Role of Microbiota-Derived Hydrogen Sulfide (H2S) in Modulating the Gut-Brain Axis: Implications for Alzheimer's and Parkinson's Disease Pathogenesis

Abstract

Microbiota-derived hydrogen sulfide (H₂S) plays a crucial role in modulating the gut-brain axis, with significant implications for neurodegenerative diseases such as Alzheimer's and Parkinson's. H₂S is produced by sulfate-reducing bacteria in the gut and acts as a critical signaling molecule influencing brain health via various pathways, including regulating inflammation, oxidative stress, and immune responses. H₂S maintains gut barrier integrity at physiological levels and prevents systemic inflammation, which could impact neuroinflammation. However, as H₂S has a dual role or a Janus face, excessive H₂S production, often resulting from gut dysbiosis, can compromise the intestinal barrier and exacerbate neurodegenerative processes by promoting neuroinflammation and glial cell dysfunction. This imbalance is linked to the early pathogenesis of Alzheimer's and Parkinson's diseases, where the overproduction of H₂S exacerbates beta-amyloid deposition, tau hyperphosphorylation, and alpha-synuclein aggregation, driving neuroinflammatory responses and neuronal damage. Targeting gut microbiota to restore H₂S homeostasis through dietary interventions, probiotics, prebiotics, and fecal microbiota transplantation presents a promising therapeutic approach. By rebalancing the microbiota-derived H₂S, these strategies may mitigate neurodegeneration and offer novel treatments for Alzheimer's and Parkinson's diseases, underscoring the critical role of the gut-brain axis in maintaining central nervous system health.

Keywords: Alzheimer’s disease; H2S; Parkinson’s disease; dysbiosis; glial cell dysfunction; gut–brain axis; microbiota; neurodegeneration; neuroinflammation; prebiotics; probiotics.

Figure 1

The dysbiosis-associated overproduction of H₂S is proposed as a contributing factor in the progression of neurodegenerative diseases, where neuroinflammation plays a pivotal role. At the same time, H₂S can have positive effects in a concentration-dependent manner.

Figure 2

Illustrative interplay between diet, gut microbiota, and their metabolites in the context of neurodegenerative diseases, particularly Alzheimer’s and Parkinson’s. Diet shapes the gut microbial composition, including diverse groups such as Clostridium, Desulfovibrio, and Prevotella, responsible for metabolic activities with systemic impacts. Microbes metabolize dietary components into various products, including hydrogen sulfide (H₂S) via sulfate reduction and short-chain fatty acids (SCFAs) like acetate, propionate, and butyrate from fiber fermentation. These metabolites influence gut permeability and barrier integrity, with butyrate supporting the gut lining. At the same time, excess H₂S may compromise it, leading to a “leaky gut” and the release of inflammatory lipopolysaccharides (LPSs) into circulation. SCFAs and other microbial metabolites reach the brain through the bloodstream and vagus nerve, potentially promoting neuroinflammation—a known factor in neurodegeneration. The figure highlights how disruptions in gut microbiota balance can affect brain health, linking gut dysbiosis and altered barrier function to neurodegenerative disease risk and suggesting that therapeutic interventions targeting the gut may help mitigate these diseases.

Figure 3

Bidirectional gut–brain axis, highlighting interactions among the hypothalamic–pituitary–adrenal (HPA) axis, gut microbiota, circulatory system, and neural pathways. The HPA axis produces cortisol, affecting immune cells, gut epithelium, and enteric muscles. Gut microbes modulate brain function via metabolites like short-chain fatty acids (SCFAs), neurotransmitters, and tryptophan metabolism. H₂S was found to regulate mucosal integrity, support the anti-inflammatory environment of the gut, and maintain the protective mucus layer.