The gut microbiome and neuroinflammation in amyotrophic lateral sclerosis? Emerging clinical evidence

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a grim prognosis. Median survival time from symptom onset is about 3 years, and only 10% of patients survive 10 years or more (Traxinger et al., 2013). The few available treatments have only modest effects on survival and rate of disease progression (Abe et al., 2017; Lacomblez et al., 1996). ALS is characterized by the degeneration of motor neurons, which manifests clinically as progressive weakness in the limbs and trunk, loss of the ability to speak and swallow, and eventually death due to respiratory failure. Poor nutritional status and weight loss are common in ALS and are associated with shorter survival (Marin et al., 2011). Delayed gastric emptying and colonic transit times as well as increased metabolic rates are also prevalent in ALS (Steyn et al., 2018; Toepfer et al., 1999). Although these signs and symptoms may be attributed to the altered dietary patterns associated with ALS, they also can be associated with gut microbiome dysbiosis. The advent of high-throughput gene sequencing, along with its declining cost, has opened the field for much research regarding the role of the microbiome in various diseases. The microbiome – defined as the micro-organisms that live in and on us, their genes, and gene products – is particularly concentrated in the gastrointestinal tract, and is now known to contribute to disease processes such as stomach ulcers, Crohn's disease, ulcerative colitis, irritable bowel disease, diabetes, obesity. The gut microbiome is also known to influence brain function and therefore behavior. In the last few years, there have been new findings identifying a relationship between gut microbiome dysbiosis and neurodegenerative diseases, in particular Parkinson's disease (PD) (Lin et al., 2018; Sun and Shen, 2018), Alzheimer's disease (AD) (Paley et al., 2018; Zhuang et al., 2018), and multiple sclerosis (MS) (Castillo-Alvarez et al., 2018; Jangi et al., 2016). In these disorders, neuroinflammation is increasingly recognized as a driver for disease progression (Skaper et al., 2018). Neuroinflammation also appears to contribute to the progression of ALS. Numerous studies have reported activation of microglia (Corcia et al., 2012; Henkel et al., 2004; Kawamata et al., 1992; Turner et al., 2004) and astrocytes (Haidet-Phillips et al., 2011) in tissue from ALS patients. Such activation has been found to correlate with the severity of disease pathology (Turner et al., 2004). A transcriptomic analysis in the ventral horn of the lumbar spinal cord of ALS patients reported depletion of neuron and oligodendrocyte populations with a reciprocal increase in transcripts from astrocytes and microglia (D'Erchia et al., 2017). Dysregulation of immune-related pathways is a prominent feature in ALS-affected brain and spinal cord tissue (D'Erchia et al., 2017; Morello et al., 2017). There are also indications of peripheral immune activation in ALS as well. Evidence of elevated complement activity has been observed in plasma and muscle from ALS patients compared to healthy controls (Bahia El Idrissi et al., 2016; Mantovani et al., 2014). Alterations in peripheral monocytes, CD4+ T cells, CD8+ T cells, natural killer T cells, and neutrophils have also been documented in ALS patients (Fiala et al., 2010; Mantovani et al., 2009; Murdock et al., 2016; Perner et al., 2018; Rentzos et al., 2012; Shi et al., 2007; Zhao et al., 2017; Zondler et al., 2016), and many of these abnormalities correlate with the rate of disease progression (Murdock et al., 2016; Perner et al., 2018; Shi et al., 2007; Zhang et al., 2005; Zhao et al., 2017). Furthermore, some of these inflammatory peripheral immune cell phenotypes have been identified in individuals in the earliest stages of the disorder (Mantovani et al., 2009) and even in pre-symptomatic subjects with ALS-associated genetic mutations (Zondler et al., 2016). Together, this evidence suggests that immune dysregulation develops early in the course of ALS and that, rather than being a passive consequence of neurodegeneration, it contributes actively to pathology and patient decline. Gut bacteria play a vital role in maintaining and regulating the immune system. Changes in gut microbial composition and the associated immune responses can impact the blood-brain barrier (BBB) and