Microbiome and intestinal barrier in ALS therapy

Jesse Brown Va Medical Center, Chicago IL

Investigators

Linked publications, trials & patents

Abstract

Background and Innovation: The goal of this renewal Merit Award application is to investigate the mechanisms of intestinal function and microbiome in Amyotrophic lateral sclerosis (ALS), meanwhile providing a novel approach through microbiome and metabolites that can potentially treat ALS by restoring gut-neuron- microbial axis. ALS is a fatal neuromuscular disease characterized by progressive death of motor neurons and muscle atrophy. Veterans are twice as likely to be diagnosed with ALS as the general population. Microbiome and intestinal homeostasis play essential roles in neurological diseases. The complex interplay of intestinal - central nervous system communication involves autonomic and enteric nervous systems, neuroendocrine and immune systems. However, little is known about the intestinal microbiome in Veterans with ALS. Our lab is the first to discover the link between intestinal homeostasis and the disease progression in an ALS SOD1G93A mouse model. Our study in human ALS further reveals the dysbiosis and intestinal inflammation. Reduced bacterial diversity and reduced butyrate-producing bacteria (dysbiosis) correlate with enteric neuromuscular and central nervous disorders. Along these lines, we have demonstrated that had damaged tight junctions, impaired enteric neuromuscular ALS mice (both SOD1G93A and TDP43 models) system, and reduced barriers. Remarkably, restoring the intestinal homeostasis by feeding the ALS model mice with butyrate significantly delayed the disease onset and prolonged the life span of ALS mice. However, the clinical applications of microbiome and beneficial microbial metabolites in ALS are in its infancy. There is still a dire need to develop novel treatments for ALS and improving the life quality of ALS patients. Based on our progress in the VA Merit Award, publications, and provocative preliminary studies, we hypothesize that targeting the gut-neuron-microbiome axis should improve the barrier function and restore microbiome, thus slowing disease progression of ALS. We have designed two Aims to rigorously examine the hypotheses: Aim 1. Determine the mechanisms that contribute to dysbiosis and barrier dysfunction through gut- microbiome-neuron axis in ALS. We will define the mechanism for abnormal barriers and dysbiosis using ALS mice and establishing a novel humanized ALS microbiome model. ALS mice will have fecal microbiota transplantation (FMT) using human microbiome from Veterans with ALS. We will investigate roles of microbiome, using novel molecular tools, human enteroid cultures, enteric glia cells, and transgenic models. We will determine mechanisms underlying ALS associated microbiome on intestinal barrier, blood-brain-barrier (BBB), and neuroprotection through the gut-microbiome-neuron axis in the pathogenesis of ALS. Aim 2. Identify metabolites for preserving intestinal barrier and neuromuscular function in ALS. We will use multi-omics to identify beneficial metabolites and perform molecular biological assessments of intestinal and neuromuscular integrity to evaluate metabolites. We will examine their efficacy of restoring gut- microbiome-neuron axis in slowing ALS progression using different ALS models. Innovation of this project lies in its: (a) therapeutic potential for ALS, (b) conceptual frame-work to discover early changes and dysbiosis and the gut barrier effects before onset of ALS, (c) multi-Omics methods to identify beneficial microbiome/metabolites, and (d) state-of–the-art experimental models that allow us to understand mechanisms by restoring gut-neuron-microbial axis in ALS. Significance and Impact to Veterans Healthcare: Military veterans, regardless of the branch of service, the era in which they served, or whether they served during a time of peace or war, are at a greater risk of dying from ALS than if they had not military service. Our study is significant because of the health burden of ALS in VA population and the novel role of the microbiome on neuromuscular function in health and disease, especially in Veterans’ care. Path to translation: It has significant translational implications for developing new therapeutic strategies by restoring gut-neuron-microbial axis for combating ALS and improving the health of Veterans.