Microbiota-gut-brain axis and its therapeutic applications in neurodegenerative diseases

Abstract

The human gastrointestinal tract is populated with a diverse microbial community. The vast genetic and metabolic potential of the gut microbiome underpins its ubiquity in nearly every aspect of human biology, including health maintenance, development, aging, and disease. The advent of new sequencing technologies and culture-independent methods has allowed researchers to move beyond correlative studies toward mechanistic explorations to shed light on microbiome-host interactions. Evidence has unveiled the bidirectional communication between the gut microbiome and the central nervous system, referred to as the "microbiota-gut-brain axis". The microbiota-gut-brain axis represents an important regulator of glial functions, making it an actionable target to ameliorate the development and progression of neurodegenerative diseases. In this review, we discuss the mechanisms of the microbiota-gut-brain axis in neurodegenerative diseases. As the gut microbiome provides essential cues to microglia, astrocytes, and oligodendrocytes, we examine the communications between gut microbiota and these glial cells during healthy states and neurodegenerative diseases. Subsequently, we discuss the mechanisms of the microbiota-gut-brain axis in neurodegenerative diseases using a metabolite-centric approach, while also examining the role of gut microbiota-related neurotransmitters and gut hormones. Next, we examine the potential of targeting the intestinal barrier, blood-brain barrier, meninges, and peripheral immune system to counteract glial dysfunction in neurodegeneration. Finally, we conclude by assessing the pre-clinical and clinical evidence of probiotics, prebiotics, and fecal microbiota transplantation in neurodegenerative diseases. A thorough comprehension of the microbiota-gut-brain axis will foster the development of effective therapeutic interventions for the management of neurodegenerative diseases.

Fig. 1

The microbiota–gut–brain axis. The bidirectional communication between the gut microbiome and the brain is mediated by the immune system, vagus nerve, enteric nervous system, neuroendocrine system, and circulatory system. Alterations in gut microbiota have been linked to the development of autism spectrum disorders, anxiety, depressive-like behavior, impaired physical performance, and motivation, as well as neurodegenerative diseases. This figure was created with BioRender (https://biorender.com/)

Fig. 2

Microglial activation and neurodegeneration. Aging induces microglial activation by activating the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway. Misfolded proteins and protein aggregates induce microglial activation by impairing microglial autophagy. Stage-1 DAM represents a transitory and functional subtype with a higher capacity of phagocytosis initiated by a TREM2-independent mechanism, whereas stage-2 DAM represents a dysfunctional state initiated by a TREM2-dependent mechanism. The microglial spleen tyrosine kinase (SYK) signaling provides metabolic support to facilitate microglial transition into stage-2 DAM. Maladaptive microglial-T-cell signaling drives neurodegeneration by releasing neurotoxic factors. Microglial activation creates a feed-forward vicious cycle that aggravates neurodegeneration as activated microglia contribute to the propagation of protein aggregates into unaffected brain regions. This figure was created with BioRender (https://biorender.com/)

Fig. 3

Microbiota–gut–brain axis in Alzheimer’s disease. a Short-chain fatty acids (SCFAs) exert their neuroprotective effects by acting as endogenous ligands for G-protein-coupled receptors (GPCRs) and modulating gene expression by inhibiting histone deacetylases (HDACs). b Trimethylamine N-oxide (TMAO) promotes microglial activation, neuroinflammation, Aβ and tau pathology. c Neuroprotective bile acids (BAs), including UDCA and TUDCA, inhibit neuroinflammation via direct and indirect pathways. In the direct pathway, UDCA and TUDCA activate the nuclear receptor Farnesoid X receptor (FXR) and membrane receptor Takeda G-protein-coupled receptor 5 (TGR5) found in microglia and neurons. In the indirect pathway, UDCA and TUDCA provide signals to the central nervous system indirectly via intestinal TGR5-dependent glucagon-like peptide-1 (GLP-1) pathway and intestinal FXR-dependent fibroblast growth factor 15 or 19 (FGF15/19) pathway. d Tryptophan and indole derivatives activate microglial aryl hydrocarbon receptor (AHR) signaling to inhibit microglial activation and neuroinflammation. e Polyunsaturated fatty acids (PUFAs): omega-3 fatty acids exhibit neuroprotective effects in Alzheimer’s disease, whereas omega-6 fatty acid arachidonic acid and its pro-inflammatory metabolites induce microglial activation. This figure was created with BioRender (https://biorender.com/)

Fig. 4

Microbiota–gut–brain axis in Parkinson’s disease. a Short-chain fatty acids (SCFAs) exert their neuroprotective effects by acting as endogenous ligands for G-protein-coupled receptors (GPCRs) and modulating gene expression by inhibiting histone deacetylases (HDACs). b Neuroprotective bile acids (BAs), including UDCA and TUDCA, inhibit neuroinflammation via direct and indirect pathways. In the direct pathway, UDCA and TUDCA activate the nuclear receptor Farnesoid X receptor (FXR) and membrane receptor Takeda G-protein-coupled receptor 5 (TGR5) found in microglia and neurons. In the indirect pathway, UDCA and TUDCA provide signals to the central nervous system indirectly via intestinal TGR5-dependent glucagon-like peptide-1 (GLP-1) pathway and intestinal FXR-dependent fibroblast growth factor 15 or 19 (FGF15/19) pathway. c Trimethylamine N-oxide (TMAO) promotes microglial activation and neuroinflammation. However, contradictory findings have been reported regarding the roles of TMAO in PD. d Tryptophan and indole derivatives activate microglial aryl hydrocarbon receptor (AHR) signaling to inhibit microglial activation and neuroinflammation. e Branched-chain amino acids (BCAAs) promote anti-inflammatory microglial phenotypes. This figure was created with BioRender (https://biorender.com/)

Fig. 5

Improving microbiota–gut–brain axis via the intestinal barrier. a High-fiber diets contribute to a healthy gut microbiome and enhance intestinal barrier integrity by increasing SCFAs-producing species, and fiber-degrading species and promoting resistance to perturbations. Indole and its derivatives improve intestinal barrier integrity by activating epithelial aryl hydrocarbon receptors (AHR). b Low-fiber diets, aging and sleep deprivation contribute to dysbiosis and disrupt intestinal barrier integrity by reducing SCFAs-producing species and fiber-degrading species while increasing mucin-degrading species. Low-fiber diets induce mucosal and systemic immune depression by impairing the metabolic fitness of CD4⁺ T cells. This figure was created with BioRender (https://biorender.com/)

Fig. 6

Improving microbiota–gut–brain axis via the blood–brain barrier. a SCFAs and p-cresol glucuronide improve BBB integrity and prevent glial activation. b Elevated levels of trimethylamine-N-oxide (TMAO) has been reported in the plasma and cerebrospinal fluid of individuals with mild cognitive impairment, Alzheimer’s disease (AD) and Parkinson’s disease (PD). TMAO is detrimental to BBB integrity and induces glial activation. This figure was created with BioRender (https://biorender.com/)