BackgroundThe pathogenesis of Multiple Sclerosis (MS) involves a dynamic interplay between (auto-)inflammation and neurodegeneration, driving its relapsing and progressive course. While both processes have been shown to be involved throughout disease with different emphasis, relapsing MS (RMS) is characterized by acute inflammatory activity, and secondary progressive MS (SPMS) involves chronic, diffuse neurodegeneration. Identifying biomarkers to predict progression independent of relapse activity (PIRA) is critical for improving diagnostic accuracy and treatment strategies. This study aimed to integrate inflammatory and neurodegenerative biomarkers into a Classification And Regression Tree (CART) model to distinguish RMS from SPMS.MethodsWe employed a multimodal approach by combining functional as well as structural retinal assessment via multifocal electroretinography (mfERG) and optical coherence tomography (OCT), serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (GFAP) levels via multiplex technology, and subsequent deep immunophenotyping. A CART model was constructed and trained to classify people with MS (PwMS) into RMS or SPMS categories based on these biomarkers.ResultsOur results revealed significant thinning of the retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GCIPL) in pwMS, with more pronounced reductions in SPMS, while functional mfERG-readouts did not differ between MS subgroups. Neurodegenerative markers sNfL and GFAP were elevated in pwMS compared to healthy controls, with higher levels in SPMS. Immunophenotyping showed increased levels of non-classic and intermediate monocytes in SPMS. The CART and Random Forest models identified sNfL, GCIPL thickness, and frequency of intermediate monocytes as the most accurate predictors, achieving approximately 80% accuracy in distinguishing RMS from SPMS.DiscussionThese findings suggest that combining sNfL, GCIPL thickness, and monocyte subsets provides an experimental, but robust diagnostic framework for differentiating RMS from SPMS. This approach could enable earlier identification of disease progression, facilitating tailored therapeutic interventions. Future studies should validate this model in larger cohorts to enhance its clinical applicability.

Anti-CD19 CAR T cell therapy represents an emerging therapeutic approach for generalized, treatment-refractory myasthenia gravis (MG), a predominantly B-cell-mediated autoimmune disease for which durable treatment-free remission remains an unmet clinical goal. Despite recent advances, current targeted therapies generally require lifelong repeated administration and rarely induce durable treatment-free remission. We report on three patients with severe, treatment-resistant MG, including one patient with concomitant rheumatoid arthritis, treated with autologous, fully human anti-CD19 CAR T cells. All three patients achieve rapid, sustained clinical MG remission for at least 19 months, allowing discontinuation of MG-specific immunotherapies and substantial improvement in clinical and functional outcomes despite persistent detectable anti-AChR autoantibody titers. B cell depletion is profound, and treatment-related adverse events remain transient and manageable during long-term follow-up. These data support anti-CD19 CAR T cell therapy as a durable, effective intervention for refractory MG and warrant further evaluation in prospective controlled clinical trials.

Constipation is a prevalent and clinically significant non-motor symptom in Parkinson’s disease (PD), affecting up to 90 https://drks.de/search/en/trial/DRKS00027061/details ). Many people with Parkinson’s disease experience constipation, which can be distressing and greatly affect daily life. Constipation may appear years before movement problems and is thought to be linked to changes in gut bacteria and reduced production of beneficial substances called short-chain fatty acids. In this clinical study, we investigated whether dietary supplementation with short-chain fatty acids, the prebiotic 2-fucosyllactose, or a combination of both could improve constipation in people with Parkinson’s disease, and 72 participants received one of these supplements for 6 months. We found that supplementation with 2-fucosyllactose improved constipation symptoms, while the combination of 2-fucosyllactose and short-chain fatty acids led to the greatest and most consistent improvements, with participants reporting better stool consistency, fewer problematic bowel movements, and an improved constipation-related quality of life. Physical activity levels did not change during the study, indicating that the observed benefits were likely related to the supplements themselves. These findings suggest that targeting the gut using specific dietary supplements may offer a safe and effective way to relieve constipation in people with Parkinson’s disease, although further studies are needed to evaluate the long-term safety of these supplements, the sustainability of symptom relief, the long-term benefits, and possible effects on disease progression.

This review examines the emerging application of chimeric antigen receptor (CAR) T-cell therapy in myasthenia gravis (MG), with emphasis on safety, efficacy signals, and future therapeutic potential in treatment-refractory disease. A comprehensive literature search was conducted across PubMed, medRxiv, bioRxiv, and Google Scholar for studies published between January 1, 2010 and July 1, 2025, using the terms "CAR T-cell," "chimeric antigen receptor," and "myasthenia gravis." Eligible reports included clinical trials, case reports, case series, and mechanistic studies describing CAR T-cell therapy outcomes in MG. Across five independent case series, seven patients receiving CAR T-cells targeting CD19, BCMA, or bispecific antigens showed consistent clinical improvement. Peak expansion occurred 8-22 days postinfusion, with persistence of 28 to ~180 days. Despite small cohorts, safety in CAR T-cell therapy was favorable versus oncology, with mainly Grade 1-2 cytokine release syndrome, rare immune effector cell-associated neurotoxicity, and no severe or life-threatening events. Seven registered trials (> 260 patients) are expected to conclude between 2026 and 2029. Overall, CAR T-cell therapy shows substantial promise for treatment-refractory MG, potentially offering greater durability than existing therapies with an acceptable safety profile. Nevertheless, current evidence is restricted to small, uncontrolled studies, and long-term efficacy, durability, and optimal patient selection require validation in larger controlled trials.

BACKGROUND:Autoimmune encephalitides are a heterogeneous group of autoantibody-associated central nervous system disorders. The clinical course of autoimmune encephalitides can be life threatening, and treatment can be challenging. OBJECTIVE:This report describes a case of treatment-refractory, anti-diacylglycerol lipase alpha (DAGLA) antibody-associated autoimmune encephalitis successfully treated with chimeric antigen receptor (CAR) T cells. METHODS:Treatment was done by single intravenous infusion of fully human, second-generation CAR T cells (KYV-101) targeting CD19 and depleting B cells. Clinical response was measured by International Cooperative Ataxia Rating Scale and Clinical Assessment Scale in Autoimmune Encephalitis scores. Autoantibodies against DAGLA were measured by a recombinant cell-based indirect immunofluorescence assay in the serum and the cerebrospinal fluid and confirmed by staining of primary murine neurons and brain sections. FINDINGS:A 36-year-old man developed rapidly progressing generalized myoclonus, cerebellar head tremor, vertical binocular nystagmus, and tetraparesis despite treatment with pulse glucocorticoid therapy, plasma exchange, and rituximab. Anti-DAGLA antibodies were positive in the indirect immunofluorescence assay, in serum and cerebrospinal fluid, and reacted with neurons and brain sections. Due to his severe clinical condition and treatment refractoriness, the patient received a single infusion of autologous anti-CD19 CAR T cells. Clinical scores improved significantly after treatment, and anti-DAGLA antibody levels in serum and cerebrospinal fluid diminished. Oligoclonal bands in the cerebrospinal fluid were initially positive and became negative after CAR T cell therapy. CONCLUSION:The report highlights the therapeutic potential of anti-CD19 CAR T cell therapy in severe, treatment-refractory autoimmune encephalitis. FUNDING:There was no external funding for the treatment or the data generated.

Parkinson’s disease is associated with a dysbiotic, proinflammatory gut microbiome, disruptions to intestinal barrier functions, and immunological imbalance. Microbiota-produced short-chain fatty acids, such as propionic and butyric acid promote gut barrier integrity and immune regulation, but their impact on Parkinson’s disease pathology remains mostly unknown. In a randomized double-blind prospective study, 72 people with Parkinson’s disease received propionic and butyric acid and/or the prebiotic fiber 2′-fucosyllactose supplementation over 6 months in combination with existing Parkinson’s disease-specific therapy. Patients underwent complete neurological assessment and provided blood and stool samples before as well as 3 and 6 months after supplementation. We observed a robust improvement in motor symptoms, with all intervention groups achieving clinically meaningful reductions. These motor benefits were paralleled by clinically relevant reductions in levodopa medication. In contrast, effects on nonmotor symptoms were more heterogeneous. Notably, the interventions also modulated peripheral immune responses and enhanced mitochondrial respiration in immunocytes. Postintervention microbiota remodeled inflammatory and barrier-related gene sets in gut organ cultures and improved in vitro barrier functions. Treatment response was associated with microbiome composition, distinct patterns of colonic transcription and permeability ex vivo. Multiobjective analysis revealed immune parameters associated with an optimal response to supplementation. Short-chain fatty acids ameliorate clinical symptoms in Parkinson’s disease patients and modulate intestinal and peripheral immunity. Registration: This clinical trial was retrospectively registered with the German Clinical Trials Register (DRKS), registration number DRKS00027061 on 11/19/2021.

Neurodegeneration in the autoimmune disease multiple sclerosis still poses a major therapeutic challenge. Effective drugs that target the inflammation can only partially reduce accumulation of neurological deficits and conversion to progressive disease forms. Diet and the associated gut microbiome are currently being discussed as crucial environmental risk factors that determine disease onset and subsequent progression. In people with multiple sclerosis, supplementation of the short-chain fatty acid propionic acid, as a microbial metabolite derived from the fermentation of a high-fiber diet, has previously been shown to regulate inflammation accompanied by neuroprotective properties. We set out to determine whether the neuroprotective impact of propionic acid is a direct mode of action of short-chain fatty acids on CNS neurons. We analysed neurite recovery in the presence of the short-chain fatty acid propionic acid and butyric acid in a reverse-translational disease-in-a-dish model of human-induced primary neurons differentiated from people with multiple sclerosis-derived induced pluripotent stem cells. We found that recovery of damaged neurites is induced by propionic acid and butyric acid. We could also show that administration of butyric acid is able to enhance propionic acid-associated neurite recovery. Whole-cell proteome analysis of induced primary neurons following recovery in the presence of propionic acid revealed abundant changes of protein groups that are associated with the chromatin assembly, translational, and metabolic processes. We further present evidence that these alterations in the chromatin assembly were associated with inhibition of histone deacetylase class I/II following both propionic acid and butyric acid treatment, mediated by free fatty acid receptor signalling. While neurite recovery in the presence of propionic acid is promoted by activation of the anti-oxidative response, administration of butyric acid increases neuronal ATP synthesis in people with multiple sclerosis-specific induced primary neurons.

Objective ranking and clustering of behavioral data that utilized different metrics is an important foundation for understanding the relationship between behavior and physiological as well as neurological processes in medicine and neuroscience. Fortunately, similar problems have been extensively studied in multi-objective optimization, where a population of solutions needs to be ranked in terms of performance within a high dimensional objective space. In this paper, we take advantage of the ordinal nature of behavioral metrics, and propose a non-dominated ranking-based approach to perform Pareto dominance-based partial ranking on the test subjects of behavioral studies regarding their performances with respect to multiple metrics. We have also proposed two indicators, interfront hypervolume and intrafront spread, to measure the separation between and diversity within non-dominated fronts. They serve to gauge the validity of the produced fronts as a basis for clustering analysis. Our approach is then applied to two different datasets and its functionalities and potentials are demonstrated.

IntroductionThe retina, a window into the brain, allows for the investigation of many disease-associated inflammatory and neurodegenerative changes affecting the central nervous system (CNS). Multiple sclerosis (MS), an autoimmune disease targeting the CNS, typically impacts on the visual system including the retina. Hence, we aimed to establish innovative functional retinal measures of MS-related damage, e.g., spatially resolved non-invasive retinal electrophysiology, backed by established morphological retinal imaging markers, i.e., optical coherence tomography (OCT).Methods20 healthy controls (HC) and 37 people with MS [17 without history of optic neuritis (NON) and 20 with (HON) history of optic neuritis] were included. In this work, we differentially assessed photoreceptor/bipolar cells (distal retina) and retinal ganglion cell (RGC, proximal retina) function besides structural assessment (OCT). We compared two multifocal electroretinography-based approaches, i.e., the multifocal pattern electroretinogram (mfPERG) and the multifocal electroretinogram to record photopic negative response (mfERGPhNR). Structural assessment utilized peripapillary retinal nerve fiber layer thickness (pRNFL) and macular scans to calculate outer nuclear thickness (ONL) and macular ganglion cell inner plexiform layer thickness (GCIPL). One eye was randomly selected per subject.ResultsIn NON, photoreceptor/bipolar cell layer had dysfunctional responses evidenced by reduced mfERGPhNR-N1 peak time of the summed response, but preserved structural integrity. Further, both NON and HON demonstrated abnormal RGC responses as evidenced by the photopic negative response of mfERGPhNR (mfPhNR) and mfPERG indices (P < 0.05). Structurally, only HON had thinned retina at the level of RGCs in the macula (GCIPL, P < 0.01) and the peripapillary area (pRNFL, P < 0.01). All three modalities showed good performance to differentiate MS-related damage from HC, 71–81% area under curve.ConclusionIn conclusion, while structural damage was evident mainly for HON, functional measures were the only retinal read-outs of MS-related retinal damage that were independent of optic neuritis, observed for NON. These results indicate retinal MS-related inflammatory processes in the retina prior to optic neuritis. They highlight the importance of retinal electrophysiology in MS diagnostics and its potential as a sensitive biomarker for follow-up in innovative interventions.

The typical way to analyze clinical data is to use one performance metric and extract the most important features by performing dimensionality reduction mechanisms. In this paper, we identify several performance metrics describing data of patients with Parkinson’s disease and observe a large variability of their performance when we consider these metrics separately. None of the patients has the same performance in all parameters, some are better in one and worse in others. This feature is well-known in the context of multi-objective optimization. In this paper, we propose a clustering of data based on multi-objective analysis and perform a correlation-based feature selection with statistical testing to quantify and understand the variability in the clinical data.

ABSTRACT Background Parkinson’s disease (PD) is associated with dysbiosis, proinflammatory gut microbiome, disruptions to intestinal barrier functions, and immunological imbalance. Microbiota-produced short-chain fatty acids promote gut barrier integrity and immune regulation, but their impact on PD pathology remains mostly unknown. Objectives To evaluate supplementation with short-chain fatty acids as an add-on intervention in PD. Methods In a randomized double-blind prospective study, 72 PD patients received short-chain fatty acids and/or the prebiotic fiber 2′-fucosyllactose supplementation over 6 months. Results We observed improvement in motor and nonmotor symptoms, in addition to modulation of peripheral immunity and improved mitochondrial respiration in immunocytes. The supplementation had no effect on microbiome diversity or composition. Finally, multiobjective analysis and comprehensive immunophenotyping revealed parameters associated with an optimal response to short-chain fatty acids and/or 2′-fucosyllactose supplementation. Conclusion Short-chain fatty acids ameliorate clinical symptoms in Parkinson’s disease patients and modulate mitochondrial function and peripheral immunity.

Background:The impact of the gut and its microbiota are increasingly appreciated in health and disease. Short-chain fatty acids (SCFAs) are among the main metabolites synthesized from bacterial fermentation. Recently, we showed the anti-inflammatory and potentially neuroprotective effect of propionic acid (PA) in multiple sclerosis (MS). Osteoporosis is one of the most common co-morbidities for MS patients with limited therapeutic options available. Osteoporosis is closely linked to an imbalance of cells of the immune system and an immune-mediated impact on bone structure via the gut has been shown. Interestingly, intake of SCFA leads to bone mass increase and concomitant reduction of inflammation-induced bone loss in mice. Objective:To determine the impact of PA supplementation on markers of bone metabolism in MS patients. Methods:We investigated the influence of 14 days supplementation with PA on bone metabolism in 20 MS patients. To this end, β-CrossLaps and osteocalcin, established markers of bone metabolism, were measured in serum before and after PA intake and correlated with phenotypic and functional immunodata. Results:Supplementation with PA induced a significant increase in serum levels of osteocalcin, a surrogate marker for bone formation. Levels of β-CrossLaps, a marker for bone resorption, were significantly decreased after therapy. Regulatory T-cell (Treg) numbers and suppressive capacity positively correlated with serum levels of osteocalcin while Th17 cell numbers showed an inverse correlation. Our findings are in line with animal studies showing that SCFA induced increased bone formation and reduced bone resorption. Conclusion:In addition to its immune regulatory, disease-modifying effect on MS disease course, supplementation with PA beneficially influences serum levels of β-CrossLaps and osteocalcin and may thus also protect against osteoporosis, a common co-morbidity in MS.

High-fat diets (HFD) are linked to obesity and associated comorbidities and induce pathogenic T helper (Th) 17 cells while decreasing regulatory T cells (Treg). This pro-inflammatory environment also aggravates immunopathology in experimental autoimmune encephalomyelitis (EAE) as a prototype model of T cell mediated autoimmunity. The strong association of HFD to obesity as well as the increasing risk of autoimmunity in the Western world stresses the importance to identify compounds that counteract this metabolically induced pro-inflammatory state in humans. One prominent candidate is the short-chain fatty acid propionate (PA) that was recently identified as potent therapy in the autoimmune disease multiple sclerosis by enhancing Treg cell frequencies and functionality. Mice were fed a HFD rich lauric acid (LA) and treated either with water or PA during MOG35-55-EAE. We analyzed Treg and Th17 cell frequencies in different tissues, antigen-specific cell proliferation and cytokine secretion, investigated Treg cell functionality by suppression assays and IL-10 signaling blockade and employed Western blotting to investigate the involvement of p38-MAPK signaling. Finally, we performed an explorative study in obese and non-obese MS patients, investigating fecal PA concentrations as well as peripheral Th17 and Treg frequencies before and after 90 days of daily PA intake. As compared to controls, mice on a HFD displayed a more severe course of EAE with enhanced demyelination and immune cell infiltration in the spinal cord. PA treatment prevented this disease enhancing effect of HFD by inhibiting Th17 mediated inflammatory processes in the gut and the spleen. Blocking experiments and signaling studies revealed p38-MAPK and IL-10 signaling as important targets linking the beneficial effects of PA treatment and reduced inflammation due to enhanced Treg frequency and functionality. An explorative study in a small group of MS patients revealed reduced PA concentrations in fecal samples of obese MS patients compared to the non-obese group, coinciding with increased Th17 but decreased Treg cells in obese patients. Importantly, PA intake could restore the Treg-Th17 homeostasis. Our data thus identify Th17 responses as an important target for the beneficial effects of PA in HFD and obesity in addition to the recently identified potential of PA as a Treg inducing therapy in T cell mediated autoimmunity.

The impact of the gut microbiome is being increasingly appreciated in health and in various chronic diseases, among them neurodegenerative disorders such as Parkinson’s disease (PD). In the pathogenesis of PD, the role of the gut has been previously established. In conjunction with a better understanding of the intestinal microbiome, a link to the misfolding and spread of alpha-synuclein via inflammatory processes within the gut is discussed. In a case-control study, we assessed the gut microbiome of 54 PD patients and 32 healthy controls (HC). Additionally, we tested in this proof-of-concept study whether dietary intervention alone or additional physical colon cleaning may lead to changes of the gut microbiome in PD. 16 PD patients underwent a well-controlled balanced, ovo-lacto vegetarian diet intervention including short fatty acids for 14 days. 10 of those patients received additional treatment with daily fecal enema over 8 days. Stool samples were collected before and after 14 days of intervention. In comparison to HC, we could confirm previously reported PD associated microbiome changes. The UDPRS III significantly improved and the levodopa-equivalent daily dose decreased after vegetarian diet and fecal enema in a one-year follow-up. Additionally, we observed a significant association between the gut microbiome diversity and the UPDRS III and the abundance of Ruminococcaceae. Additionally, the abundance of Clostridiaceae was significantly reduced after enema. Dietary intervention and bowel cleansing may provide an additional non-pharmacologic therapeutic option for PD patients.

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.

Objective: The autoimmune disease Multiple Sclerosis (MS) represents a heterogeneous disease pattern with an individual course that may lead to permanent disability. In addition to immuno-modulating therapies patients benefit from symptomatic approaches like intrathecal corticosteroid therapy (ICT), which is frequently applied in a growing number of centers in Germany. ICT reduces spasticity, which elongates patient's walking distance and speed, thus improves quality of life. Methods: In our study we set out to investigate cerebrospinal fluid (CSF) parameters and clinical predictors for response to ICT. Therefore, we analyzed 811 CSF samples collected from 354 patients over a time period of 12 years. Patients who received ICT were divided in two groups (improving or active group) depending on their EDSS-progress. As control groups we analyzed data of ICT naïve patients, who were divided in the two groups as well. Additionally we observed the clinical progress after receiving ICT by comparison of patients in both groups. Results: The results showed clinical data had a significant influence on the probability to benefit from ICT. The probability (shown by Odds Ratio of 1.77-2.43) to belong to the improving group in contrast to the active group is significantly (p < 0.0001) higher at later stages of disease with early disease onset (< 35 years, OR = 2.43) and higher EDSS at timepoint of ICT-initiation (EDSS > 6, OR = 2.06). Additionally, we observed lower CSF cell counts (6.68 ± 1.37 μl) and lower total CSF protein (412 ± 18.25 mg/l) of patients who responded to ICT compared to patients who did not (p < 0.05). In the control group no significant differences were revealed. Furthermore analyses of our data revealed patients belonging to the improving group reach an EDSS of 6 after ICT-initiation less often than patients of the active group (after 13 years 39.8% in the improving group, 67.8% in the active group). Conclusion: Our study implies two relevant messages: (i) although the study was not designed to prospectively assess clinical data, in this cohort no severe side effects were observed under ICT; (ii) disease onset, EDSS, CSF cell count, and total protein may serve as predictive markers for therapy response.

Objective To validate a previously discovered microRNA (miRNA) panel in the CSF of patients with MS, we now tested the diagnostic value of CSF-derived candidate miRNAs in a case-control study in a larger MS cohort. Methods The levels of miR-181c, miR-633, and miR-922 were analyzed in the CSF of 218 patients with MS and 211 patients with other neurologic diseases (OND) by real-time quantitative reverse transcriptase PCR. Results CSF levels of both miR-181c (p < 0.001 and miR-633 p < 0.001) were higher in patients with MS patients compared with patients with OND. Both miR-181c (area under the curve [AUC] 0.75, 95% CI 0.70–0.80, p < 0.001) and miR-633 (AUC 0.75, 95% CI 0.68–0.83, p < 0.001) differentiated MS from OND. Combining both miRNAs yielded a sensitivity of 62% and specificity of 89% to differentiate MS from OND. miR-922 was not confirmed to be differentially expressed in this validation cohort. Conclusions The results of this so far largest study on CSF-based miRNAs confirm the diagnostic value of miR-181c and miR-633 for MS. The present study may help to extend the diagnostic tools for patients with suspected MS and may add further knowledge to the pathology of the disease. Classification of Evidence This study provides Class III evidence that CSF-derived miR-181c and miR-633 distinguish patients with MS from patients with OND.

Objective: Dimethyl fumarate (DMF) exerts immunomodulatory and neuroprotective effects in the animal model of experimental autoimmune neuritis (EAN) in the Lewis rat. DMF has been shown to modulate gut microbiota in veterinary medicine, however the effects of oral DMF on the gut-associated lymphoid tissue (GALT) remain unknown. Methods: Lewis rats were treated orally twice daily with DMF up to day 10 after immunization with immunogenic P2 peptide. Histological, flow cytometric and RT-PCR analyses of the GALT (intraepithelial layer, lamina propria, and Peyer patches) in duodenum, jejunum, and ileum were performed ex vivo. Moreover, cell transfer experiments were used to examine the protective effects of GALT regulatory T cells of the Peyer patches. Results: In the upper layers of duodenum, DMF induced a reduction of the toll-like receptor 4 (TLR4) mRNA expression. This was combined by a decrease of the pro-inflammatory lamina propria IFN-γ mRNA expression. In the ileum, we detected an immunoregulatory phenotype characterized by an increase of FoxP3 mRNA expression and of the nuclear factor (erythroid-derived-2)- like 2 (Nrf2) downstream molecule heme oxygenase-1 (HO-1) mRNA. Finally, CD4+ CD25+ regulatory T cells were increased in the Peyer patches. In vivo, the protective effect of these regulatory cells was verified by cell transfer into recipient EAN rats. Conclusions: Our results identified a novel immunomodulatory effect of DMF through the different regions and layers of the small intestine, which led to an increase of regulatory T cells, exerting a protective role in experimental neuritis.

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.

ObjectiveImmunological studies have demonstrated a plethora of beneficial effects of dimethyl fumarate (DMF) on various cell types. However, the cellular and molecular targets are incompletely understood and response markers are scarce. Here, we focus on the relation between nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway induction under DMF therapy and the composition of the blood immune cell compartment and clinical efficacy in relapsing-remitting multiple sclerosis (MS) patients. MethodsWe explored effects of DMF on peripheral immune cell subsets by flow cytometric and transcriptional analysis of serial blood samples obtained from 43 MS patients during the first year of therapy. ResultsGene expression analysis proved activation of NRF2 signaling under DMF therapy that was paralleled by a temporal expansion of FoxP3(+) regulatory T cells, CD56(bright) natural killer cells, plasmacytoid dendritic cells, and a decrease in CD8(+) T cells, B cells, and type 1 myeloid dendritic cells. In a subgroup of 28 patients with completely available clinical data, individuals with higher levels of the NRF2 target gene NAD(P)H quinone dehydrogenase 1 (NQO1) 4-6 weeks after DMF therapy initiation were more likely to achieve no evidence of disease activity status 1 year later. The degree of NQO1 induction further correlated with patient age. InterpretationWe demonstrate that positive effects of DMF on the clinical outcome are paralleled by induction of the antioxidant NRF2 transcriptional pathway and a shift toward regulatory immune cell subsets in the periphery. Our data identify a role of the NRF2 pathway as potential biomarker for DMF treatment in MS.