Specific Bacterial Taxa and Their Metabolite, DHPS, May Be Linked to Gut Dyshomeostasis in Patients with Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis

Abstract

Background: Neurodegenerative diseases (NDDs) are multifactorial disorders frequently associated with gut dysbiosis, oxidative stress, and inflammation; however, the pathophysiological mechanisms remain poorly understood. Methods: Using untargeted mass spectrometry-based metabolomics and 16S sequencing of human stool, we investigated bacterial and metabolic dyshomeostasis in the gut microbiome associated with early disease stages across three NDDs-amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD)-and healthy controls (HC). Results: We discovered a previously unrecognized link between a microbial-derived metabolite with an unknown role in human physiology, 2,3-dihydroxypropane-1-sulfonate (DHPS), and gut dysbiosis in NDDs. DHPS was downregulated in AD, ALS, and PD, while bacteria involved in DHPS metabolism, Eubacterium and Desulfovibrio, were increased in all disease cohorts. Additionally, select taxa within the Clostridia class had strong negative correlations to DHPS, suggesting a potential role in DHPS metabolism. A catabolic product of DHPS is hydrogen sulfide, and when in excess, it is known to promote inflammation, oxidative stress, mitochondrial damage, and gut dysbiosis, known hallmarks of NDDs. Conclusions: These findings suggest that cryptic sulfur metabolism via DHPS is a potential missing link in our current understanding of gut dysbiosis associated with NDD onset and progression. As this was a hypothesis generating study, more work is needed to elucidate the role of DHPS in gut dysbiosis and neurodegenerative diseases.

Keywords: 2,3-dihydroxypropane-1-sulfonate (DHPS); Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; bacterial-derived; metabolomics; microbiome; neurodegenerative disease.

Figure 1

Patients with NDDs have an altered gut metabolic profile. Partial least squares discriminant analysis (PLS-DA) comparing metabolomes associated with NDD and HC and corresponding variable importance in projection (VIP) scores. Individual participants are shown with respective confidence intervals; HC samples are yellow; (a) AD samples are blue; (b) ALS samples are shown in red; (c) PD samples are purple. VIP scores are shown for the corresponding PLS-DA models showing the top 25 metabolites contributing most to the differences in metabolic profiles.

Figure 2

There were 19 metabolic markers for all NDDs in this study, as well as unique markers for each disease. DHPS was one of the 19 markers for NDDs, as it was significantly decreased in NDD cohorts. DHPS was strongly correlated to acetylated amino acids and taurine. (a–c) Volcano plots showing metabolites significantly different between cohorts. The x-axis is the log₂ foldchange and y-axis is the -log p value. The following cutoffs were used: fold change > |1.5| (p < 0.1). (d) Venn diagram shows unique and shared metabolic markers. These metabolites had fold change > |1.5| (p < 0.1) or VIP score > 1. (e) Metabolites strongly correlated with DHPS in PD. (f) Eight OTUs were significantly correlated with DHPS across all three NDDs. These OTUs were the following: OTU136 (d__Bacteria;p__Firmicutes;c__Clostridia;__;__;__); OUT127 (d__Bacteria;p__Firmicutes;c__Clostridia;o__Clostridia;f__Hungateiclostridiaceae;__); OTU121 (d__Bacteria;p__Firmicutes;c__Clostridia;o__Oscillospirales;f__Oscillospiraceae;g__Oscillospira); OTU091 (d__Bacteria;p__Firmicutes;c__Clostridia;o__Oscillospirales;f__UCG-010;g__UCG-010); OTU045 (d__Bacteria;p__Firmicutes;c__Clostridia;o__Clostridia_vadinBB60_group;f__Clostridia_vadinBB60_group;g__Clostridia_vadinBB60_group); OTU060 (d__Bacteria;p__Bacteroidota;c__Bacteroidia;o__Bacteroidales; f__Marinifilaceae;g__Odoribacter); OTU050 (d__Bacteria;p__Firmicutes;c__Clostridia;o__Oscillospirales;f__Oscillospiraceae;__); and OTU038 (d__Bacteria;p__Firmicutes;c__Clostridia;o__Oscillospirales;f__[Eubacterium]_coprostanoligenes_group;g__[Eubacterium]_coprostanoligenes_group).

Figure 3

Gut microbial composition is altered in NDDs. (a) Phyla-level differences in microbial composition. (b) Box and whisker plot showing alpha diversity was significantly higher in PD cohort compared to the HC cohort. However, there were no significant differences in the AD and ALS cohort compared to HC. (c) Log₂ fold change of taxa significantly altered across AD, ALS, and PD cohorts. Orange represents higher abundance in disease compared to HC, while blue represents lower abundance in disease compared to HC.

Figure 4

DHPS can be obtained through dietary consumption of leafy greens and degraded to H₂S. The abundance of DHPS-producing and -consuming microbes is increased in NDD, while DHPS is decreased in NDD, suggesting the rapid degradation of DHPS to yield H₂S. Other microbes (Enterococcus and Clostridium) can ferment dietary sulfoquinovose (SQ) to H₂S with DHPS as a transient intermediate as well. Figure was created using biorender.com and adapted from Hanson et al. [56].