Propionic Acid Shapes the Multiple Sclerosis Disease Course by an Immunomodulatory Mechanism.

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.

Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism.

AIMS: Atherosclerotic cardiovascular disease (ACVD) is a major cause of mortality and morbidity worldwide, and increased low-density lipoproteins (LDLs) play a critical role in development and progression of atherosclerosis. Here, we examined for the first time gut immunomodulatory effects of the microbiota-derived metabolite propionic acid (PA) on intestinal cholesterol metabolism. METHODS AND RESULTS: Using both human and animal model studies, we demonstrate that treatment with PA reduces blood total and LDL cholesterol levels. In apolipoprotein E-/- (Apoe-/-) mice fed a high-fat diet (HFD), PA reduced intestinal cholesterol absorption and aortic atherosclerotic lesion area. Further, PA increased regulatory T-cell numbers and interleukin (IL)-10 levels in the intestinal microenvironment, which in turn suppressed the expression of Niemann-Pick C1-like 1 (Npc1l1), a major intestinal cholesterol transporter. Blockade of IL-10 receptor signalling attenuated the PA-related reduction in total and LDL cholesterol and augmented atherosclerotic lesion severity in the HFD-fed Apoe-/- mice. To translate these preclinical findings to humans, we conducted a randomized, double-blinded, placebo-controlled human study (clinical trial no. NCT03590496). Oral supplementation with 500 mg of PA twice daily over the course of 8 weeks significantly reduced LDL [-15.9 mg/dL (-8.1%) vs. -1.6 mg/dL (-0.5%), P = 0.016], total [-19.6 mg/dL (-7.3%) vs. -5.3 mg/dL (-1.7%), P = 0.014] and non-high-density lipoprotein cholesterol levels [PA vs. placebo: -18.9 mg/dL (-9.1%) vs. -0.6 mg/dL (-0.5%), P = 0.002] in subjects with elevated baseline LDL cholesterol levels. CONCLUSION: Our findings reveal a novel immune-mediated pathway linking the gut microbiota-derived metabolite PA with intestinal Npc1l1 expression and cholesterol homeostasis. The results highlight the gut immune system as a potential therapeutic target to control dyslipidaemia that may introduce a new avenue for prevention of ACVDs.

Conditional Deletion of LRP1 Leads to Progressive Loss of Recombined NG2-Expressing Oligodendrocyte Precursor Cells in a Novel Mouse Model.

The low-density lipoprotein receptor-related protein 1 (LRP1) is a transmembrane receptor, mediating endocytosis and activating intracellular signaling cascades. LRP1 is highly expressed in the central nervous system (CNS), especially in oligodendrocyte precursor cells (OPCs). Previous studies have suggested LRP1 as a regulator in early oligodendrocyte development, repair of chemically induced white matter lesions, and cholesterol homeostasis. To circumvent embryonic lethality observed in the case of global LRP1 deletion, we generated a new inducible conditional knockout (KO) mouse model, which enabled an NG2-restricted LRP1 deficiency (NG2-CreERT2ct2/wtxR26eGFPflox/floxxLRP1flox/flox). When characterizing our triple transgenic mouse model, we noticed a substantial and progressive loss of recombined LRP1-deficient cells in the oligodendrocyte lineage. On the other hand, we found comparable distributions and fractions of oligodendroglia within the Corpus callosum of the KO and control animals, indicating a compensation of these deficits. An initial study on experimental autoimmune encephalomyelitis (EAE) was performed in triple transgenic and control mice and the cell biology of oligodendrocytes obtained from the animals was studied in an in vitro myelination assay. Differences could be observed in these assays, which, however, did not achieve statistical significance, presumably because the majority of recombined LRP1-deficient cells has been replaced by non-recombined cells. Thus, the analysis of the role of LRP1 in EAE will require the induction of acute recombination in the context of the disease process. As LRP1 is necessary for the survival of OPCs in vivo, we assume that it will play an important role in myelin repair.

Predictors for Therapy Response to Intrathecal Corticosteroid Therapy in Multiple Sclerosis.

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.

Elevated levels of miR-181c and miR-633 in the CSF of patients with MS: A validation study.

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.