Targeting the Gut Dysbiosis to Treat Inflammation-driven Synaptopathy in MS

NCT05779449 | Recruiting

• 1 other identifier: Pre-Pro-MS
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

Inflammatory synaptopathy is a prominent pathogenic process in multiple sclerosis (MS) induced by imbalanced immune system homeostasis. Its persistence causes excitotoxic neuronal damage, leading to motor and cognitive deficits. Although many advances have been made in MS treatment, the development of effective strategies for managing disease progression driven by excitotoxic synaptic dysfunctions is of great significance. Gut dysbiosis is commonly associated with both MS and obesity and high-fat diet (HFD) can exacerbate disease by acting on gut microbiota. Since gut microbiota can shape the immune response and brain functions, we propose to target gut dysbiosis by dietary supplementation of prebiotics and probiotics (Pre-Pro) to treat synaptopathy in both human and experimental model of MS, even when exacerbated by HFD. Overall, this project aims at unveiling the anti-inflammatory and neuroprotective pathways activated by Pre-Pro supplementation to modulate the immune-synaptic axis.

Conditions

Patient Participation

Keywords

gut microbiota; dysbiosis; multiple sclerosis; glutamate-mediated excitotoxicity; synaptopathy

Outcome Measures

Primary Outcomes (8)

• Changes in gut microbiota diversity or composition

  Relative taxa abundance in fecal samples assessed by rDNA-seq (Operational Taxonomy Unit, OTU).

  T0 vs T12 (months), Pre-Pro versus Placebo groups

• Changes in microbiota metabolites - indican

  Quantification of the ration between indican and creatinine (μg/mg) in urine samples

  T0 vs T12 (months), Pre-Pro versus Placebo groups

• Changes in microbiota metabolites - skatole

  Quantification of the ration between skatole and creatinine (μg/mg) in urine samples

  T0 vs T12 (months), Pre-Pro versus Placebo groups

• Changes in serum glutamate

  Absolute quantification of glutamate in the serum (uM)

  T0 vs T12 (months), Pre-Pro versus Placebo groups

• Changes in serum synaptotoxic miRNAs

  Relative quantification by Real-time PCR

  T0 vs T12 (months), Pre-Pro versus Placebo groups

• Changes in plasma inflammatory molecules

  Absolute quantification of inflammatory molecules in the serum (pg/ml)

  T0 vs T12 (months), Pre-Pro versus Placebo groups

• Changes in immunophenotype

  The percentage of Treg in the activated CD4+CD25- T cells isolated from PMBCs will be evaluated by Fluorescence-activated Cell Sorting (FACS).

  T0 vs T12 (months), Pre-Pro versus Placebo groups

• Changes in T cell metabolic asset

  The metabolic profile of CD4+ T cells will be assessed by real-time measurement of extracellular acidification rate (ECAR) and oxygen consumption rate (OCR), using an XFe-96 Extracellular Flux Analyzer.

  T0 vs T12 (months), Pre-Pro versus Placebo groups

Secondary Outcomes (17)

• Changes in neurophysiological response

  T0 vs T12 (months), Pre-Pro versus Placebo groups

• Changes in clinical disability

  T0 vs T12 (months), Pre-Pro versus Placebo groups

• Changes in lower extremity function

  T0 vs T12 (months), Pre-Pro versus Placebo groups

• Changes in upper extremity function

  T0 vs T12 (months), Pre-Pro versus Placebo groups

• Changes in quality of life

  T0 vs T12 (months), Pre-Pro versus Placebo groups

Study Arms (2)

Pre-Pro group

EXPERIMENTAL

Patients with RRMS under dimethyl fumarate or Ocrelizumab treatment according to the good clinical practice, who will recieve the following dietary supplementation with pre- and probiotics: 1st-15th days: One capsule containg 6 billions of Saccharomyces boulardii and 8,5 billions of probiotics including Bifidobacterium lactis Bi-07®, Bifidobacterium lactis Bl-04, Lacticaseibacillus paracasei Lpc-37, Lactobacillus acidophilus NCFM® (Probactiol Duo cps, Metagenics) One packet with 4 g of prebiotics including inulin enriched with oligofructose (Probactiol Stips bustine Metagenics). 16th-365th days: Two capsules, each containg 7,5 billions of Lactobacillus acidophilus NCFM®, 7,5 billions of Bifidobacterium lactis Bi-07®, 2,5 ug Vitamine D3, 320 ug Vitamine A, 100 mg Threonine, 250 mg 2'-Fucosyllactose (Probactiol HMO Combi cps, Metagenics).

Dietary Supplement: Prebiotics and Probiotics supplementation; Procedure: peripheral blood withdrawal; Procedure: Transcranial Magnetic Stimulation (TMS)

Placebo group

PLACEBO COMPARATOR

Patients with RRMS under dimethyl fumarate or Ocrelizumab treatment according to the good clinical practice, who will receive only starch, the probiotic bacteria carrier: 1st-15th days: One capsule and one packet only with starch. 16th-365th days: Two capsules containg starch.

Dietary Supplement: Placebo supplementation; Procedure: peripheral blood withdrawal; Procedure: Transcranial Magnetic Stimulation (TMS)

Interventions

Prebiotics and Probiotics supplementation DIETARY_SUPPLEMENT

From the 1st day to the 15th day (included) patients with MS in the Pre-Pro group will receive daily: 1 capsule of Probactiol Duo, Metagenics (6 billions of Saccharomyces boulardii and 8,5 billions of probiotics including Bifidobacterium lactis Bi-07®, Bifidobacterium lactis Bl-04, Lacticaseibacillus paracasei Lpc-37, Lactobacillus acidophilus NCFM®) 1. packet of Probactiol Stips, Metagenics (4 g inulin enriched with oligofructose) From the16th day to the 365th day (included) patients with MS in the Pre-Pro group will receive daily: 2. capsules of Probactiol HMO Combi, Metagenics (7,5 billions of Lactobacillus acidophilus NCFM®, 7,5 billions of Bifidobacterium lactis Bi-07®, 2,5 ug Vitamine D3, 320 ug Vitamine A, 100 mg Threonine, 250 mg 2'-Fucosyllactose).

Pre-Pro group

Placebo supplementation DIETARY_SUPPLEMENT

1-year supplementation with two placebo capsules/day containing starch, the probiotic bacteria carrier.

Placebo group

peripheral blood withdrawal PROCEDURE

40 ml of blood for the isolation of Peripheral Blood Cells (PBMCs) and T cells.

Placebo group; Pre-Pro group

Transcranial Magnetic Stimulation (TMS) PROCEDURE

Intermittent theta burst stimulation (iTBS) protocol

Placebo group; Pre-Pro group

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• RRMS diagnosis, as Polman et al 2011. Ann Neurol. PMID: 21387374
• Age \<= 18 and =\> 65 years
• EDSS score \<= 7
• Disease duration \< 10 years
• On DMF or Ocrelizumab treatment from at least 3 months
• No corticosteroid administration in the previous month
• Ability to provide written informed consent.

You may not qualify if:

• Adverse effects to gadolinium
• Blood count basal alteration
• Pregnant or lactating women
• Vegetarians or vegans
• History of food allergies or food intolerance
• Clinically significant medical condition other than MS, (latent infections, other autoimmune disease)
• Diagnosis of past eating disorders (anorexia, bulimia, or binge eating) or relevant psychiatric disorders.

Sponsors & Collaborators

• Neuromed IRCCS: lead
• I.R.C.C.S. Fondazione Santa Lucia: collaborator

Study Sites (1)

IRCCS INM-Neuromed

Pozzilli, Isernia, 86077, Italy

RECRUITING

Related Publications (9)

• Mandolesi G, Gentile A, Musella A, Fresegna D, De Vito F, Bullitta S, Sepman H, Marfia GA, Centonze D. Synaptopathy connects inflammation and neurodegeneration in multiple sclerosis. Nat Rev Neurol. 2015 Dec;11(12):711-24. doi: 10.1038/nrneurol.2015.222. Epub 2015 Nov 20.

  PMID: 26585978 BACKGROUND

• De Vito F, Musella A, Fresegna D, Rizzo FR, Gentile A, Stampanoni Bassi M, Gilio L, Buttari F, Procaccini C, Colamatteo A, Bullitta S, Guadalupi L, Caioli S, Vanni V, Balletta S, Sanna K, Bruno A, Dolcetti E, Furlan R, Finardi A, Licursi V, Drulovic J, Pekmezovic T, Fusco C, Bruzzaniti S, Hornstein E, Uccelli A, Salvetti M, Matarese G, Centonze D, Mandolesi G. MiR-142-3p regulates synaptopathy-driven disease progression in multiple sclerosis. Neuropathol Appl Neurobiol. 2022 Feb;48(2):e12765. doi: 10.1111/nan.12765. Epub 2021 Oct 6.

  PMID: 34490928 BACKGROUND

• Stampanoni Bassi M, Iezzi E, Buttari F, Gilio L, Simonelli I, Carbone F, Micillo T, De Rosa V, Sica F, Furlan R, Finardi A, Fantozzi R, Storto M, Bellantonio P, Pirollo P, Di Lemme S, Musella A, Mandolesi G, Centonze D, Matarese G. Obesity worsens central inflammation and disability in multiple sclerosis. Mult Scler. 2020 Sep;26(10):1237-1246. doi: 10.1177/1352458519853473. Epub 2019 Jun 4.

  PMID: 31161863 BACKGROUND

• Buckman LB, Hasty AH, Flaherty DK, Buckman CT, Thompson MM, Matlock BK, Weller K, Ellacott KL. Obesity induced by a high-fat diet is associated with increased immune cell entry into the central nervous system. Brain Behav Immun. 2014 Jan;35:33-42. doi: 10.1016/j.bbi.2013.06.007. Epub 2013 Jul 4.

  PMID: 23831150 BACKGROUND

• Haase S, Wilck N, Haghikia A, Gold R, Mueller DN, Linker RA. The role of the gut microbiota and microbial metabolites in neuroinflammation. Eur J Immunol. 2020 Dec;50(12):1863-1870. doi: 10.1002/eji.201847807. Epub 2020 Dec 7.

  PMID: 33188704 BACKGROUND

• Mirashrafi S, Hejazi Taghanaki SZ, Sarlak F, Moravejolahkami AR, Hojjati Kermani MA, Haratian M. Effect of probiotics supplementation on disease progression, depression, general health, and anthropometric measurements in relapsing-remitting multiple sclerosis patients: A systematic review and meta-analysis of clinical trials. Int J Clin Pract. 2021 Nov;75(11):e14724. doi: 10.1111/ijcp.14724. Epub 2021 Aug 19.

  PMID: 34379879 BACKGROUND

• Siracusa F, Schaltenberg N, Villablanca EJ, Huber S, Gagliani N. Dietary Habits and Intestinal Immunity: From Food Intake to CD4+ T H Cells. Front Immunol. 2019 Jan 15;9:3177. doi: 10.3389/fimmu.2018.03177. eCollection 2018.

  PMID: 30697217 BACKGROUND

• Valizadeh S, Majdi Seghinsara A, Maleki Chollou K, Bahadori A, Abbaszadeh S, Taghdir M, Behniafar H, Riahi SM. The efficacy of probiotics in experimental autoimmune encephalomyelitis (an animal model for MS): a systematic review and meta-analysis. Lett Appl Microbiol. 2021 Oct;73(4):408-417. doi: 10.1111/lam.13543. Epub 2021 Aug 11.

  PMID: 34310737 BACKGROUND

• Sichetti M, De Marco S, Pagiotti R, Traina G, Pietrella D. Anti-inflammatory effect of multistrain probiotic formulation (L. rhamnosus, B. lactis, and B. longum). Nutrition. 2018 Sep;53:95-102. doi: 10.1016/j.nut.2018.02.005. Epub 2018 Feb 14.

  PMID: 29674267 BACKGROUND

MeSH Terms

Conditions

Patient Participation; Dysbiosis; Multiple Sclerosis

Interventions

Prebiotics; Transcranial Magnetic Stimulation

Condition Hierarchy (Ancestors)

Patient Acceptance of Health Care; Treatment Adherence and Compliance; Health Behavior; Behavior; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Dietary Fiber; Dietary Carbohydrates; Carbohydrates; Polysaccharides, Bacterial; Polysaccharides; Food; Diet, Food, and Nutrition; Physiological Phenomena; Dietary Supplements; Food and Beverages; Magnetic Field Therapy; Therapeutics

Central Study Contacts

Silvia Caioli, MD

CONTACT

+39 3332790061; silviacaioli@yahoo.it

Diego Centonze, MD

CONTACT

+39 3934444159; centonze@uniroma2.it

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Head of Neurology Unit

Study Record Dates

• First Submitted: March 6, 2023
• First Posted: March 22, 2023
• Study Start: July 26, 2023
• Primary Completion: November 2, 2024
• Study Completion: May 1, 2026
• Last Updated: August 14, 2023

Record last verified: 2023-08

Locations

IT (1)