The Role of Gut Microbiota-Derived Trimethylamine N-Oxide in the Pathogenesis and Treatment of Mild Cognitive Impairment

Abstract

Mild cognitive impairment (MCI) represents a transitional stage between normal aging and dementia, often considered critical for dementia prevention. Despite its significance, no effective clinical treatment for MCI has yet been established. Emerging evidence has demonstrated a strong association between trimethylamine-N-oxide (TMAO), a prominent metabolite derived from the gut microbiota, and MCI, highlighting its potential as a biomarker and therapeutic target. TMAO has been implicated in increasing MCI risk through its influence on factors such as hypertension, cardiovascular disease, depression, diabetes, and stroke. Moreover, it contributes to MCI by promoting oxidative stress, disrupting the blood-brain barrier, impairing synaptic plasticity, inducing inflammation, causing mitochondrial metabolic disturbances, and facilitating abnormal protein aggregation. This review further explores therapeutic strategies targeting TMAO to mitigate MCI progression.

Keywords: brain disease; gut microbiota; mechanism; metabolism; mild cognitive impairment; risk factor; therapy; trimethylamine-N-oxide.

Figure 5

Treatment Strategy for improving MCI by affecting TMAO.

Figure 1

Origins and Excretion of TMAO. TMAO is absorbed directly from dietary sources through the intestines. Exogenous TMAO is subsequently produced via oxidation by the gut microbiome and the liver. The primary excretion pathways for TMAO include urine, feces, and respiration. Abbreviations: TMA, trimethylamine; TMAO, trimethylamine N-oxide; FMO, flavin-containing monooxygenase; OCT, organic cation transporter.

Figure 2

Contributions of TMAO to the pathogenesis of MCI. TMAO potentially contributes to the pathogenesis of MCI by promoting oxidative stress, neuroinflammation, and abnormal protein accumulation. TMAO induces oxidative stress by enhancing the production of reactive oxygen species (ROS) and reducing antioxidant activity. It also triggers neuroinflammation by activating NF-κβ and the NLRP3 inflammasome. Furthermore, TMAO exacerbates the formation of amyloid plaques and neurofibrillary tangles by impairing the intracellular ubiquitin–proteasome system. Abbreviations: TMAO, trimethylamine N-oxide; GSH, glutathione; GPX, glutathione peroxidase; SOD, superoxide dismutase; MsrA, methionine sulfoxide reductase A; NF-κB, nuclear factor kappa B; NLRP3, NOD-like receptor family pyrin domain containing 3; Sirt3, sirtuin 3; mtROS, mitochondrial reactive oxygen species; IL, interleukin; TXNIP, thioredoxin-interacting protein; NFTs, neurofibrillary tangles.

Figure 3

Effects of TMAO on the blood–brain barrier and synaptic plasticity. TMAO impairs the structural integrity and function of the blood–brain barrier (BBB) and reduces synaptic plasticity, contributing to the pathogenesis of MCI. It reduces hippocampal synaptic plasticity by activating the PI3K/Akt/mTOR and PERK signaling pathways. Simultaneously, TMAO disrupts the BBB, facilitating the accumulation of neurotoxic molecules in the brain and inducing oxidative stress and neuroinflammation. Abbreviations: SYN, synaptophysin; NMDAR, N-methyl-D-aspartate receptor; GluA1, glutamate receptor ionotropic AMPA 1; GluN2A, glutamate receptor ionotropic NMDA 2A; PSD95, postsynaptic density protein 95; PERK, protein kinase R-like endoplasmic reticulum kinase; ATF4, activating transcription factor 4; CREB, cAMP response element-binding protein; p-PI3K, phosphorylated phosphoinositide 3-kinase; p-Akt, phosphorylated Akt protein; p-mTOR, phosphorylated mammalian target of rapamycin; ZO-1, zonula occludens-1; PDGFRβ, platelet-derived growth factor receptor beta.

Figure 4

Effects of TMAO on mitochondrial metabolism. TMAO adversely affects mitochondrial metabolism, contributing to the pathogenesis of MCI. It significantly inhibits the oxidation of pyruvate and fatty acids in mitochondria, leading to energy metabolism disorders. Abbreviations: CAT, carnitine acylcarnitine translocase; CPT2, carnitine palmitoyl transferase II; TCA cycle, tricarboxylic acid cycle; IMM, inner mitochondrial membrane; OMM, outer mitochondrial membrane; ATP, adenosine triphosphate.