Abstract
Background and Rationale: Among the key players in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS), microglia and T regulatory lymphocytes (Treg) are candidate cells for modifying the course of the disease. The gut microbiota (GM) acts by shaping immune tolerance and regulating the Treg number and suppressive function, besides circulating neuropeptides, and other immune cells that play in concert through the gut-brain axis. Previous mouse models have shown an altered enteric flora in early stage ALS, pointing to a possible GM role in ALS pathogenesis. Fecal Microbial Transplantation (FMT) is a well-known therapeutic intervention used to re-establish the proper microenvironment and to modulate enteric and systemic immunity.Methods: We are going to perform a multicenter randomized double-blind clinical trial employing FMT as a therapeutic intervention for ALS patients (NCT0376632). Forty-two ALS patients, at an early stage, will be enrolled with a 2:1 allocation ratio (28 FMT-treated patients vs. 14 controls). Study duration will be 12 months per patient. Three endoscopic procedures for intestinal biopsies in FMT and control groups are predicted at baseline, month 6 and month 12; at baseline and at month 6 fresh feces from healthy donors will be infused at patients in the intervention arm. The primary outcome is a significant change in Treg number between FMT-treated patients and control arm from baseline to month 6. Secondary outcomes include specific biological aims, involving in-depth analysis of immune cells and inflammatory status changes, central and peripheral biomarkers of ALS, besides comprehensive analysis of the gut, saliva and fecal microbiota. Other secondary aims include validated clinical outcomes of ALS (survival, forced vital capacity, and modifications in ALSFRS-R), besides safety and quality of life.Expected Results: We await FMT to increase Treg number and suppressive functionality, switching the immune system surrounding motorneurons to an anti-inflammatory, neuroprotective status. Extensive analysis on immune cell populations, cytokines levels, and microbiota (gut, fecal and saliva) will shed light on early processes possibly leading the degenerative ALS course.Conclusions: This is the first trial with FMT as a potential intervention to modify immunological response to ALS and disease progression at an early stage.
Highlights
When questioning why so many failures in clinical trials in amyotrophic lateral sclerosis (ALS), the lack of a complete comprehension of the pathogenic systems behind the disease onset and progression might be accounted as one of the main reasons
Our trial aims at evaluating the biological basis of a potential treatment for ALS in order to plan a following efficacy study
Our trial aims at evaluating the biological bases of Fecal Microbial Transplantation (FMT) as a potential treatment for ALS in order to plan a following efficacy study on fecal microbiota transplantation for this disease
Summary
When questioning why so many failures in clinical trials in amyotrophic lateral sclerosis (ALS), the lack of a complete comprehension of the pathogenic systems behind the disease onset and progression might be accounted as one of the main reasons. Recent studies highlighted the role of microglia and opened new perspectives in the knowledge of the non-cell autonomous molecular mechanisms possibly contributing to ALS, launching them as a plausible target for many clinical trials. During ALS progression, activated microglia switch from the M2 phenotype, which is neuroprotective and supports tissue repair and neuron survival through the release of neuroprotective factors, to M1 phenotype, which is toxic and contributes to neuronal death through pro-inflammatory cytokines production, and tissue destruction. Among the key players in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS), microglia and T regulatory lymphocytes (Treg) are candidate cells for modifying the course of the disease. Fecal Microbial Transplantation (FMT) is a well-known therapeutic intervention used to re-establish the proper microenvironment and to modulate enteric and systemic immunity
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