Gut metabolite trimethylamine N-oxide induces aging-associated phenotype of midbrain organoids for the induced pluripotent stem cell-based modeling of late-onset disease

Abstract

Brain organoids are valuable research models for human development and disease since they mimic the various cell compositions and structures of the human brain; however, they have challenges in presenting aging phenotypes for degenerative diseases. This study analyzed the association between aging and the gut metabolite trimethylamine N-oxide (TMAO), which is highly found in the midbrain of elderly and Parkinson’s disease (PD) patients. TMAO treatment in midbrain organoid induced aging-associated molecular changes, including increased senescence marker expression (P21, P16), p53 accumulation, and epigenetic alterations. In addition, TMAO-treated midbrain organoids have shown parts of neurodegeneration phenotypes, including impaired brain-derived neurotrophic factor (BDNF) signaling, loss of dopaminergic neurons, astrocyte activation, and neuromelanin accumulation. Moreover, we found TMAO treatment-induced pathophysiological phosphorylation of α-synuclein protein at Ser-129 residues and Tau protein at Ser202/Thr205. These results suggest a role of TMAO in the aging and pathogenesis of the midbrain and provide insight into how intestinal dysfunction increases the risk of PD. Furthermore, this system can be utilized as a novel aging model for induced pluripotent stem cell (iPSC)-based modeling of late-onset diseases.

Gut–brain communication mediates the impact of dietary lipids on cognitive capacity

“…26 A study using midbrain organoid models has demonstrated that TMAO influences the pathogenesis of Parkinson's disease. 27…”

From 2D to 3D: Development of Monolayer Dopaminergic Neuronal and Midbrain Organoid Cultures for Parkinson’s Disease Modeling and Regenerative Therapy

“…Aside from disease modeling, PD MOs clearly represent a useful platform for testing the neurotoxic effects of compounds. For example, MOs exposed to the gut metabolite trimethylamine N-oxide-that was found elevated in the midbrains of PD patients-trigger neurodegeneration phenotypes including the loss of DA neurons, accumulation of neu-romelanin, aberrant BDNF signaling, and astrocyte activation [210]. Indeed, hMOs are used as viable models for such toxicity testing [194,196,203,212], and even in machine learning-assisted neurotoxicity prediction [195].…”

The Embodied Microbiome

“…While many other bioactive compounds contribute to behavior, oxytocin and TMAO drive starkly opposite behaviors and interactions. One of the apparent actions of higher levels of TMAO is rapid aging of mid-brain regions connected to TMAO-stimulated inflammatory cytokine production [48].…”