Within the last century, human lifestyle and dietary behaviors have changed dramatically. These changes, especially concerning hygiene, have led to a marked decrease in some diseases, i.e., ...infectious diseases. However, other diseases that can be attributed to the so-called 'Western' lifestyle have increased, i.e., metabolic and cardiovascular disorders. More recently, multifactorial disorders, such as autoimmune and neurodegenerative diseases, have been associated with changes in diet and the gut microbiome. In particular, short chain fatty acid (SCFA)-producing bacteria are of high interest. SCFAs are the main metabolites produced by bacteria and are often reduced in a dysbiotic state, causing an inflammatory environment. Based on advanced technologies, high-resolution investigations of the abundance and composition of the commensal microbiome are now possible. These techniques enable the assessment of the relationship between the gut microbiome, its metabolome and gut-associated immune and neuronal cells. While a growing number of studies have shown the indirect impact of gut metabolites, mediated by alterations of immune-mediated mechanisms, the direct influence of these compounds on cells of the central nervous system needs to be further elucidated. For instance, the SCFA propionic acid (PA) increases the amount of intestine-derived regulatory T cells, which furthermore can positively affect the central nervous system (CNS), e.g., by increasing remyelination. However, the question of if and how PA can directly interact with CNS-resident cells is a matter of debate. In this review, we discuss the impact of an altered microbiome composition in relation to various diseases and discuss how the commensal microbiome is shaped, starting from the beginning of human life.
Dimethyl fumarate (DMF) is one of the newer additions to the armamentarium of potent immunomodulators for the treatment of relapsing-remitting multiple sclerosis (RRMS). After more than 2 years of ...real-world experience and more than 190,000 patients currently treated with DMF worldwide, it is a good timepoint to review the experience gathered so far and to re-evaluate the potential of this first-line oral multiple sclerosis (MS) drug. Post-hoc analyses of clinical and magnetic resonance imaging (MRI) data, some comprising more than 6 years of drug exposure including patients from the clinical trials, and the overall notion in clinical practice widely confirm the good efficacy of DMF in RRMS. Despite an overall good safety profile, it became also clear that the necessary clinical vigilance while using DMF may not be neglected. So far, four reported cases of progressive multifocal leukoencephalopathy (PML), a towering shadow over many MS therapies, warrant proper attention in newly-updated risk management plans. This review recapitulates efficacy and safety aspects of DMF therapy in relation to reported data from the pivotal clinical trials. In addition, we summarize recent insights into DMF mechanisms of action drawn from the field of basic research which may have important implications for clinical practice.
Amplitude modulated transcranial alternating current stimulation (AM-tACS) is a novel method of electrostimulation which enables the recording of electrophysiological signals during stimulation, ...thanks to an easier removable stimulation artefact compared to classical electrostimulation methods. To gauge the neuromodulatory potential of AM-tACS, we tested its capacity to induce phosphenes as an indicator of stimulation efficacy. AM-tACS was applied via a two-electrode setup, attached on FpZ and below the right eye. AM-tACS waveforms comprised of different carrier (50 Hz, 200 Hz, 1000 Hz) and modulation frequencies (8 Hz, 16 Hz, 28 Hz) were administered with at maximum 2 mA peak-to-peak stimulation strength. TACS conditions in the same frequencies were used as a benchmark for phosphene induction. AM-tACS conditions using a 50 Hz carrier frequency were able to induce phosphenes, but with no difference in phosphene thresholds between modulation frequencies. AM-tACS using a 200 Hz or 1000 Hz carrier frequency did not induce phosphenes. TACS conditions induced phosphenes in line with previous studies. Stimulation effects of AM-tACS conditions were independent of amplitude modulation and instead relied solely on the carrier frequency. A possible explanation may be that AM-tACS needs higher stimulation intensities for its amplitude modulation to have a neuromodulatory effect.
Summary
A vast number of studies have demonstrated a remarkable role for the gut microbiota and their metabolites in the pathogenesis of inflammatory diseases, including multiple sclerosis (MS). ...Recent studies in experimental autoimmune encephalomyelitis, an animal model of MS, have revealed that modifying certain intestinal bacterial populations may influence immune cell priming in the periphery, resulting in dysregulation of immune responses and neuroinflammatory processes in the central nervous system (CNS). Conversely, some commensal bacteria and their antigenic products can protect against inflammation within the CNS. Specific components of the gut microbiome have been implicated in the production of pro‐inflammatory cytokines and subsequent generation of Th17 cells. Similarly, commensal bacteria and their metabolites can also promote the generation of regulatory T‐cells (Treg), contributing to immune suppression. Short‐chain fatty acids may induce Treg either by G‐protein‐coupled receptors or inhibition of histone deacetylases. Tryptophan metabolites may suppress inflammatory responses by acting on the aryl hydrocarbon receptor in T‐cells or astrocytes. Interestingly, secretion of these metabolites can be impaired by excess consumption of dietary components, such as long‐chain fatty acids or salt, indicating that the diet represents an environmental factor affecting the complex crosstalk between the gut microbiota and the immune system. This review discusses new aspects of host–microbiota interaction and the immune system with a special focus on MS as a prototype T‐cell‐mediated autoimmune disease of the CNS.
Recent studies revealed that modifying distinct intestinal bacterial populations may influence immune cell activation in the periphery, thus resulting in dysregulation of immune responses and neuroinflammatory processes in the central nervous system (CNS). While some bacteria and their antigenic products may protect against inflammation, others have been implicated in the production of pro‐inflammatory cytokines and subsequent generation of Th17 cells. This review discusses new aspects of host–microbiota interaction and the immune system with a special focus on multiple sclerosis as a prototype T‐cell‐mediated autoimmune disease of the CNS.
Short-chain fatty acids are processed from indigestible dietary fibers by gut bacteria and have immunomodulatory properties. Here, we investigate propionic acid (PA) in multiple sclerosis (MS), an ...autoimmune and neurodegenerative disease. Serum and feces of subjects with MS exhibited significantly reduced PA amounts compared with controls, particularly after the first relapse. In a proof-of-concept study, we supplemented PA to therapy-naive MS patients and as an add-on to MS immunotherapy. After 2 weeks of PA intake, we observed a significant and sustained increase of functionally competent regulatory T (Treg) cells, whereas Th1 and Th17 cells decreased significantly. Post-hoc analyses revealed a reduced annual relapse rate, disability stabilization, and reduced brain atrophy after 3 years of PA intake. Functional microbiome analysis revealed increased expression of Treg-cell-inducing genes in the intestine after PA intake. Furthermore, PA normalized Treg cell mitochondrial function and morphology in MS. Our findings suggest that PA can serve as a potent immunomodulatory supplement to MS drugs.
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•PA is reduced in MS patients, particularly early after disease manifestation•PA reduction is associated with an altered gut microbiome composition•After 14 days of PA supplementation, Treg cell/TH17 imbalance was restored•Longitudinal PA supplementation might have clinical implications
Supplementation of the short-chain fatty acid propionic acid (PA) in multiple sclerosis (MS) patients reverses the Treg cell/Th17 cell imbalance via increased Treg cell induction and enhancement of Treg cell function and is associated with disease course improvement.
Cognitive fatigue is highly prevalent in people with multiple sclerosis (pwMS) and significantly limits their quality of life. Fatigue can be subdivided into a subjective feeling of constant (trait) ...or current (state) exhaustion, as well as an objective performance decline, also known as fatigability. However, the current fatigue diagnosis in pwMS is purely subjective, leaving fatigability mostly unattended. Sensorimotor and sensory gating deficits have recently been described as possible objective markers for fatigability in healthy subjects. Thus, this study aimed to investigate the potential of prepulse inhibition (PPI) ratios and the P50 sensory gating suppression as surrogate markers for cognitive fatigue in pwMS.
PPI and P50 sensory gating ratios were assessed before and after a 30-min fatigability-inducing AX- continuous performance task. Subjective trait fatigue was operationalized via self-report questionnaires, subjective state fatigue via visual analog scales (VAS), and fatigability via the change in both gating ratios. The data were analyzed using Linear Mixed Models and Pearson correlations.
We included 18 pwMS and 20 healthy controls (HC) in the final analyses. The task-induced fatigability was more pronounced in pwMS. While the initial PPI and P50 ratios were similar in both groups, P50 sensory gating was significantly disrupted after fatigability induction in pwMS. PPI, on the other hand, decreased in both groups. Moreover, initial P50 sensory gating ratios were negatively associated with subjective trait fatigue in pwMS, indicating that higher trait fatigue is associated with disrupted sensory gating. Finally, fatigability-related changes in P50 sensory gating were associated with the changes in VAS ratings, but only in HC.
This study demonstrated that P50 sensory gating is a promising objective fatigue and fatigability parameter. Importantly, P50 sensory gating correlated with subjective trait and state fatigue ratings. Our results extend the subjective fatigue diagnosis and broaden the understanding of pathophysiological neuronal mechanisms in MS-related fatigue. This is the first study to present fatigue-related disruption of sensory gating in pwMS.
•P50 sensory gating is a promising objective fatigue and fatigability parameter.•Sensory gating deficits are associated with fatigue severity in people with multiple sclerosis.•Fatigability disrupts sensory gating.•Extending the understanding of pathophysiological neuronal mechanisms in MS-related fatigue.
Microglia serve as the innate immune cells of the central nervous system (CNS) by providing continuous surveillance of the CNS microenvironment and initiating defense mechanisms to protect CNS ...tissue. Upon injury, microglia transition into an activated state altering their transcriptional profile, transforming their morphology, and producing pro-inflammatory cytokines. These activated microglia initially serve a beneficial role, but their continued activation drives neuroinflammation and neurodegeneration. Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the CNS, and activated microglia and macrophages play a significant role in mediating disease pathophysiology and progression. Colony-stimulating factor-1 receptor (CSF1R) and its ligand CSF1 are elevated in CNS tissue derived from MS patients. We performed a large-scale RNA-sequencing experiment and identified CSF1R as a key node of disease progression in a mouse model of progressive MS. We hypothesized that modulating microglia and infiltrating macrophages through the inhibition of CSF1R will attenuate deleterious CNS inflammation and reduce subsequent demyelination and neurodegeneration. To test this hypothesis, we generated a novel potent and selective small-molecule CSF1R inhibitor (sCSF1R
) for preclinical testing. sCSF1R
blocked receptor phosphorylation and downstream signaling in both microglia and macrophages and altered cellular functions including proliferation, survival, and cytokine production. In vivo, CSF1R inhibition with sCSF1R
attenuated neuroinflammation and reduced microglial proliferation in a murine acute LPS model. Furthermore, the sCSF1R
attenuated a disease-associated microglial phenotype and blocked both axonal damage and neurological impairments in an experimental autoimmune encephalomyelitis (EAE) model of MS. While previous studies have focused on microglial depletion following CSF1R inhibition, our data clearly show that signaling downstream of this receptor can be beneficially modulated in the context of CNS injury. Together, these data suggest that CSF1R inhibition can reduce deleterious microglial proliferation and modulate microglial phenotypes during neuroinflammatory pathogenesis, particularly in progressive MS.
Following an acute COVID-19 infection, a large number of patients experience persisting symptoms for more than four weeks, a condition now classified as Long-COVID syndrome. Interestingly, the ...likelihood and severity of Long-COVID symptoms do not appear to be related to the severity of the acute COVID-19 infection. Fatigue is amongst the most common and debilitating symptoms of Long-COVID. Other symptomes include dyspnoea, chest pain, olfactory disturbances, and brain fog. Fatigue is also frequently reported in many other neurological diseases, affecting a broad range of everyday activities. However, despite its clinical significance, limited progress has been made in understanding its causes and developing effective treatment options. Non-invasive brain stimulation (NIBS) methods offer the unique opportunity to modulate fatigue-related maladaptive neuronal activity. Recent data show promising results of NIBS applications over frontoparietal regions to reduce fatigue symptoms. In this current paper, we review recent data on Long-COVID and Long-COVID-related fatigue (LCOF), with a special focus on cognitive fatigue. We further present widely used NIBS methods, such as transcranial direct current stimulation, transcranial alternating current stimulation, and transcutaneous vagus nerve stimulation and propose their use as possible therapeutic strategies to alleviate individual pathomechanisms of LCOF. Since NIBS methods are safe and well-tolerated, they have the potential to enhance the quality of life in a broad group of patients.
Fatigue is associated with a dramatically decreased quality of life in people with multiple sclerosis (pwMS). It refers to a constant subjective feeling of exhaustion and performance decline, known ...as fatigability. However, inconsistency and heterogeneity in defining and assessing fatigue have led to limited advances in understanding and treating MS-associated fatigue. Transcranial direct current stimulation (tDCS) has emerged as a promising, non-pharmaceutical treatment strategy for subjective fatigue. However, whether repetitive tDCS also have long-term effects on time-on-task performance has not yet been investigated. This pseudorandomized, single-blinded, and sham-controlled study investigated tDCS effects on behavioral and electrophysiological parameters. 18 pwMS received eight twice-weekly 30 min stimulations over the left dorsolateral prefrontal cortex. Fatigability was operationalized as time-on-task-related changes in reaction time variability and P300 amplitude. Additionally, subjective trait and state fatigue ratings were assessed. The results revealed an overall decrease in subjective trait fatigue ratings that lasted at least four weeks after the stimulations. However, the ratings declined after both anodal and sham tDCS. No effects were found on subjective state fatigue and objective fatigability parameters. Linear Mixed Models and Bayesian Regression models likewise favored the absence of a tDCS effect on fatigability parameters. The results confirm the complex relationship between MS-associated fatigue and fatigability. Reliable and clinically relevant parameters need to be established to extend the potential of tDCS for treating fatigability. Furthermore, our results indicate that consecutive stimulations rather than twice-weekly stimulations should be the preferred stimulation scheme in future studies.
Growing empirical evidence suggests that nutrition and bacterial metabolites might impact the systemic immune response in the context of disease and autoimmunity. We report that long-chain fatty ...acids (LCFAs) enhanced differentiation and proliferation of T helper 1 (Th1) and/or Th17 cells and impaired their intestinal sequestration via p38-MAPK pathway. Alternatively, dietary short-chain FAs (SCFAs) expanded gut T regulatory (Treg) cells by suppression of the JNK1 and p38 pathway. We used experimental autoimmune encephalomyelitis (EAE) as a model of T cell-mediated autoimmunity to show that LCFAs consistently decreased SCFAs in the gut and exacerbated disease by expanding pathogenic Th1 and/or Th17 cell populations in the small intestine. Treatment with SCFAs ameliorated EAE and reduced axonal damage via long-lasting imprinting on lamina-propria-derived Treg cells. These data demonstrate a direct dietary impact on intestinal-specific, and subsequently central nervous system-specific, Th cell responses in autoimmunity, and thus might have therapeutic implications for autoimmune diseases such as multiple sclerosis.
•Dietary fatty acids have profound influence on T cell differentiation in the gut•Middle- and long-chain fatty acids (LCFAs) support Th1 and Th17 cell differentiation•Short-chain fatty acids (SCFAs) lead to increased Treg cell differentiation•LCFAs worsen disease in an animal model of MS; SCFAs exert the opposite effect
Haghikia and colleagues show that dietary fatty acids (FAs) influence T cell differentiation in the gut, with short FAs leading to increased Treg cell differentiation and long FAs supporting Th1 and/or Th17 cell differentiation. These FAs differentially affect EAE severity, demonstrating a direct dietary impact on central nervous system autoimmunity.
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