The immune system and the nervous system evolved to regulate bodily homeostasis, protect against invading organisms, and provide neurological communication between the CNS and organs. The immune system is mediated by organs, cells, and chemicals, which control inflammation, neutralising pathogens, and repairing damaged tissues. Inflammation can, however, become harmful resulting in chronic inflammation and autoimmune diseases [42]. Where the nervous system must allow for communication between the varying components of the body via neurotransmitters and biological regulatory molecules. These complex evolutionary systems maintain optimal bodily conditions allowing for survival and growth in the environment of the organism. In cases of functional somatic syndrome, however, there is a disconnect between these two systems resulting in chronic pain conditions, neuropathic pain, and functional issues of the digestive tract amongst other issues. Central sensitization is associated with neuroinflammation via activation of inflammatory immune cells (macrophages, mast cells, fibroblasts, etc.) and inflammatory molecules (cytokine, chemokines). As these immune mediators interact with nociceptors on the CNS and PNS changes occur in pain pathways (excitability, conductivity, and transmission) leading to increasing pain or amplification of pain in the patient [93]. Studies demonstrate that fibroblasts secrete cytokines and chemokines that can induce peripheral neuron sensitization causing peripheral neuron hypersensitivity and chronic pain [94]. Neuropathic pain occurs from a primary lesion or dysfunction of the central and peripheral nervous systems [95] and is usually chronic and persistent with limited treatment options.

Fibromyalgia is a syndrome presenting with widespread musculoskeletal pain, muscular dysfunction, hyperalgesia, allodynia, sleep disorders, cognitive issues, fatigue, and mood disorders with a prevalence of 5% predominantly affecting females [96]. Typically, FM patients have a reduced ability to tolerate pain and extreme variations in heat and cold temperatures [97]. Studies indicate that FM pain is comparable to the pain of RA, which is dysesthetic, such as painful burning, prickling, aching, or paroxysmal and temperature sensitive [98]. Establishing the role of the immune system in FM is an ongoing area of research where studies have shown altered levels of certain cytokines in FM patients, including IFN-γ, IL-5, IL-6, IL-8, and anti-inflammatory IL-10 upon activation of peripheral blood mononuclear cells (PBMCs) [99]. Importantly, the pro-inflammatory pleiotropic cytokine IL-6 is associated with neoplasia and autoimmune diseases [71]. Studies also report increased levels of pro-inflammatory cytokines post PBMC stimulation [96] leading to chronic low-grade inflammation. Adipose tissue also acts as a source of such pro-inflammatory cytokines, where increased nociceptive activity is also present in obese individuals [100]. The constant low-grade inflammation present in FSS patients sensitizes the neurons involved in sensing pain, transmitting pain signals, and representing pain in the CNS, making them more excitable. Excitable neurons then signal the perception of pain to the CNS more easily with less irritation than the non-excitable neurons of non-FM patients [3]. There is an evident alteration in the brain in FM patients with a default present between the pain inhibitory centres and the insular cortex and higher levels of glutamate compared to healthy persons [63]. Glutamate is the primary neurotransmitter released by vagus nerve sensory neurons [40]. Neurogenic inflammation also results from pro-inflammatory cytokines activating innate and adaptive immunity, which are secreted by afferent nerves in local tissues sending pain signals to the CNS. Central neuroinflammation and elevated neuropeptides (substance P), brain-derived neurotrophic factor, and Nerve Growth Factor (NGF) have been identified at elevated levels in the spinal fluid of FM patients [97]. The substance P neuropeptide engages in the pathophysiology of pain where NGF is associated with hyperalgesia and detection of painful stimuli (nociception). Studies also show an increased presence of mast cells in the skin and blood vessels of FM patients where secretory granules can release inflammatory and neuro-sensitising molecules including bradykinin, histamine, TNF, and tryptase [97]. The communication between mast cells and microglia via histamine and tryptase can also release inflammatory cytokines causing an innate immune reaction in the brain contributing to brain inflammation and brain disorders [101]. Microglia cells are macrophages that survey and clear pathogens in the CNS. Histamine and tryptase can change nociceptive visceral sensory nerve function resulting in nerve stimulation and hypersensitivity [102]. FM pain involves neuroinflammatory processes triggered by mast cells and microglia immune cells via the secretion of cytokines in the CNS. FM patients also have increased levels of the inflammatory chemokines CCL17, CXCL9, CCL22, CXCL11, and CCL11, which attract innate and immune cells [45]. Studies also report increased activity of the sympathetic nervous system in FM patients, which can moderate the peripheral nociceptor neurons indicating peripheral neuroinflammation [63]. Peripheral nociceptors involved in pathological pain express cytokine and chemokine receptors suggesting neuro activity is directly activated by the immune system resulting in excitability, termed peripheral sensitization [93]. There is evidence of abnormalities in the small nerve fibres of approximately 50% of FM patients where nerves are thinly myelinated or unmyelinated (small fibre polyneuropathy) and the average axon diameter is also reduced [103], highlighting the importance of the peripheral nervous system in FM. Alterations of C-fibres and Schwann cells are also evident [104]. The alterations in Schwann cells, nerve fibre density, and the diameter of the axons in FM patients have been observed in many chronic pain conditions [105]. Schwann cells function to detect and respond to nerve injury by altering their phenotype, proliferating, and releasing growth factors, immune mediators, i.e., cytokines, chemokines, and other molecules that interact with nociceptive neurons [95], impacting on neuropathic pain. C-fibres of primary afferent nerves are activated by stimuli and result in the sensation of pain [98]. Certain FM patients appear to suffer from the spontaneous activity of peripheral nerves and sensitisation of C-fibre nociceptors [98]. Additional observations in FM patients include dopamine dysregulation [17], alteration of endogenous cerebral opioids, neuroendocrine factors, oxidative stress, genetics, and psychosocial factors [100]. The HPA contains stress-induced neurotransmitter and neuroendocrine response systems, which are also believed to be involved in FM. Increased levels of free radicals are present in FM patients who also have a decreased antioxidant ability; free radicals excessively impact the CNS due to their high lipid content [100].

IBS is considered a functional gastrointestinal condition with intermittent abdominal pain and cramping associated with bowel movements. Visceral hypersensitivity is also considered a symptom of IBS where patients have a lower tolerance for and increased sensitivity to pain [106]. While recognised as an FSS, IBS also falls into the category of disorders of gut–brain interactions (DGBIs), or functional gastrointestinal disorders (FGIDs) [49]. IBS is generally divided into four types depending on the bowel manifestations including IBS diarrhoea (IBS-D), IBS constipation (IBS-C), IBS mixed (IBS-M), and unclassified IBS [102]. IBS has a prevalence rate of 10–25%; the pathogenesis of disease, however, remains unclear. It is generally accepted that dysregulation of the autonomic nervous system (dysautonomia), the HPA, increased sensitivity to pain, and gut dysbiosis contribute to IBS [62]. The role of the immune system in IBS pathology remains an area of much interest. Studies highlight the role of the immune system in IBS as symptoms often manifest post-gastrointestinal infection, and there is a greater prevalence in inflammatory bowel disease (IBD) patients in remission [19]. Ongoing research also demonstrates the presence of low-grade inflammation, innate immune dysfunction, and cytokine imbalance in IBS patients [102]. TNF-α, IL-1β, and IL-17 serum levels have been associated with abdominal pain and severity of symptoms in IBS patients with IL-6 and IL-8 elevated in some cohorts [71]. Decreased levels of the anti-inflammatory cytokine IL-10 are also present. The pro-inflammatory IL-1β can induce an inflammatory reaction, affect smooth muscle, and damage the mucosal barrier of the GIT [62]. The GIT also has an abundance of resident eosinophils and mast cells, which are found near nerve tissue allowing for communication between the nervous and immune systems [107]. These intestinal eosinophils secrete chemokines, cytokines, substance P, CRF, and other peptides, which may play a role in GIT disease states including IBS [108]. Studies demonstrate elevated levels of CRF in intestinal eosinophils correlate with the severity of symptoms in IBS-D patients [108]. Interestingly, 70% of mast cells in the GIT are in direct contact with nerve cells and function to regulate intestinal permeability, peristalsis, nociception, and innate and adaptive immunity amongst other functions [109]. Mast cells are also activated to release chemical mediators (histamine, serotonin, cytokines, chemokines, and tryptase) by stress-induced neural stimulation in IBS patients [107]. Enteric mast cells are triggered by neuropeptides such as vasoactive intestinal peptides to release histamine and other immune mediators resulting in neurogenic inflammation in IBS patients [49]. The role of the enteric nervous system in the pathophysiology of IBS is also not fully elucidated. The enteric nervous system consists of millions of neurons and glial cells (present in ganglia) and is sub-divided into the submucosal plexus and the myenteric plexus regulating muscular, neuro-hormonal, and secretory systems of the GIT, allowing for digestive action [110]. The findings of Ostertag, 2015, show altered neuron activity in the submucosal plexus of patients presenting with IBS, which were stimulated by immune mediators [111]. The enteric nervous system influences the intestinal epithelia, endocrine and immune systems, and the gut microbiota [43]. The enteric system has a central role in regulating gastrointestinal activity and physiology where alterations in this complex nervous system result in imbalanced GIT homeostasis, and gastrointestinal and extra-gastrointestinal disease states [49]. The communication pathway between the gut microbes and the VN is also implicated in GIT disorders where dysbiosis impacts both IBS and IBD in patients [59]. The neuroactive biologics secreted by the resident microbes (GABA, serotonin, dopamine, and acetylcholine) influence the enteric nervous system and the VN to influence the brain and peripheral organs [112]. Dysbiosis of the GIT is associated with leaky gut, visceral hypersensitivity, immune activation, inflammation, mood disorders, and chronic fatigue in IBS patients [113].

Chronic fatigue syndrome/myalgic encephalomyelitis is a chronic condition of debilitating fatigue without relief after rest, musculoskeletal pain, sleep disturbances, neuroinflammation, and cognitive impairment [114] in the absence of a patho-physiologic cause. CFS is classified by the WHO as a disease of the nervous system [115]. Viral pathogenesis is the most common trigger for CFS; stress, trauma, and childhood adverse events, however, are also risk factors impacting the severity of illness [3]. Pathogens can trigger glial cells to release neuroexcitatory molecules that act on the VN causing a pain response, which can lead to hyperalgesia and allodynia, which supports the theory of post-infection development of CFS [115]. Stress as a causative factor of CFS relates to the HPA where stress leads to a loss of cortisol production impacting immune function. A decrease in cortisol (anti-inflammatory) and adrenocorticotropic hormone (ACTH) production causes serotonin and CRH dysfunction in CFS patients [115]. CFS shares many features with FM with differentiating factors of predominant fatigue and post-exertional illness with evidence of HPA dysfunction [114]. Additional symptoms include slight fever, pharyngodynia, laterocervical, or axillary lymphadenopathy, generalized myasthenia, myalgia, headache, sleep disorders, and neuropsychological disorders such as photophobia, amnesia, irritability, mental confusion, and difficulty concentrating [115]. Symptoms vary from mild to severe with approximately 75% of patients unable to work and 25% housebound and even bedbound [116]. The aetiology of CFS remains undetermined; however, neurologic, immunologic, and autonomic mechanisms are considered important factors [116]. Additionally, energy metabolism and the mitochondria appear important in the aetiology of CFS. The mitochondria are the energy-producing powerhouse of cells where ATP is manufactured, where impaired ATP production and energy metabolism may cause the chronic fatigue featured in CFS [117]. Indeed, studies have shown a deficit in the energy-producing pathways involving simple sugars, proteins, and fatty acids [58]. Dysfunction of the autonomic nervous system is characteristic of CFS including orthostatic hypotonia, GIT disturbances, and orthostatic tachycardia syndrome [118]. Certain CFS patients present with antibodies towards muscarinic, acetylcholine and beta (β) adrenergic receptors, and cerebral cytokine dysregulation [119]. Neuro activity via β-adrenergic receptors, specifically β2-adrenergic receptors, modulates anti-inflammatory activity [40]. Studies show additional characteristics of reduced cerebral blood flow and altered sympathetic and para-sympathetic signalling in the brain stem [119]. Dysfunction of the VN is also present in CFS patients where the vagal tone is abnormal, leading to changes in heart rate and respiration [52]. The neuro-immune or inflammatory reflex mediated by the VN appears important in the development of CFS. Immune system dysfunction in CFS patients relates to the presence of autoantibodies, impaired natural killer cells, excess cytotoxic T cells, and higher levels of pro-inflammatory cytokines [58].

Phycological disorders are prominent in FSS patients, with 25% of IBS and 51% of FM patients being diagnosed with depression or anxiety in the 5 years pre-diagnosis [6]. Studies demonstrate an overlap in IBS and mood disorders in FM patients having similar neurobiological alterations [4]. As with FSS, alterations of the CRF and HPA axis are present in patients with anxiety and depression [106]. FM is also associated with migraine, TMJ dysfunction, pelvic pain, complex regional pain syndrome, restless legs syndrome, IBS, interstitial cystitis, hypotension, and hypersensitivities [63]. Neuroinflammation in FM patients is believed to be triggered by stress, pain, dysbiosis of the gut, and vitamin D deficiency, which are also predisposing factors for autoimmune diseases [114]. Furthermore, there is a higher prevalence of autoimmune disease in FM patients including RA, lupus erythematosus, Sjogren’s syndrome, IBD, and Type 1 diabetes (T1D), amongst others. Increased levels of mast cells and their mediators in close proximity to enteric neurons is a feature of both IBD and IBS [49] where there is also an overlap of IBS in IBD patients. Autoantibodies anti-polymer antibody (APA), anti-68/48 kDa, and anti-45 kDa have been detected in FM, CFS, and patients presenting with psychiatric disorders [100], which may serve as biomarkers in certain cases. The higher prevalence of autoimmune diseases and FSS in females suggests some risk factors relating to the sex hormones in both conditions. Sex hormones can also trigger masts cell activity contributing to innate immunity, autoimmunity, and inflammation where oestrogen receptors have been identified on rodent mast cells [93].

Cyclic vomiting syndrome is a chronic FGID with symptoms of nausea, vomiting (emesis), and intestinal pain; gastroparesis (delayed gastric emptying) and migraine are also co-morbidities of IBS [120]. Some hypothesise that CVS is due to psychological or infectious triggers causing alterations or neuroendocrine dysfunction of the gut–brain pathway and activation of the CRF system [121]. Activation of CRF can result in emesis and gastroparesis by stimulation of the inhibitory motor nerves in the dorsal motor nucleus of the VN [122]. The autonomic nervous system has a major role in both emesis and nausea via the visceral afferent fibres of the VN in the GIT [123]. Co-morbidities of CFS/ME include FM, IBS, chemical sensitivity, thyroiditis, Raynaud’s syndrome, interstitial cystitis, TMJ syndrome, and headaches [26]. CFS patients may also be more prone to acute viral infections due to immune dysfunction [58]. Importantly, the prevalence of FSS may increase in a post-pandemic era where studies show that patients suffering from long-covid post-COVID-19 infection meet the criteria for CFS diagnosis [116].

Treatment options for FSS patients remain under question, with exercise, diet, cognitive behavioural therapy (CBT), and sleep recommended for preventing an FSS flare-up. CBT appears most beneficial in the treatment of FSS [2]. Regular exercise improves sleep, fatigue, and physical function in FSS patients having similar benefits to CBT. Treatments aimed at preventing nociceptive neurotransmitters in the CNS have been trialled for FM patients. Currently, pregabalin an active pharmaceutical ingredient (API), which decreases neuronal activity, and duloxetine and milnacipran (serotonin and noradrenaline reuptake inhibitors) are approved for the treatment of FM [4]. Studies reporting the efficacy of antidepressant drug therapy for the treatment of FSS are lacking. Indeed, some studies report a lack of efficacy of antidepressant therapy in FSS patients [2]. Typically, non-steroidal anti-inflammatory therapeutics are ineffective in FSS. The use of CRF antagonists may offer some advantages such as decreasing visceral hypersensitivity and colonic motility [106]. The use of chromones (mast cell stabilizers) in patients with IBS is also an area of potential therapy [19].