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Advanced Neurology TMAO and stroke

4. TMAO and atherosclerosis by elevated TMAO levels. Endothelial inflammation and
dysfunction are thought to originate from the activation of
The occurrence and progression of atherosclerosis have the NLRP-3 inflammasome. Tightly junction proteins act as
been directly linked to plasma TMAO concentrations. 17-19 barriers to regulating cell permeability and maintaining cell
The scavenger receptor A1 (SR-A1) and differentiation polarity. TMAO disrupts the tight junction protein ZO-1 by
cluster 36 (CD36) have the effect of controlling immune activating the NLRP-3 inflammasome, inducing excessive
cells and inflammatory cytokines. The CD36/MAPK/JNK endothelial cell permeability, leading to endothelial
pathway may be important in the formation of foam cells barrier dysfunction, and promoting the development of
induced by TMAO. They are able to identify oxidized low- atherosclerosis. Data showed that TMAO activates the
density lipoproteins and phagocytose them. According ROS-TXNIP-NLRP3 inflammasome, which releases
to research by Koeth et al., TMAO can increase the inflammatory cytokines interleukin (IL)-1β and IL-18
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expression of these two proatherogenic SRs, which in turn and inhibits NO secretion in a time- and dose-dependent
can lead to the buildup of cholesterol. Wang et al. conducted manner. The inflammatory reactions caused by IL-1β
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an animal experiment that further confirmed that foam and IL-18 contribute to the formation of lipid plaques and
cell formation is an early event in atherogenesis, as it destabilizing atherosclerotic plaques. In addition, Koay
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promotes the accumulation of cholesterol in macrophages, et al. demonstrated the connection between plasma levels
leading to lipid accumulation and foam cell formation. of TMAO and atherosclerotic plaque instability. Clearly,
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Animals supplemented with choline, TMAO, or betaine TMAO has a huge influence on many processes related to
had higher levels of SR-A1 and CD36 in macrophages the onset and progression of atherosclerosis, such as lipid
and higher endogenous formation of foam cells. It is accumulation, suppression of bile acid synthesis, inhibition
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well known that hypercholesterolemia plays a causal role of reverse cholesterol transport, and endothelial damage.
in the development of atherosclerosis. The primary Consequently, TMAO is also likely to have a significant
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physiological function of bile acid is to digest and absorb impact on the development of IS.
lipids. Cyp7al is a key enzyme that converts cholesterol
into bile acid, mediating the elimination of cholesterol and 5. Induction of inflammatory responses
promoting the excretion of bile acid. Ding et al. reported Stroke is characterized by complex pathophysiology, with
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that TMAO reduces Cyp7a1 expression by activating the a growing body of research indicating that IS is associated
nuclear receptor farnesoid X receptor and small molecule with an inflammatory milieu. Increased inflammation
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heterodimer partner (SHP), thus inhibiting the synthesis can lead to secondary substantial damage after a stroke.
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of bile acids and ultimately promoting the progression Apart from its influence on the AS process, TMAO also
of atherosclerosis. Moreover, TMAO can exacerbate triggers the development of proinflammatory cytokines,
atherosclerosis by preventing the reverse transport which leads to brain damage after IS. Indeed, the increase
of cholesterol and altering the activity of cholesterol in TMAO secretion is considered to be a key nexus
transporters in macrophages. The ABCG5/8 transporter connecting peripheral and central inflammation. 30
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facilitates the excretion of excess cholesterol into the gut
or bile. The liver X receptor is activated in response to It has been shown that TMAO uses a number of
elevated intracellular cholesterol levels, and it facilitates different signaling mechanisms to initiate the inflammatory
cholesterol efflux by upregulating the expression of the cascade. Through activating the NF-κB pathway, TMAO
ABCG5/8 transporter. Experiments have shown that increases the synthesis of several inflammatory cytokines,
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dietary supplementation with TMAO significantly reduces including E-selectin, cyclooxygenase-2, IL-6, tumor
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the expression of the intestinal cholesterol transporters necrosis factor-α (TNF-α), and ICAM-1. As one of
the most potent proinflammatory cytokines, IL-1β has the
Niemann–Pick C1-like 1 (Npc1L1) and ABCG 5/8. 18
ability to both exacerbate blood–brain barrier dysfunction
Endothelial injury and the adhesion of monocytes and increase IL-6 expression. In the ischemic region, these
are crucial in the initial stages of atherosclerosis. The two mechanisms work together to increase damage, and
upregulation of cell adhesion molecules such as vascular the resultant vicious cycle is chronic inflammation. After
cell adhesion protein 1 (VCAM-1) and intercellular IS, it triggers apoptosis, which exacerbates brain damage.
adhesion molecule 1 (ICAM-1) significantly contributes A higher risk of IS is linked to elevated blood IL-6 levels.
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to endothelial dysfunction. As a positive regulator of Microglia, astrocytes, and endothelial cells in the ischemic
endothelial dysfunction, TMAO upregulates the expression hemisphere are the main sources of IL-6, which is regarded
of VCAM-1 by activating NF-κB-dependent protein kinase C as a bad prognostic factor. The patients are at a higher
(PKC), thereby increasing monocyte adhesion. Moreover, risk for systemic inflammatory response after IS. One of
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endothelial cells’ capacity for self-healing is diminished the characteristics of this response is the increased levels

Volume 3 Issue 3 (2024) 3 doi: 10.36922/an.3005