Neuroimmunomodulation by gut bacteria: Focus on inflammatory bowel diseases

Table 1 List of neuromediators and their role in gut inflammation

Neuromediator	Distribution	Binding receptor	Function
SP	Neurons and inflammatory cells like lymphocytes, macrophages, and dendritic cells	NK-1R	Exerts pro-inflammatory effects in epithelial and immune cells and contributes to inflammatory diseases. In murine model of colitis, it plays regulatory role
NT	Nervous system and intestine	NTR1	Recognized as an immunomodulator. By interacting with immune cells, it enhances the chemotaxis and induces the cytokine release to modulate the immune response. In IBD, it exerts its pro-inflammatory effects by promoting the expression of miR-210 in intestinal epithelial cells
NPY	Central and peripheral nervous system and immune cells	Out of five receptors of NPY, NPYY1 is known to play a crucial role in immunomodulation	Regulates various immune cell functions such as T helper cell differentiation, neutrophil chemotaxis, natural killer cell activity, and granulocyte oxidative burst and NO production. In the gut, NPY is known to exert pro-inflammatory effects
VIP	Neuronal and lymphoid cells	VIPR1 and VIPR2	Identified as an anti-inflammatory molecule. administration of VIP nanomedicine in the form of VIP-SSM are capable of alleviating the symptoms of DSS- induced mice model of colitis
GAL	Vasculature, immune cells and colonic epithelial cells	GAL (1-3) receptor	Exerts anti-inflammatory effects in TNBS induced colitis model by reducing the expression and activity of iNOS
CRH	Immune cells	CRH-R1 and CRH-R2	It acts as a pro-inflammatory peptide. The expression pattern of CRH 1 and CRH 2 varies in ulcerative colitis. Inhibition of CRH1 and overexpression of CRH2 may have the therapeutic potential in IBD
CGRP	Sensory nerves projecting to the lymphoid organs, airways, and pulmonary neuroendocrine cells	CGRP receptors	CGRP negatively regulates innate immune responses and thus has potential anti-inflammatory effects. Its expression reduced in the colon of an animal model of colitis
NA	Nerves innervating the peripheral lymphoid organs	Adrenergic α and β receptors	immunomodulatory effect of NA is administered via cAMP. Activation of NA receptors that stimulate cAMP resulting in a shift toward Th2 responses which are anti-inflammatory and neuroprotective whereas decreased cAMP stimulates Th1 responses resulting in cell destruction and inflammation
Acetylcholine	Central and peripheral nervous system, immune cells, keratinocytes, endothelial cells, urothelial cells of the urinary bladder, airways and epithelial cells of the placenta	Nicotinic and muscarinic receptors	Muscarinic receptors mediate pro-inflammatory responses and nicotinic receptors enhance anti-inflammatory responses. Treatment of UC via nicotine suggests the role of the cholinergic pathway in colonic inflammation
NO	Neuron synapses and immune cells	NO does not act via receptors. its specificity for target cell depends on its concentration, its activity and response, and territory of target cells	NO is oxidised to reactive nitrogen oxide species which mediate most of the immunological effects. It regulates the growth, functional activity, and death of immune cells. It acts as a biomarker for monitoring disease activity due to its increased serum concentration during the active phase of both UC and CD and reduced concentration during the inactive phase of the disease
Serotonin or 5-HT	Central nervous system and EC cells of GIT	5-HT receptor	It promotes activation of lymphocytes and secretion of pro-inflammatory cytokines. It activates the signalling molecules of the NF-kB pathway during gut inflammation
GABA	Nervous system and immune system	GABA- AR and GABA-BR	GABA has several effects on immune cells, including modulation of cytokine secretion, regulation of cell proliferation, and migration. Activation of GABA-A receptor aggravates DSS induced mice model of colitis

SP: Substance P; GABA: γ-aminobutyric acid; 5-HT: 5-hydroxytryptamine; EC: Enterochromaffin; NF-kB: Nuclear factor kB; NO: Nitric oxide; NA: Noradrenaline; CD: Crohn’s disease; UC: Ulcerative colitis; cAMP: Cyclic adenosine monophosphate; CGRP: Calcitonin gene-related peptide; IBD: Inflammatory bowel disease; CRH: Corticotropin-releasing hormone; iNOS: Inducible nitric oxide synthase; GAL: Galanin; TNBS: 2,4,6-trinitrobenzenesulfonic acid; VIP: Vasoactive intestinal peptide; SSM: Sterically stabilised micelles; NPY: Neuropeptide Y; NK-1R: Neurokinin-1 receptor; NTR1: Neurotensi receptor 1; DSS: Dextran sodium sulfate.