Explore the vast range of titles available.

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.

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.

The 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). 20 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 (mfERG ). 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. In NON, photoreceptor/bipolar cell layer had dysfunctional responses evidenced by reduced mfERG -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 mfERG (mfPhNR) and mfPERG indices ( < 0.05). Structurally, only HON had thinned retina at the level of RGCs in the macula (GCIPL, < 0.01) and the peripapillary area (pRNFL, < 0.01). All three modalities showed good performance to differentiate MS-related damage from HC, 71-81% area under curve. In 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.

Building upon a study published in The Lancet Neurology showing the feasibility of transiently expressed B-cell maturation antigen (BCMA)-targeted RNA chimeric antigen receptor (CAR) T-cell therapy in patients with myasthenia gravis,1 we report a case that indicates that a different CAR T-cell approach that targets CD19 with a stably expressed CAR, delivered following a conventional lymphodepleting regimen, might be safe and effective in the treatment of severe and refractory myasthenia gravis. Previous treatment attempts, including thymectomy (in April, 2022, performed at another academic centre), acetylcholinesterase inhibitors (initiated in 2012 at our institution), and B-cell-depleting antibodies (rituximab, administered in April and October, 2021, at our institution) did not stabilise the disease course, which was class V according to the Myasthenia Gravis Foundation of America criteria (defined as intubation, with or without mechanical ventilation, except when used during routine postoperative management).3 Moreover, a proteasome inhibitor (bortezomib, administered in May and November, 2022), immunosuppressive drugs (mycophenolate mofetil, administered for 21 months preceding the CAR T-cell infusion), and immunoglobulin therapy (initiated in October, 2021) had proven futile in providing long-term relief (appendix p 4). The serological findings were paralleled by the patient's improved muscle strength and fatigue over the first 2 months after CD19 CAR T infusion, evidenced by the steady increase in the time that the patient could hold out her arm horizontally, her enhanced walking ability without any supportive devices, and the reduction of the clinical multiparameter Besinger disease activity and the Quantitative Myasthenia Gravis scores3,8 (figure).

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. This clinical trial was retrospectively registered with the German Clinical Trials Register (DRKS), registration number DRKS00027061 on 11/19/2021.