Gut- and oral-dysbiosis differentially impact spinal- and bulbar-onset ALS, predicting ALS severity and potentially determining the location of disease onset

Abstract

Background Prior studies on the role of gut-microbiome in Amyotrophic Lateral Sclerosis (ALS) pathogenesis have yielded conflicting results. We hypothesized that gut- and oral-microbiome may differentially impact two clinically-distinct ALS subtypes (spinal-onset ALS (sALS) vs. bulbar-onset ALS (bALS), driving disagreement in the field. Methods ALS patients diagnosed within 12 months and their spouses as healthy controls (n = 150 couples) were screened. For eligible sALS and bALS patients (n = 36) and healthy controls (n = 20), 16S rRNA next-generation sequencing was done in fecal and saliva samples after DNA extractions to examine gut- and oral-microbiome differences. Microbial translocation to blood was measured by blood lipopolysaccharide-binding protein (LBP) and 16S rDNA levels. ALS severity was assessed by Revised ALS Functional Rating Scale (ALSFRS-R). Results sALS patients manifested significant gut-dysbiosis, primarily driven by increased fecal Firmicutes/Bacteroidetes-ratio (F/B-ratio). In contrast, bALS patients displayed significant oral-dysbiosis, primarily driven by decreased oral F/B-ratio. For sALS patients, gut-dysbiosis (a shift in fecal F/B-ratio), but not oral-dysbiosis, was strongly associated with greater microbial translocation to blood (r = 0.8006, P < 0.0001) and more severe symptoms (r = 0.9470, P < 0.0001). In contrast, for bALS patients, oral-dysbiosis (a shift in oral F/B-ratio), but not gut-dysbiosis, was strongly associated with greater microbial translocation to blood (r = 0.9860, P < 0.0001) and greater disease severity (r = 0.9842, P < 0.0001). For both ALS subtypes, greater microbial translocation was associated with more severe symptoms (sALS: r = 0.7924, P < 0.0001; bALS: r = 0.7496, P = 0.0067). Importantly, both sALS and bALS patients displayed comparable oral-motor deficits with associations between oral-dysbiosis and severity of oral-motor deficits in bALS but not sALS. This suggests that oral-dysbiosis is not simply caused by oral/bulbar/respiratory symptoms but represents a pathological driver of bALS. Conclusions We found increasing gut-dysbiosis with worsening symptoms in sALS patients and increasing oral-dysbiosis with worsening symptoms in bALS patients. Our findings support distinct microbial mechanisms underlying two ALS subtypes, which have been previously grouped together as a single disease. Our study suggests correcting gut-dysbiosis as a therapeutic strategy for sALS patients and correcting oral-dysbiosis as a therapeutic strategy for bALS patients.

Macrophage-Targeted Sodium Chlorite (NP001) Slows Progression of Amyotrophic Lateral Sclerosis (ALS) through Regulation of Microbial Translocation

“…Changes in these factors included those regulated by NFkB, a known target of TauCl produced by the metabolism of NP001. Once LPS is removed as a perpetual driver of MT signaling, LPS reactive factors such as hepatocyte growth factor (HGF), neopterin, LPS-binding protein (LBP), IL-18 and epidermal growth factor (EGF) are up and down regulated relatively quickly [ 33 , 34 , 35 , 36 ]. The removal of CNS disease-associated activation signaling causes a decrease in monocyte migration into the CNS, which is reflected by decreased levels of soluble CD163 [ 37 ].…”

The Tryptophan and Kynurenine Pathway Involved in the Development of Immune-Related Diseases

“…Modifications in the composition of gut microbiota with a number of pathological microorganisms might play a crucial role in the pathogenesis of several diseases. Consistently, growing evidence has also linked gut dysbiosis to the exacerbation of compromised autophagy in certain inflammations [ 114 ]. Remarkably, metformin, a pleiotropic drug that is capable of modulating autophagy, could modify the metabolic process of gut microbiota [ 115 ].…”

The Association between Dysbiosis and Neurological Conditions Often Manifesting with Chronic Pain

“…Amyotrophic Lateral Sclerosis is a neuromuscular disease due to the progressive death of motor neurons and muscle atrophy [ 64 ]. Compared to PD and AD, there is less research available on the impact of dysbiosis on ALS.…”

“…Animal studies have demonstrated the impact of dysbiosis on ALS, where a reduced content of butyrate-producing bacteria resulted in gut permeability [ 53 ]. Animal studies have demonstrated intestinal dysbiosis in rodents prior to ALS manifestation, where leaky gut was also present [ 64 ]. Furthermore, alleviating dysbiosis improved ALS progression with worsening dysbiosis associated with more severe clinical symptoms [ 64 ].…”