Gut Metabolite TMAO Induces Synaptic Plasticity Deficits by Promoting Endoplasmic Reticulum Stress

Abstract

Dysbiosis of gut microbiota is strongly associated with metabolic diseases including diabetes mellitus, obesity, and cardiovascular disease. Recent studies indicate that Trimethylamine N-oxide (TMAO), a gut microbe-dependent metabolite is implicated in the development of age-related cognitive decline. However, the mechanisms of the impact of TMAO on neuronal function has not been elucidated. In the current study, we investigated the relationship between TMAO and deficits in synaptic plasticity in an Alzheimer’s model (3×Tg-AD) and insulin resistance (Leptin deficient db/db) mouse by measuring plasma and brain levels of TMAO. We observed increased TMAO levels in the plasma and brain of both db/db and 3×Tg-AD mice in comparison to wild-type mice. Besides, TMAO levels further increased as mice progressed in age. Deficits in synaptic plasticity, in the form of reduced long-term potentiation (LTP), were noted in both groups of mice in comparison to wild-type mice. To further explore the impact of TMAO on neuronal function, we utilized an ex-vivo model by incubating wild-type hippocampal brain slices with TMAO and found impaired synaptic transmission. We observed that TMAO induced the PERK-EIF2α-ER stress signaling axis in TMAO treated ex-vivo slices as well as in both db/db and 3×Tg-AD mice. Lastly, we also observed altered presynaptic and reduced postsynaptic receptor expression. Our findings suggest that TMAO may induce deficits in synaptic plasticity through the ER stress-mediated PERK signaling pathway. Our results offer novel insight into the mechanism by which TMAO may induce cognitive deficits by promoting ER stress and identifies potential targets for therapeutic intervention.

Trimethylamine N-Oxide Exacerbates Renal Inflammation and Fibrosis in Rats With Diabetic Kidney Disease

“…pathways. Finally, several recent studies have reported that TMAO can directly increase the production of reactive oxygen species ( Govindarajulu et al, 2020 ; Wu et al, 2020 ; Chang et al, 2021 ). The excessive production of reactive oxygen species caused by oxidative stress plays an important role in the pathogenesis of DKD ( Jha et al, 2016 ).…”

Doxorubicin induces dysregulation of AMPA receptor and impairs hippocampal synaptic plasticity leading to learning and memory deficits

“…Each train contains four pulses at 100 Hz, with an inter-burst interval of 200 ms. The recording was continued for 60 min post-TBS ( Bloemer et al., 2019 ; Govindarajulu et al., 2020 ). LTP was calculated as an average of fEPSP slopes from 50-60 min post induction.…”

The Accumulation and Molecular Effects of Trimethylamine N-Oxide on Metabolic Tissues: It’s Not All Bad

“…However, it must be noted that carnitine is not a primary pre-curser of TMA, as discussed below. Aged animal models show higher TMA absorption into the portal vein and eventual TMAO accumulation compared to the young, indicating that changes at the host enterocytes also influences serum TMAO accumulation [ 92 , 93 , 94 ].…”

“…This elevated expression may be compensatory due to increased TMA substrate load but may also represent FMO3 expression regulation by TMAO [ 36 ]. Mice models of over-nutrition have elevated FMO3 expression [ 36 , 93 , 117 , 134 ]. Conversely, one hepatocyte cell culture study showed that free fatty acid treatment inhibited FMO1, 3, and 5 expression [ 135 ].…”

“…TMAO crosses the blood–brain barrier, making it a candidate for influencing cognitive function and neurological diseases [ 93 , 129 , 204 , 205 , 206 ]. Research on the gut–brain axis reveals that microbiome alterations accompany changes to the cardio-sympathetic nervous system, the central nervous system, and brain chemistry [ 207 , 208 , 209 ].…”