Macrophages in MS lesions show an intermediate phenotype expressing both pre-inflammatory (M1) and growth-promoting (M2) markers depending on their polarization. It is still not clear whether the macrophage phenotype determines lesion pathology. However, we propose that a decrease in SS function is a factor contributing to MS pathology. Since the microbiome is a major regulator of the SS, we also suggest that the root cause of this alteration may lie in an unstable microflora during early life, when the SS in the periphery and in the CNS is shaped, or later through modulation of peripheral 5-HT levels. The reduced 5-HT levels affect neuroinflammation in the CNS directly or through skewing macrophages and T cells to an autoinflammatory phenotype
5-HT has an effect on immune response through 5-HTRs expressed on cells of the innate and adaptive immune systems, and changes in the communication between the SS and leukocytes are related to diseases with an inflammatory pathological component (rheumatoid arthritis, psoriasis, asthma). 5-HT are important to regulate the function of macrophages, dendritic cells (DCs), and T cells which are major immunological components of MS.
Evidence for an altered Serotonergic System in MS comes from structural-MRI studies on a cohort of 56 MS patients and 30 healthy controls. The analysis reveals a reduction in (serotonin transporter (SERT)) expression in the parahippocampal regions of patients with secondary–progressive multiple sclerosis (SPMS) and an increase in the prefrontal cortex of patients with primary-progressive multiple sclerosis (PPMS). The data also suggests differential 5-HT signaling in SPMS and PPMS and underline the necessity of a deeper understanding of the role of the SS in MS pathology. It is speculated that altered SERT expression might reflect the homeostatic function of the CNS in response to changed 5-HT availability, and be involved in MS pathology.
The microbiome also affects the central serotonergic system (SS). This system originates from the raphe nucleus where the bodies of 5-HT–producing neurons are located. Almost all brain regions express 5-HTR and are innervated by serotonergic neurons, but the main target of these afferent pathways is the limbic system, including the hippocampus and amygdala. In the CNS, 5-HT has been found to have a wide spectrum of functions ranging from motor activation and perception to control over addictive behavior. The microbiome modulates the central SS affecting both 5-HT levels and 5-HTR expression. For instance, elevated levels of bacterium in the gut disable the increase in 5-HT receptor found in the frontal cortex of mice in response to treatment with Lipopolysaccharide (LPS). This effect is combined with steady levels of central 5-HT indicating a mechanism of peripheral SS modulation, which bypasses the 5-HT synthesis in the gut.
About 90% of the human 5-HT is synthesized by the gut enterochromaffin cells through a process controlled by the intestinal microflora. In the gut, 5-HT controls, secretion, vasodilation, nociperception, peristalsis and nausea through 5-HT receptors (5-HTR) expressed on efferent nerves in the lamina propria of the intestinal endothelium. Comparison of the 5-HT serum levels between germfree (GF) mice and mice with humanized microbiome proved that the gut microbiome accounts for 74% 5-HT concentrations.
Neurotransmitters(NTs) are neuronal signaling chemicals controlling all sort of physiological functions ranging from motor, sensory , and autonomic to immunity and cognition. Altered levels of Neurotransmitters have been related to various diseases such as Alzheimer’s disease. NTs are synthesized in neurosecretory cells found in the central and peripheral nervous system. However, Intestinal bacterial communities can alter the production of NTs in the central nervous system (CNS).Moreover, the gut microbiome produces many NTs of their own such as 5-HT, GABA, and dopamine, and in this way play an important role in regulating peripheral nervous system. The Microbiome produced NTs exert an effect on the immune system through various immune cell receptors. The link between NTs and neuroinflammatory diseases, and their function in the nervous and immune system, makes them potent candidates for mediators of the gut–brain interactions in MS, of which 5-HT may be the dominant one.
Neurotransmitters – a link between Gut and Brain ?
Over the past few years, various studies demonstrated that individual microbial species affect the progression of experimentally induced MS in transgenic mice and showed that altered microbiota is related to multiple sclerosis. Notwithstanding the proof for the role of the gut–brain axis in MS, the underlying machinery behind it still remains unknown. To address this question, our lab has used serotonin (5-hydroxytetramine (5-HT)) as a link between microbial regulated neurotransmitters and MS pathogenesis.
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the human central nervous system (CNS) that affects young adults and over the subsequent decades develops into a progressive neurodegenerative disorder associated with major clinical disabilities. Specific symptoms can include, blindness in one eye, double vision, trouble with sensation, blurred vision, muscle weakness or trouble with coordination. The pathophysiology and progression of MS is highly varied and unpredictable. MS is considered to be an autoimmune disorder, striking when Th1 cells recognizes proteins found in the myelin sheath. The pathological hallmark of MS is the demyelinated plaque, which consists of a defined hypercellular area characterized by loss of myelin, astrocytes and oligodendrocytes. Lesions are typically observed in the, periventricular white matter, optic nerves, cerebellum, brainstem and spinal cord. Demyelination can also involve the gray matter, associated with meningeal inflammation. In most of the patients, the disease is characterized initially by episodes of reversible neurological deficits, often followed by progressive neurological deterioration over the time period. It affects almost 400,000 people in the United States and onset in most of the cases is usually during the young adulthood. There are four clinical forms of MS, of which relapsing-remitting type is the most common.
The significance of the gut microbiome in the pathogenesis of multiple sclerosis (MS) has been established recently, although the underlying signaling mechanism of this interaction has not not been sufficiently explored. This paper addresses this point and use serotonin (5-hydroxytetramine (5-HT))—a microbial-modulated neurotransmitter to prove that Neurotransmitters regulated by the gut microbiome are strong candidates for mediators of the gut–brain axis in Multiple Sclerosis.
Serotonin serves as a mediator of the gut–brain axis in multiple sclerosis disease.