basic mechanisms underlying visceral sensitivity. Accumulating evidence suggests that gut microbiota is an important determinant of visceral sensitivity. Clinical and basic research studies also show that sex plays a role in pain perception, although the precise pathways are not elucidated. We investigated pain responses in germ-free and conventionally raised mice of both sexes, and assessed visceral sensitivity to colorectal distension, neuronal excitability of dorsal root ganglia (DRG) neurons and the production of substance P and calcitonin gene-related peptide (CGRP) in response to capsaicin or a mixture of G-protein coupled receptor (GPCR) agonists. Germ-free mice displayed greater in vivo responses to colonic distention than conventional mice, with no differences between males and females. Pretreatment with intracolonic capsaicin or GPCR agonists increased responses in conventional, but not in germ-free mice. In DRG neurons, gut microbiota and sex had no effect on neuronal activation by capsaicin or GPCR agonists. While stimulated production of substance P by DRG neurons was similar in germ-free and conventional mice, with no additional effect of sex, the CGRP production was higher in germ-free mice, mainly in females. Absence of gut microbiota increases visceral sensitivity to colorectal distention in both male and female mice. This is, at least in part, due to increased production of CGRP by DRG neurons, which is mainly evident in female mice. However, central mechanisms are also likely involved in this process.

The composition of intestinal microbiota is influenced by a number of factors, including medications, which may have a substantial impact on host physiology. Nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics are among those widely used medications that have been shown to alter microbiota composition in both animals and humans. Although much effort has been devoted to identify microbiota signatures associated with these medications, much less is known about the underlying mechanisms. Mucosal inflammation, changes in intestinal motility, luminal pH and bile acid metabolism, or direct drug-induced inhibitory effect on bacterial growth are all potential contributors to NSAID- and opioid-induced dysbiosis, however, only a few studies have addressed directly these issues. In addition, there is a notable overlap between the microbiota signatures of these drugs and certain diseases in which they are used, such as spondyloarthritis (SpA), rheumatoid arthritis (RA) and neuropathic pain associated with type 2 diabetes (T2D). The aims of the present review are threefold. First, we aim to provide a comprehensive up-to-date summary on the bacterial alterations caused by NSAIDs and opioids. Second, we critically review the available data on the possible underlying mechanisms of dysbiosis. Third, we review the current knowledge on gut dysbiosis associated with SpA, RA and neuropathic pain in T2D, and highlight the similarities between them and those caused by NSAIDs and opioids. We posit that drug-induced dysbiosis may contribute to the persistence of these diseases, and may potentially limit the therapeutic effect of these medications by long-term use. In this context, we will review the available literature data on the effect of probiotic supplementation and fecal microbiota transplantation on the therapeutic efficacy of NSAIDs and opioids in these diseases.

Diabetes mellitus is a disease with multiple gastrointestinal symptoms (diarrhea or constipation, abdominal pain, bloating) whose pathogenesis is multifactorial. The most important of these factors is the enteric nervous system, also known as the "second brain"; a part of the peripheral nervous system capable of functioning independently of the central nervous system. Modulation of the enteric nervous system can be done by short-chain fatty acids, which are bacterial metabolites of the intestinal microbiota. In addition, these acids provide multiple benefits in diabetes, particularly by stimulating glucagon-like peptide 1 and insulin secretion. However, it is not clear what type of nutraceuticals (probiotics, prebiotics, and alimentary supplements) can be used to increase the amount of short-chain fatty acids and achieve the beneficial effects in diabetes. Thus, even if several studies demonstrate that the gut microbiota modulates the activity of the ENS, and thus, may have a positive effect in diabetes, further studies are needed to underline this effect. This review outlines the most recent data regarding the involvement of SCFAs as a disease modifying agent in diabetes mellitus type 2. For an in-depth understanding of the modulation of gut dysbiosis with SCFAs in diabetes, we provide an overview of the interplay between gut microbiota and ENS.

Limosilactobacillus fermentum CECT5716, a probiotic strain isolated from human milk, has reported beneficial effects on different gastrointestinal disorders. Moreover, it has shown its ability to restore altered immune responses, in association with microbiome modulation in different pathological conditions. Therefore, our aim was to assess the effects of a Limosilacbacillus fermentum CECT5716 in a rat experimental model of irritable bowel syndrome (IBS) that resembles human IBS. The experimental IBS was induced by deoxycholic acid (DCA) in rats and then, Limosilactobacillus fermentum CECT5716 (109 CFU/day/rat) was administered. Behavioral studies, hyperalgesia and intestinal hypersensitivity determinations were performed and the impact of the probiotic on the inflammatory and intestinal barrier integrity was evaluated. Additionally, the gut microbiota composition was analyzed. Limosilactobacillus fermentum CECT5716 attenuated the anxiety-like behavior as well as the visceral hypersensitivity and referred pain. Moreover, this probiotic ameliorated the gut inflammatory status, re-establishing the altered intestinal permeability, reducing the mast cell degranulation and re-establishing the gut dysbiosis in experimental IBS. Therefore, our results suggest a potential use of Limosilactobacillus fermentum CECT5716 in clinical practice for the management of IBS patients.

The gut microbiota is involved in the regulation of pain, which is proved by plenty of evidence. Although a substantial quantity of research on the link between the gut microbiota and pain has emerged, no study has focused on the bibliometric analysis of this topic. We aim to present a bibliometric review of publications over the past 20 years and predict research hot spots.

Relevant publications between 2002 and 2021 were extracted from the Science Citation Index-Expanded (SCI-EXPANDED) of the Web of Science Core Collection (WoSCC) database on April 22, 2022. CiteSpace (version 5.8 R3c), VOSviewer, the Online Analysis Platform of Literature Metrology, and the R package bibliometrix were used to analyze and visualize.

A total of 233 articles have been published between 2002 and 2021. The number of publication outputs increased rapidly since 2016. The collaboration network revealed that the USA, Baylor College of Medicine, and Vassilia Theodorou were the most influential country, institute, and scholar, respectively. Alimentary pharmacology and therapeutics and Gut were the most co-cited journal and Neurogastroenterology and Motility was the most productive journal. Visceral sensitivity, fibromyalgia, gastrointestinal, chronic pain, stress, gut microbiome, LGG, brain-gut axis, SLAB51, and sequencing were the top 10 clusters in co-occurrence cluster analysis. Keyword burst detection indicated that the brain-gut axis and short-chain fatty acid were the current research hot spots.

Research on the links between the gut microbiota and pain has increased rapidly since 2016. The current research focused on the brain-gut axis and short-chain fatty acid. Accordingly, the SCFAs-mediated mechanism of pain regulation will be a research direction of great importance on the links between the gut microbiota and pain. This study provided instructive assistance to direct future research efforts on the links between the gut microbiota and pain.

Functional dyspepsia (FD) is a common and debilitating gastrointestinal disorder attributed to altered gut-brain interactions. While the etiology of FD remains unknown, emerging research suggests the mechanisms are likely multifactorial and heterogenous among patient subgroups. Small bowel motor disturbances, visceral hypersensitivity, chronic microinflammation, and increased intestinal tract permeability have all been linked to the pathogenesis of FD. Recently, alterations to the gut microbiome have also been implicated to play an important role in the disease. Changes to the duodenal microbiota may either trigger or be a consequence of immune and neuronal disturbances observed in the disease, but the mechanisms of influence of small intestinal flora on gastrointestinal function and symptomatology are unknown.

This review summarizes and synthesizes the literature on the link between the microbiota, low-grade inflammatory changes in the duodenum and FD. This review is not intended to provide a complete overview of FD or the small intestinal microbiota, but instead outline some of the key conceptual advances in understanding the interactions between altered gastrointestinal bacterial communities; dietary factors; host immune activation; and stimulation of the gut-brain axes in patients with FD versus controls. Current and emerging treatment approaches such as dietary interventions and antibiotic or probiotic use that have demonstrated symptom benefits for patients are reviewed, and their role in modulating the host-microbiota is discussed. Finally, suggested opportunities for diagnostic and therapeutic improvements for patients with this condition are presented.

Many veterans who served in Operation Desert Storm (August 1990 to March 1991) experienced a complex of symptoms of unknown etiology called Gulf War illness (GWI), which significantly impacts the health and quality of life (QOL) and may have contributed to irritable bowel syndrome (IBS).

We performed a prospective, double-blind placebocontrolled study to determine the efficacy of the multistrain De Simone Formulation probiotic containing 8 strains of bacteria on symptoms of IBS and GWI. Veterans of Operation Desert Storm who had IBS and ≥ 2 nonintestinal symptoms of GWI were included. The primary study endpoint was change in bowel symptom score. The secondary endpoints were mean change in symptoms, QOL, and extra-intestinal and posttraumatic stress disorder (PTSD) symptoms.

A total of 101 Gulf War veterans with IBS and GWI were screened at the Veteran Affairs Medical Center in Salt Lake City, Utah. The study was completed by 53 veterans; 47 (89%) were male with a mean (SD) age of 55 (8) years. The probiotic did not improve IBS symptoms or other extra-intestinal symptoms common to IBS and GWI.

Our study did not demonstrate statistically significant improvement in IBS symptoms or QOL after treatment with the probiotic. We also did not find any improvement in symptoms of GWI or PTSD.

Inflammatory bowel disease (IBD), comprising Crohn's disease and Ulcerative colitis, is a relapsing and remitting disease of the gastrointestinal tract, presenting with chronic inflammation, ulceration, gastrointestinal bleeding, and abdominal pain. Up to 80% of patients suffering from IBD experience acute pain, which dissipates when the underlying inflammation and tissue damage resolves. However, despite achieving endoscopic remission with no signs of ongoing intestinal inflammation or damage, 30-50% of IBD patients in remission experience chronic abdominal pain, suggesting altered sensory neuronal processing in this disorder. Furthermore, effective treatment for chronic pain is limited such that 5-25% of IBD outpatients are treated with narcotics, with associated morbidity and mortality. IBD patients commonly present with substantial alterations to the microbial community structure within the gastrointestinal tract, known as dysbiosis. The same is also true in irritable bowel syndrome (IBS), a chronic disorder characterized by altered bowel habits and abdominal pain, in the absence of inflammation. An emerging body of literature suggests that the gut microbiome plays an important role in visceral hypersensitivity. Specific microbial metabolites have an intimate relationship with host receptors that are highly expressed on host cell and neurons, suggesting that microbial metabolites play a key role in visceral hypersensitivity. In this review, we will discuss the techniques used to analysis the metabolome, current potential metabolite targets for visceral hypersensitivity, and discuss the current literature that evaluates the role of the post-inflammatory microbiota and metabolites in visceral hypersensitivity.

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).

Trillions of bacteria reside within our gastrointestinal tract, ideally forming a mutually beneficial relationship between us. However, persistent changes in diet and lifestyle in the western diet and lifestyle contribute to a damaging of the gut microbiota-host symbiosis leading to diseases such as obesity and irritable bowel syndrome. Many symptoms and comorbidities associated with these diseases stem from dysfunctional signaling in peripheral neurons. Our peripheral nervous system (PNS) is comprised of a variety of sensory, autonomic, and enteric neurons which coordinate key homeostatic functions such as gastrointestinal motility, digestion, immunity, feeding behavior, glucose and lipid homeostasis, and more. The composition and signaling of bacteria in our gut dramatically influences how our peripheral neurons regulate these functions, and we are just beginning to uncover the molecular mechanisms mediating this communication. In this review, we cover the general anatomy and function of the PNS, and then we discuss how the molecules secreted or stimulated by gut microbes signal through the PNS to alter host development and physiology. Finally, we discuss how leveraging the power of our gut microbes on peripheral nervous system signaling may offer effective therapies to counteract the rise in chronic diseases crippling the western world.

Recent findings linked gastrointestinal disorders characterized by abdominal pain to gut microbiota composition. The present work aimed to evaluate the power of gut microbiota as a visceral pain modulator and, consequently, the relevance of its manipulation as a therapeutic option in reversing postinflammatory visceral pain persistence. Colitis was induced in mice by intrarectally injecting 2,4-dinitrobenzenesulfonic acid (DNBS). The effect of faecal microbiota transplantation from viscerally hypersensitive DNBS-treated and naive donors was evaluated in control rats after an antibiotic-mediated microbiota depletion. Faecal microbiota transplantation from DNBS donors induced a long-lasting visceral hypersensitivity in control rats. Pain threshold trend correlated with major modifications in the composition of gut microbiota and short chain fatty acids. By contrast, no significant alterations of colon histology, permeability, and monoamines levels were detected. Finally, by manipulating the gut microbiota of DNBS-treated animals, a counteraction of persistent visceral pain was achieved. The present results provide novel insights into the relationship between intestinal microbiota and visceral hypersensitivity, highlighting the therapeutic potential of microbiota-targeted interventions.