A complex bidirectional communication system exists between the gastrointestinal tract and the brain. Initially termed the “gut-brain axis” it is now renamed the “microbiota-gut-brain axis” considering the pivotal role of gut microbiota in maintaining local and systemic homeostasis. Different cellular and molecular pathways act along this axis and strong attention is paid to neuroactive molecules (neurotransmitters, i.e., noradrenaline, dopamine, serotonin, gamma aminobutyric acid and glutamate and metabolites, i.e., tryptophan metabolites), sustaining a possible interkingdom communication system between eukaryota and prokaryota. This review provides a description of the most up-to-date evidence on glutamate as a neurotransmitter/neuromodulator in this bidirectional communication axis. Modulation of glutamatergic receptor activity along the microbiota-gut-brain axis may influence gut (i.e., taste, visceral sensitivity and motility) and brain functions (stress response, mood and behavior) and alterations of glutamatergic transmission may participate to the pathogenesis of local and brain disorders. In this latter context, we will focus on two major gut disorders, such as irritable bowel syndrome and inflammatory bowel disease, both characterized by psychiatric co-morbidity. Research in this area opens the possibility to target glutamatergic neurotransmission, either pharmacologically or by the use of probiotics producing neuroactive molecules, as a therapeutic approach for the treatment of gastrointestinal and related psychiatric disorders.

The complex bidirectional communication system existing between the gastrointestinal tract and the brain initially termed the “gut–brain axis” and renamed the “microbiota–gut–brain axis”, considering the pivotal role of gut microbiota in sustaining local and systemic homeostasis, has a fundamental role in the pathogenesis of Inflammatory Bowel Disease (IBD). The integration of signals deriving from the host neuronal, immune, and endocrine systems with signals deriving from the microbiota may influence the development of the local inflammatory injury and impacts also more distal brain regions, underlying the psychophysiological vulnerability of IBD patients. Mood disorders and increased response to stress are frequently associated with IBD and may affect the disease recurrence and severity, thus requiring an appropriate therapeutic approach in addition to conventional anti-inflammatory treatments. This review highlights the more recent evidence suggesting that alterations of the microbiota–gut–brain bidirectional communication axis may concur to IBD pathogenesis and sustain the development of both local and CNS symptoms. The participation of the main microbial-derived metabolites, also defined as “postbiotics”, such as bile acids, short-chain fatty acids, and tryptophan metabolites in the development of IBD-associated gut and brain dysfunction will be discussed. The last section covers a critical evaluation of the main clinical evidence pointing to the microbiome-based therapeutic approaches for the treatment of IBD-related gastrointestinal and neuropsychiatric symptoms.

Visceral pain, of which the pathogenic basis is currently largely unknown, is a hallmark symptom of both functional disorders, such as irritable bowel syndrome, and inflammatory bowel disease. Intrinsic sensory neurons in the enteric nervous system and afferent sensory neurons of the dorsal root ganglia, connecting with the central nervous system, represent the primary neuronal pathways transducing gut visceral pain. Current pharmacological therapies have several limitations, owing to their partial efficacy and the generation of severe adverse effects. Numerous cellular targets of visceral nociception have been recognized, including, among others, channels (i.e., voltage-gated sodium channels, VGSCs, voltage-gated calcium channels, VGCCs, Transient Receptor Potential, TRP, and Acid-sensing ion channels, ASICs) and neurotransmitter pathways (i.e., GABAergic pathways), which represent attractive targets for the discovery of novel drugs. Natural biologically active compounds, such as marine toxins, able to bind with high affinity and selectivity to different visceral pain molecular mediators, may represent a useful tool (1) to improve our knowledge of the physiological and pathological relevance of each nociceptive target, and (2) to discover therapeutically valuable molecules. In this review we report the most recent literature describing the effects of marine toxin on gastrointestinal visceral pain pathways and the possible clinical implications in the treatment of chronic pain associated with gut diseases.

The commensal microbiota plays a fundamental role in maintaining host gut homeostasis by controlling several metabolic, neuronal and immune functions. Conversely, changes in the gut microenvironment may alter the saprophytic microbial community and function, hampering the positive relationship with the host. In this bidirectional interplay between the gut microbiota and the host, hyaluronan (HA), an unbranched glycosaminoglycan component of the extracellular matrix, has a multifaceted role. HA is fundamental for bacterial metabolism and influences bacterial adhesiveness to the mucosal layer and diffusion across the epithelial barrier. In the host, HA may be produced and distributed in different cellular components within the gut microenvironment, playing a role in the modulation of immune and neuronal responses. This review covers the more recent studies highlighting the relevance of HA as a putative modulator of the communication between luminal bacteria and the host gut neuro-immune axis both in health and disease conditions, such as inflammatory bowel disease and ischemia/reperfusion injury.

Background: Intestinal ischemia and reperfusion (IRI) injury induces acute and long-lasting damage to the neuromuscular compartment and dysmotility. This study aims to evaluate the pathogenetic role of hyaluronan (HA), a glycosaminoglycan component of the extracellular matrix, as a modulator of the enteric neuronal and immune function and of the colonic microbiota during in vivo IRI in the rat small intestine. Methods: mesenteric ischemia was induced in anesthetized adult male rats for 60 min, followed by 24 h reperfusion. Injured, sham-operated and non-injured animals were treated with the HA synthesis inhibitor, 4-methylumbelliferone (4-MU 25 mg/kg). Fecal microbiota composition was evaluated by Next Generation Sequencing. Neutrophil infiltration, HA homeostasis and toll like receptor (TLR2 and TLR4) expression in the small intestine were evaluated by immunohistochemical and biomolecular approaches (qRT-PCR and Western blotting). Neuromuscular responses were studied in vitro, in the absence and presence of the selective TLR2/4 inhibitor, Sparstolonin B (SsnB 10, 30 µM). Results: 4-MU significantly reduced IRI-induced enhancement of potentially harmful Escherichia and Enterococcus bacteria. After IRI, HA levels, neutrophil infiltration, and TLR2 and TLR4 expression were significantly enhanced in the muscularis propria, and were significantly reduced to baseline levels by 4-MU. In the injured, but not in the non-injured and sham-operated groups, SsnB reduced both electrical field-stimulated (EFS, 0.1–40 Hz) contractions and EFS-induced (10 Hz) non-cholinergic non-adrenergic relaxations. Conclusions: enhanced HA levels after intestinal IRI favors harmful bacteria overgrowth, increases neutrophil infiltration and promotes the upregulation of bacterial target receptors, TLR2 and TLR4, in the muscularis propria, inducing a pro-inflammatory state. TLR2 and TLR4 activation may, however, underlay a provisional benefit on excitatory and inhibitory neuronal pathways underlying peristalsis.

Perturbations of the gastrointestinal (GI) microbiota (i.e. dysbiosis) in early life may induce vulnerability of the enteric nervous system (ENS), contributing to early onset GI disorders, such as irritable bowel syndrome (IBS). Probiotics, such as Lacticaseibacillus rhamnosus GG (LGG), may improve pediatric digestive disorders; however, the mechanisms involved, including effects on the ENS, are not yet fully understood. In this study, the long-lasting consequences of antibiotic-induced dysbiosis on intestinal neuromuscular function, as well as the effect of LGG, were evaluated in juvenile female and male mice. One week after antibiotic treatment cessation, broad-spectrum antibiotic treatment induced significant taxonomic changes in both sexes compared to untreated control animals. These changes appeared earlier and involved more potentially harmful bacterial taxa in females than in males. LGG effectively prevented alterations in microbial communities in both sexes, with a more pronounced protective effect in males. Dysbiosis reduced transit efficiency, nitrergic relaxations, and tachykinergic contractions only in females, with no significant effect of LGG in this group. In both sexes, dysbiosis decreased cholinergic contractions; however, LGG restored the excitatory responses to control levels only in males. In summary, early antibiotic-induced dysbiosis in juvenile mice leads to persistent effects during late adolescence on both gut microbiota composition and neuromuscular function. These alterations are more pronounced and less responsive to LGG treatment in females. The findings underscore the critical role of the enteric microbiota in early-life development of functional gastrointestinal disorders with sex-specific features, such IBS.