Clinical Significance and Potential Role of Trimethylamine N-Oxide in Neurological and Neuropsychiatric Disorders

Sowjanya Mudimela; Narahari Koppa Vishwanath; Anilkumar Pillai; Rodrigo Morales; Sean P Marrelli; Tatiana Barichello; Vijayasree V Giridharan

doi:10.1016/j.drudis.2022.08.002

. Author manuscript; available in PMC: 2023 Oct 23.

Published in final edited form as: Drug Discov Today. 2022 Aug 23;27(11):103334. doi: 10.1016/j.drudis.2022.08.002

Clinical Significance and Potential Role of Trimethylamine N-Oxide in Neurological and Neuropsychiatric Disorders

Sowjanya Mudimela ¹, Narahari Koppa Vishwanath ¹, Anilkumar Pillai ^2,^3,⁴, Rodrigo Morales ^5,⁶, Sean P Marrelli ⁵, Tatiana Barichello ^3,^7,⁸, Vijayasree V Giridharan ^7,^*

PMCID: PMC10392962 NIHMSID: NIHMS1914426 PMID: 35998800

Abstract

Research in the last three decades has attracted the attention of many scientists and industrialists on the gut microbiome and its metabolites. Among many of these metabolites, trimethylamine oxide. Dietary choline, phosphatidylcholine, carnitine, and betaine produces TMAO that with other gut metabolites such as TMA (trimethylamine), and short-chain fatty acids (SCFA) enter the circulation. Finally they reach the brain through the blood-brain barrier (BBB) where they are involved in several physiological functions such as brain development, neurogenesis, and behavior. Gut-microbiota composition is influenced by diet, lifestyle, antibiotics, and age resulting in dysbiosis. Several studies have confirmed that altered TMAO levels can be harmful, contributing to several metabolic, vascular, psychiatric and neurodegenerative disorders. This review focuses on how altered TMAO levels impact oxidative stress, microglial activation, and apoptosis of neurons that subsequently lead to the development of psychiatric, cognitive, and behavioral disorders. In addition, possible therapeutic strategies targeting TMAO are discussed.

Keywords: trimethylamine oxide, gut microbiome, neurological disorder, neuropsychiatric disorder

1. Introduction

It is a well established fact that in host physiology and pathology, gut microbiota plays a predominant role. A complex, bidirectional communication exists between the central and intrinsic nervous system, that regulates gastrointestinal homeostasis and has multiple effects on brain’s higher functions like behavior, cognition, and emotions [1]. The gut-microbiota transforms dietary components including macro-and micronutrients, fibers, and polyphenols into a highly diverse reservoir of metabolites including trimethyl amines (TMA), trimethylamine N-oxide (TMAO), short-chain fatty acids, branched-chain amino acids (BCAAs), bile acids, tryptophan and indole-derivatives [2]. These gut-derived microbial metabolites fundamentally participate in host-microbiota cross-talk to maintain the host’s homeostasis, modulate blood-brain barrier (BBB) integrity, and influence brain development and function through neural, immunological, and endocrine pathways [2,3]. The above-mentioned gut metabolites have been reported to promote both beneficial and detrimental effects on the host.

A recent metabolomics approach demonstrated that a choline metabolite called TMAO in plasma, may be a new emerging risk factor for a wide variety of diseases [4]. Various cardiovascular diseases such as atherosclerosis, hypertension, ischemic stroke, atrial fibrillation, heart failure, and acute myocardial infarction were reported to be influenced by proatherogenic TMAO [5]. Development of various diseases such as chronic kidney disease, diabetes mellitus, metabolic syndrome, and colon cancer had direct relationship with TMAO concentrations [6]. Researchers have been in pursuit of determining the role of TMAO in CNS function in the last decade; however the evidence is still relatively scarce. In this review, the rational function of TMAO in the backdrop of aging, neurological / neuropsychiatric disorders are explored. Herein, we have summarized the role of TMAO as an osmolyte and defining oxidative stress, BBB integrity, and glial cell activation in the CNS. We put forth evidence from clinical and preclinical studies in which alteration in TMAO levels was determined in neurological and neuropsychiatric disorders. Additionally, therapeutic strategies and potential significance in modifying TMAO levels in disease scenarios are discussed.

2. TMAO production and metabolism.

2.1. Gut microbiota-derived TMAO.

The gut milieu in healthy individuals is primarily composed of Firmicutes (79%) followed by Bacteroidetes (17%), Actinobacteria (3%), Proteobacteria (0.9%), and Verrucomicrobia (0.1%). The human gut bacterial diversity is characterized using enterotyping technique, expessed as bacterial Prevotella to Bacteroides (P/B) ratio [7]. Microbiota lives in a harmonic relationship by metabolizing nutritional substrates such as red meat, poultry, fish, soy, and dietary supplements rich in choline, phosphatidylcholine, carnitine, betaine, γ-butyrobetaine (GBB), dimethylglycine, and ergothioneine [8]. Eight different types of commensal bacteria that produce TMAO and reside in the human intestine belong to two phyla: Firmicutes and Proteobacteria. These include Escherichia fergusonii, Providencia rettgeri, Anaerococcus hydrogenalis, Clostridium asparagiforme, C. hathewayi, C. sporogenes, Proteus penneri, and Edwardsiella tarda [9,10].

2.2. TMAO metabolism and binding.

The dietary substrates rich in choline, carnitine, dimethylglycine, phosphatidylcholine, betaine, GBB and ergothioneine are catabolized to produce a variety of biochemical metabolites by gut enzymes. The predominant metabolite,TMA, a colorless gas at room temperature with a strong fishy odor which is subsequently oxidized to TMAO via flavin monooxygenase (FMO)-3 [11].

The biosynthesis of TMAO constitutes a metaorganismal pathway involving diet-gut microbiota-liver. The following four enzymes are involved in the production of TMA. 1) choline-TMA lyase (gene: cutC/D in sulfate-reducing bacterium Desulfovibrio desulfuricans); 2) carnitine monooxygenase (gene: cntA/B); 3) betaine reductase; and 4) TMAO reductase. Also, the gene yeaW/X with choline, GBB, and betaine as substrates produce TMA [12]. By the action of the enzymes - choline TMA lyase, betaine reductase, and carnitine oxidoreductase on Choline, betaine, and L-carnitine respectively are converted to TMA. Conversion of choline and lecithin is bidirectional, where choline is converted to lecithin, catalysed by choline kinase and lecithin is formed from choline, catalysed by the enzyme phospholipase DAnother enzyme, carnitine TMA lyase converts carnitine, choline, betaine, and GBB to TMA [13]. The enzymes L-carnitine dehydrogenase and butyrobetainyl CoA: carnitine CoA transferase convert L-carnitine to betaine and GBB respectively, where L-carnitine is regenerated from GBB by the enzyme butyrobetaine hydroxylase. TMA can also be generated from ergothineine by the action of the enzyme ergothionase. Thus, formed TMA enters the systemic circulation by passive diffusion, where it gets oxidized by hepatic FMO1 and FMO3 to TMAO (Figure 1). FMO3 is tenfolds more in specific activity than FMO1. Most of the TMA is oxidized to TMAO and is eliminated through the urine in 3 (TMA): 95 (TMAO) ratio. The characteristic fishy odor is because of TMA formed from TMAO by bacterial activity or by the enzyme TMAO reductase. Certain methanogenic bacteria containing TMAO demethylase convertTMAO to Dimethyl Amine (DMA), formaldehyde, ammonia and methane [14].

Figure 1. — Certain foods are enriched in TMAO (e.g., fish) or its dietary precursors, choline (e.g., eggs) and carnitine (e.g., meat). While dietary TMAO can bypass processing by the gut microbiome before absorption, choline and carnitine require conversion to trimethylamine (TMA) by gut microbes. Once formed, TMA can be absorbed and subsequently converted to TMAO by the hepatic enzyme flavin-containing monooxygenase 3 (FMO3). Dietary and endogenously produced TMAO can be released by the liver and taken up by extrahepatic tissues or excreted in urine

Abbreviations: choline utilization (CuT), carnitine oxygenase (CntA), flavin-containing monooxygenase 3 (FMO3), trimethylamine (TMA), trimethylamine N-oxide (TMAO).

Recently Chen et al., reported PERK (protein kinase R [PRK]-like endoplasmic reticulum kinase, or EIF2AK3 [eukaryotic translation initiation factor 2-alpha kinase 3]) as the receptor for TMAO for glucose-related metabolic effects [15]. However, participation of PERK on TMAO-driven renal function is reported to be questionable. It is also proposed that TMAO may act via other alternate mechanisms, such as an alternate or still un-identified receptor or via modulation of protein conformation and stability [16]. Similarly, there are no reports associating TMAO receptors and neuronal function.

2.3. Potential gut microbiota associated with TMAO levels and disease condition.

The composition of the microbiota is relatively stable. However, its composition might be altered during infant transitions, age, lifestyle changes, intestinal comorbidities, surgery, geographical location, diet, geographical location, antibiotic intake, and even from individual to individual [17,18]. The proper development of immune system depends upon the composition of gut flora right from the birth of the individual.The intestinal microbiota is shaped from birth and plays a key role in the development of the immune system. The composition of microbiota is metabolically related to the dietary intake of an individual, which in turn affects the TMAO concentrations. Some studies indicate that consumption of diet rich in fish such as salmon [19] or a high-fat and high-calorie diet results in increased production of TMAO. A study comparing the urinary profiles of Swedish and British populations [20] demonstrated that Swedish people consuming fish-based products possesed higher urinary excretion of TMAO compared with British population who were on non-fish diet for 24 hours just before the stdy. that avoided fish intake 24 hours before the study. Another study also showed increased levels of urinary TMAO excretion in Japanese population who were on regular fish diet. [20].

In a different human-based study, omnivorous human subjects on L-carnitine supplement diet were associated with higher TMAO levels compared to vegetarians. [21]. In the same study conducted on mice, subjected to chronic L-carnitine supplementation resulted in increased TMA and TMAO synthesis as well as atherosclerosis [21]. Evidences are increasing to support that increased TMAO levels alters hormonal and lipid homeostasis [22]. Atherosclerotic lesions are the result of increased blood TMAO levels which cause influx of cholesterol in Macrophages, resulting in formation of foamcell [22]. These pathological conditions increase the danger of ischemic stroke and several other neurological disorders [23]. Metabolomic studies suggest that altered gut floral composition as well as the leaky gut can cause bioactive endotoxins reaching CNS through systemic circulation.. These physiological alterations lead to exacerbation of several pathological conditions such as obesity, cardiovascular diseases, hypertension, inflammatory bowel diseases, cancers, AD, PD, ASD, resulting in a simultaneous decrease of healthy bacteria and increase of opportunistic bacterial species [24–26]. Hence the studies suggest that controlling plasma TMAO concentration can be a potential target in the treatment of several chronic disorders.. Most of the patients with ASD were observed to have decreased ratio of Bacteroidetes to Firmicutes, while their Lactobacillus sp. was elevated [27]. Certain neuropathological conditions were found to be associated with higher occurrence of TMAO producing gut genera especially Bacteroides, Parabacteroides, Clostridium, Faecalibacterium, and Phascolarctobacterium in comparison with other gut flora.[28]. In a similar study on MS lower abundance of Faecalibacterium and Fusobacterium were found in comparison with Escherichia sp, Shigella sp, Clostridium sp, Eubacterium sp, Corynebacterium sp, and Firmicutes [29,30].

3. Significance of TMAO in the central nervous system.

Certain neuropathological conditions related to neurodegeneration may be influenced by external factors beyond the neural origin. Dysbiosis can be one of those factors, as alterations in microbiota concentration and composition may result in altered levels of metabolites such as TMAO, which are linked with the development of behavioral and neurodegenerative disorders. Altered TMAO levels combined with oxidative stress and neuroinflammatory changes associated with glial cells were found to be responsible for the development of several neuropsychiatric and neurodegenerative disorders. (Figure 2).

Figure 2. — Roles of trimethylamine N-oxide (TMAO) in the central nervous system (CNS).

3.1. Oxidative stress

The imbalance between the anioxidant defence and free radicals (reactive oxygen species (ROS), etc.) may cause destruction of several biomolecules such as lipids, proteins, and genetic materials such as DNA and RNA resulting in oxidative stress. This Oxidative stress was found to be the culprit for the generation of several pathological conditions including NDDs such as AD, PD, ALS, MS, HD etc. [31]. In a study, higher TMAO levels were observed in Cerebrospinal fluids of AD individuals. [32]. This elevated TMAO levels causes upregulation of ROS, hydrogen peroxide, lipid peroxidation etc. resulting in oxidative stress in hippocampal slices [31,33]. Growing evidences suggest that oxidative stress very strongly influence cognitive impairment by an essential cross-talk between gut-liver and brain resulting in reduced quality of life expectancy.. In astudy on old mice, antibiotics suppressed the gut flora which backpedeled age related endothelial dysfunction and aortic stiffening, similar to the levels observed in young mice. [34]. Hence, these studies suggest that aging is associated with elevated TMAO levels which in turn promote oxidative stress and inflammation. [34].

A study conducted on vascular aging in 186 subjects suggested that TMAO may deteriorate endothelial function by increasing oxidative stress in Human Umblical Vein Endothelial Cells (HUVECs) [35]. In anotherstudy, the TMAO-treated endothelial progenitor cells (EPCs) showed upregulation of interleukins especially IL-6, interleukin (IL-6), C-reactive protein, tumour necrosis factor- α, ROS etc. and downregulation of nitric oxide production[35]. Several studies revealed a correlation between TMAO and ROS. TMAO may increase intracellular ROS production and activate the NLRP/NALP (Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain)3-TXNIP (thioredoxin interacting protein) pathway, cause increased release of inflammatory cytokines (IL-1 β & IL-18) which are very toxic to EPCs [35]. A study conducted on young mice revealed that TMAO impaired carotid artery by increasing vascular tyrosine which is a biomarker of oxidative stress.. The higher circulating TMAO also altered nitric oxide pathway by inhibiting its activation and nitricoxide mediated dilation, thus leading to endothelial disfunction. [36].

Elevated TMAO levels was shown to influence surgery-induced cognitive decline in a study on male F344xBN F1 rats [37]. The Fischer 344 x Brown Norway (F344xBN) rats shown to have a lower incidence of age-related pathology as compared to other rat strains [38]. Its treatment also caused decreased expression of methionine sulfoxide reductase, an important antioxidant enzyme which controls microglia mediated neuroinflammation by nhibiting ROS and NF-κB signalling pathways [37].

The cell organelle, endoplasmic reticulum (ER), aids in folding of aggregated proteins, but under stress conditions these proteins are left unfolded resulting in their accumulation resulting in ER stress.. Govindarajulu et al. demonstrated that this accumulated proteins alter long-term potentiation and synaptic plasticity in hippocampus by presynaptic ER oxidoreductin-1α dependent release acting through gut-brain signalling axis. were the first to demonstrate the impact of gut-brain signaling axis on hippocampal synaptic plasticity, reporting that elevated levels of TMAO-induced protein misfolding leads to altered long-term potentiation and impaired synaptic plasticity. They further suggested that this may be due to ER oxidoreductin-1α dependent presynaptic release [39]. This ER stress in brain causes several pathological conditions, including cerebral ischemia, AD, and PD [40]. TMAO also influence mitogen-activated protein kinase and NF-κB which triggers vascular inflammation. All these studies confirm that TMAO-induced oxidative stress is associated with cognitive impairment resulting in brain tissue degeneration [33,41,42].

3.2. Blood-brain barrier (BBB).

The presence of TMAO in human CSF [9,32,43] have been proved by several studies suggesting that TMAO can cross the BBB and thus contribute to neurological and neuropsychiatric disorders. The gut-brain axis has been greatly influenced by gastrointestinal microbiota bidirectionally using neuronal, immune-mediated, and neuro-endocrine-mediated signaling pathways [44]. Various neurological disorders like stress response, anxiety, depression, and NDDs are associated with altered or dysbiotic flora [45,46].

Brain microvascular endothelial cells, pericytes and astrocytes constitute BBB. As discussed previously, choline is the primary source of TMAO, and it enters the brain through choline transporters, such as protein 1 (CTL1) and CTL2, and the latter is highly expressed on mitochondria [47]. As TMAO levels are increased in mitochondria, itleads to oxidative stress and ultimately leads to neurodegeneration. Many studies revealed the role of gut microbiota in neurogenesis, brain development and interaction between ENS & CNS through bidirectional communication of gut & brain, influencing behavior and cognition especially memory, learning, and attention [48].

3.3. Glial cells.

Microglia are resident cells of the brain that regulate brain development, maintain neuronal networks, and participate in injury and repair [49]. Alterations in microglia and astrocytes lead to overexpression of inflammatory mediators. In the presence of amyloid-beta (Aβ) plaques, these glial cells are activated for a long duration; failing to clear Aβ plaques from brain parenchyma resulting in neurodegenerative process [50,51]. In vivo studies revealed that TMAO crosses the BBB, causing increased neuroinflammation and astrocyte activation. Astrocyte activation and upregulation of pro-inflammatory mediators contribute to Neuroinflammation. In middle-aged and older humans, the relation between TMAO levels and performance on NIH toolbox cognitive Function Battery was found to be inversely proportional. Along this line, increased circulating levels of TMAO represent a novel catalyst in driving systemic and neuro inflammation , thereby altering the cognitive function with aging [52].

A study on regulation of IL-6 and iNOS levels under glucose deprived conditions found that ER stress inducer, tunicamycin, up- and down-regulated prostaglandin E (PGE)2 + IFN γ-induced IL-6 and iNOS expressions in the glial cells play a key role. The experimental results indicated that TMAO reduced the neurological function restoration by promoting reactive astrogliosis and glial scar formation. The mechanism involves upregulation of the transforming growth factor-beta receptor I (ALK5) through SMAD-specific E3 ubiquitin-protein ligase (Smurf)2 inhibition [53]. Such mechanisms potentially cause damaged CNS functions like alterations in cognition, behavior, and stress responses that finally results in neurodegeneration.

4. Role of TMAO in neurological and neurodegenerative disorders.

The implication of TMAO in different neurological and psychiatric disorders from clinical and preclinical studies are given in Table 1 and Table 2, respectively.

Table 1:

Alteration in TMAO levels in different neurological and neuropsychiatric disorders – Clinical studies

S.No	Study author (year)	Study design and sample details	Intervention	Analytical Method/Tissue	Tissue	Behavioral test	Key findings
				Alzheimer’s disease
1	Vogt et al., 2018¹.	Alzheimer’s clinical syndrome, n = 40, mild cognitive impairment (MCI) n = 35, and cognitively-unimpaired, n = 335.	None.	Ultra high-performance liquid chromatography (UHPLC) tandem mass spectrometry (MS).	CSF.	None.	• The TMAO levels in cerebrospinal fluid (CSF) is elevated in MCI and AD dementia group as compared to cognitively-unimpaired. • Elevated CSF-TMAO is associated with AD pathological markers such as p-tau and p-tau/Aβ42 and neuronal degeneration such as total tau and neurofilament light chain protein (NFL).
2	Rio et al., 2017².	AD, n = 22; Non-AD, n = 16; other neurological disorder, n = 20.	None.	UHPLC DIONEX Ultimate 3000 - triple quadrupole TSQ vantage fitted with a heated-ESI (H-ESI)	CSF.	None.	• The levels of TMAO in the CSF were not different among the groups.
3	Zhuang et al., 2021³.	Bidirectional Mendelian randomization study, AD, n = 455,258	None.	N/A	N/A	None.	• The genetic prediction of TMAO was unrelated to the risk of AD. • There is no causal link between TMAO or its precursors and AD.
				Parkinson’s disease
4	Sankowski et al., 2020⁴.	PD, n = 18l; control n = 9.	None.	Chromatographic separation by SeQuant ZICHILIC Column.	Plasma and CSF.	None.	• Patients suffering from motor fluctuations had significantly higher levels of TMAO in their CSF and plasma.
5	Kumari et al., 2020⁵.	PD, n = 76; control, n = 37.	None.	1D-proton NMR spectrum using 700-MHz NMR Spectrometer.	Saliva.	None.	• Patient’s with early-stage PD have elevated levels of TMAO
6	Chung et al., 2021⁶.	Drug-naïve early stage PD, n = 85; controls, n = 20.	None.	LC tandem MS.	Plasma.	None.	• Patients with PD had reduced plasma TMAO levels. • Levodopa-equivalent dose elevates more quickly in patients with less baseline TMAO. • TMAO can be used to predict outcome in early-stage PD.
7	Tan et al., 2021⁷	PD, n = 77; control, n = 77.	None.	LC/MS.	Feces.	None.	• PD patients had lower levels of TMAO.
				Amyotrophic lateral sclerosis
8	Chen et al., 2020⁸.	ALS, n = 160; compared with their spouses, n = 63; and compared with controls, n = 148, age 18-75 years.	None.	LC tandem MS.	Plasma.	None.	• TMAO concentrations were lower in ALS compared to controls. • TMAO metabolic pathway disturbed in both ALS patients and their spouses.
9	Lee et al., 2020⁹	ALS, n = 50; controls, n = 40.	None.	LC- multiple reaction monitoring (MRM)-MS.	Plasma.	None.	• TMAO levels were not significantly different between healthy controls and patients but were greater in ALS subjects with elevated formaldehyde levels than those with normal levels.
				Autism spectrum disorder
10	Quan et al., 2020¹⁰	Cross-sectional study. ASD n = 164; controls n = 164. Age 3 – 8 years old.	None.	LC/MS/MS	Plasma.	None.	• Elevated plasma levels of TMAO are associated with ASD and symptom severity.
				Stroke
11	Heyse et al., 2021¹¹.	Prospective, case-control study. symptommatic (42) and asymptomatic (40) large-artery atherosclerosis patients. n = 82. Median age - 70 years; 65% M.		LC-MS/MS.	Plasma.	None.	• When adjusted for age and glomerular filtration rate (GFR), TMAO did not predict symptoms of cerebrovascular disease • The TMAO did not correlate with symptomatic stenosis.
12	Chen et al., 2021¹².	Cross-sectional analysis. Ischemic stroke or transient ischemic attack patients, n = 1159, age > 18 years.		LC-MS QTRAP 5500.	Plasma.	None.	• Severe white matter hyperintensities were associated with elevated TMAO levels.Microbleeds or lacunes were not significantly associated with TMAO.
13	Rexidamu et al., 2019¹³.	Acute ischemic stroke patients and age matched control, n = 255.	None.	Ultra HPLC-MS/MS using heated electrospray ionization.	Serum.	None.	• An increased level of TMAO was associated with a greater risk of adverse outcomes. As serum TMAO levels increased by *M, stroke risks increased by 14%.
14	Wu et al., 2018¹⁴.	Multicenter, prospective cohort study. Severe carotid artery stenosis patients prepared for carotid artery stenting, n = 268, mean age = 64.4.	None.	LC-MS.	Plasma.	None.	• Patients with new (DWI) lesions had higher TMAO levels than those without new lesions.There was an increased risk of new lesions on DWI after CAS when plasma TMAO levels increased.
15	Nie et al., 2018¹⁵.	Nested case-control design, n = 622 patients with first stroke and matched controls. Men and women aged 45 to 75 years.	None.	LC-MS (6460 Series Triple Quadrupole).	Serum.	None.	• The risk of the first stroke increased with each increment of TMAO level. • A significantly higher risk of the first stroke was found in those in higher TMAO tertiles.
16	Yin et al., 2015¹⁶.	Large-artery atherosclerotic ischemic stroke and transient ischemic attack patients. Age range from 18 - 80 years. Patients, n = 322; controls n = 231.	None.	LC-MS (6460 Series Triple Quadrupole).	Plasma.	None.	• Asymptomatic atherosclerosis did not exhibit a change in TMAO levels. • A significant dysbiosis of the gut microbiota was observed in stroke and transient ischemic attack patients, and their TMAO levels were significantly lower.
17	Tang et al., 2013¹⁷.	Study 1: 40 healthy adults. Study 2: 4007 adults undergoing elective diagnostic cardiac catheterization	Dietary phosphatidylcholine challenge. n = 6 were given metronidazole plus ciprofloxacin for 1 week.	HPLC with online electrospray ionization tandem MS on an AB SCIEX QTRAP 5500 mass spectrometer.	Plasma and urine.	None.	• Plasma and urine TMAO levels elevated time-dependently after the phosphatidylcholine challenge. • When antibiotics were administered, TMAO levels were suppressed and then resurrected after antibiotics were withdrawn.Plasma TMAO was significantly higher in patients with adverse events, including stroke.
18	Hou et al., 2020¹⁸.	First acute ischemic stroke patients, n = 362. Mean age, 62.5 ± 9.6 years; 52.2% (M).	None.	HPLC with electrospray ionization tandem MS using a Shimadzu LCMS-8050 CL Triple Quadrupole MS.	Plasma.	None.	• TMAO levels were increased in patients with neurological deterioration at an early stage. • A significant relationship between TMAO and early neurological deterioration in stroke patients was observed.
19	Xu et al., 2021¹⁹.	Cross-sectional comparative study - Large-artery atherosclerotic stroke patients, n = 50. Age > 18.	None.	LC tandem MS.	Plasma.	None.	• Elevated plasma TMAO level in large-artery atherosclerotic stroke patients. • Plasma TMAO levels are important biomarkers for large-artery atherosclerotic stroke patients.
20	Gong et al., 2021²⁰.	Longitudinal, prediction model development and validation study with acute ischemic stroke patients, n = 228. Age > 18 years.	None.	LC tandem MS.	Plasma.	Montreal Cognition Assessment (MoCA).	• Patients with cognitive impairment showed elevated plasma TMAO levels than those without.
21	Schneider et al., 2020²¹.	Prospective, case-control study - Ischemic stroke, n = 196; controls, n = 100.	None.	LC tandem MS.	Plasma.	None.	• Plasma TMAO levels on admission were significantly higher; at 48 hours after stroke, TMAO decreased, and 3 months after TMAO increased in stroke patients.
22	Schwedhelm et al., 2021²².	Stroke, n = 374; control, n = 167.	None.	LC tandem MS.	Plasma.	None.	• The plasma TMAO level was markedly increased in acute ischemic stroke.
23	Sun et al., 2021²³.	Ischemic stroke, n = 953; control, n = 953	None.	HPLC-MS/MS; AB Sciex Q-Trap 4500; Applied Biosystems.	Plasma.	None.	• Significantly higher plasma TMAO concentration in stroke patients. • An increased risk of ischemic stroke was associated with higher plasma TMAO levels.
24	Tan et al., 2020²⁴.	Acute ischemic stroke, n = 204; control, n = 108.	None.	LC tandem MS (6460 Series Triple Quadrupole LC/MS; Agilent.	Plasma.	None.	• The levels of TMAO did not change significantly before and within 24 h of the stroke, but they declined considerably later. • TMAO levels were elevated at an earlier point in time, indicating a poor stroke outcome
				Depression
25	Meinitzer et al., 2019²⁵.	Ambulatory patients admitted for carbohydrate malabsorption (CMA) testing, n = 251.	None.	HPLC with electrospray ionization tandem MS on a SCIEX QTRAP 4500 triple quadrupole instrument.	Serum.	Beck Depression Inventory (BDI-II).	• There was a difference between non-CMA and CMA in the relationship between TMAO and the BDI-II score. • Male and female without CMA showed the strongest associations between TMAO and depressive symptoms.
				Bipolar
26	Ren et al., 2020²⁶	Bipolar, n = 37; control, n = 48. Age 15-50.	None.	¹H NMR	Plasma.	None.	• BD patients presented elevated TMAO levels.
				Schizophrenia
27	Nguyen et al., 2021²⁷	Schizophrenia, n = 48; control, n = 48. Age 27 – 76 years.	None.	Functional analysis	Feces.	Depression assessed using the Patient Health Questionnaire (PHQ-9) Health-related quality of life and functioning was evaluated using the physical and mental health component scores from the Medical Outcomes Study 36-item Short Form (SF-36)	• TMAO reductase level is reduced in schizophrenia patients. • TMAO reductase levels are believed to be lower in individuals with schizophrenia, which may decrease their ability to clear TMAO.
				Post-traumatic stress disorder
28	Baranyi et al., 2021²⁸.	Acute myocardial infarction (AMI), n = 114.	None.	HPLC with ESI tandem MS on a SCIEX QTRAP 4500 triple quadrupole instrument equipped with an Agilent 1260 Infinity HPLC system.	Serum.	None.	• Patients with PTSD-symptomatology had significantly higher levels of TMAO immediately following AMI than those without these symptoms. TMAO became a significant predictor of PTSD-symptomatology. • TMAO levels may be a biological correlate of severe stress that is associated with PTSD.
				Aging
29	Li et al., 2018²⁹.	Young adults (18–44 years), n = 168; middle-aged adults (45–64 years), n = 118); elderly (above 65 years), n = 141.	None.	Liquid chromatography (LC) coupled with triple quadrupole mass spectrometry (MS).	Plasma.	None.	• Elderly showed increased TMAO levels.
30	Brunt et al., 2021³⁰.	Young, n = 18-27; middle-aged; old aged, n = 103.		LC tandem mass spectrometry	Plasma.	NIH Toolbox Cognition Battery Test - working memory (List sorting Test), episodic memory (Picture sequence memory test), processing speed (Pattern Comparison processing speed Test), executive function (Flanker inhibitory control and attention test; Dimensional change card sort test), and language [Picture vocabulary test; Oral reading recognition test).	• Higher plasma TMAO levels are associated with lower memory and fluid cognition in middle-aged to older adults.

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Abbreviations: acute myocardial infarction (AMI), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Beck Depression Inventory (BDI), carotid artery stenting (CAS), cerebrospinal Fluid (CSF), carbohydrate malabsorption (CMA), 3,3-dimethyl-1-butanol (DMB), electrospray ionization (ESI), female (F), glomerular filtration rate (GFR), high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC/MS), male (M), mass spectrometry (MS), mild cognitive impairment (MCI), montreal cognitive assessment (MoCA), National institutes of health stroke scale (NIHSS), neurofilament-light chain (NFL), nicotinamide adenine dinucleotide phosphate (NADPH), nuclear magnetic resonance (NMR), reactive oxygen species (ROS), senescence-accelerated mouse-prone-8 (SAMP8), senescence-accelerated mouse resistant 1 (SAMR1), trimethylamine N-oxide (TMAO),

Table 2:

Alteration in TMAO levels in different neurological and neuropsychiatric disorders – Preclinical studies

S.No	Study author (year)	Study design and sample details	Intervention	Analytical Method/Tissue	Tissue	Behavioral test	Key findings
				Alzheimer’s disease
1	Govindarajulu et al., 2020¹.	3XTg-AD mice (F). 8-months old, db/db mice.	None.	Elisa Abbkine (Cat#KTE71902).	Serum. Brain (Cortex and hippocampus).	None.	• 3XTg-AD and db/db mice showed higher TMAO concentration. • By increasing ER stress, TMAO may cause cognitive loss. • Through the PERK signaling pathway, TMAO may impair synaptic plasticity.
2	Wang et al., 2020².	C57BL/6J mice, 8-week-old (M); PrP-hAβPPswe/PS1ΔE9 mice, 6-month-old (M).	Chow diet supplemented with 1% choline for three months. 1×10⁹ CFU/mL of Lactobacillus plantarum.	Agilent 6410 Triple Quad LC/MS.	Plasma.	Spontaneous locomotor activity test, nest building test, novel object recognition test, a Morris-water maze test, and shuttle-box test	• Treatment with L. plantarum significantly declined TMAO synthesis and improved cognition, reduced Aβ levels, and preserved neuronal integrity and plasticity.
3	Gao et al., 2019³.	WT and APP/PS1, 7-month-old (M), 3-month, 6-month, 9-month, and 12-month old.	1.0% DMB in drinking water for 8 weeks.	LC/MS.	Plasma.	Spontaneous locomotor activity test, nest building test, novel object recognition test, Morris water maze test, and shuttle-box test	• The reduction of TMAO in APP/PS1 mice by DMB treatment ameliorated cognitive decline. • An increase in circulating TMAO during aging impairs cognitive function in APP/PS1 mice.
				Stroke
4	Su et al., 2021⁴.	Sprague Dawley rats subjected to middle cerebral artery occlusion/reperfusion (MCAO/R).	TMAO or/and sh-ALK5.	Liquid phase spectrometer.		Spontaneous activity, symmetry of limb movements. forepaw extension, climbing, body proprioception, vibrotactile response, and beam walking)	• Rats submitted to MCAO/R showed higher levels of TMAO. . • MCAO/R rats developed glial scars owing to TMAO-induced proliferation of reactive astrocytes. Signaling by TMAO/ Smurf2/ALK5 in ischemic strokes is a major genetic factor controlling reactive proliferation of astrocytes and formation of glial scars.
				Depression
5	Liu et al., 2012⁵.	Sprague–Dawley rats (M).	Rats submitted to chronic unpredictable stress (CUMS). Xiaoyaosan (92.4 g/kg, 46.2 g/kg, and 23.1 g/kg).	Metabolic profiling using NMR, followed by multivariate analysis.	Plasma.	Open-field test and sucrose preference.	• Lower TMAO levels were observed in CUMS rats • CUMS caused a change in the concentration of TMAO, implicating a significant association between major depression and irritable bowel syndrome.
				Aging
6	Li et al., 2018⁶.	24-week-old, SAMP8 and SAMR1 (M).	TMAO in water (1.5%) for 16 weeks.	Liquid chromatography (LC) coupled with triple quadrupole mass spectrometry (MS).	Plasma.	Y-maze test and Morris water maze test.	• TMAO increased in aged mice. SAMP8-control mice had a cognitive dysfunction and brain aging phenotype. • TMAO treatment affected synaptic plasticity, and exacerbated aging-related cognitive dysfunction in aging mouse model..
7	Brunt et al., 2021⁷.	Male C57BL/6N Mice, 8-week-old.	Low-choline diet (0.07%; to control for precursors of TMAO, but sufficient to avoid choline deficiency) that was either not supplemented (control) or supplemented with 0.12% TMAO	LC tandem mass spectrometry	Plasma and brain.	NIH Toolbox Cognition Battery Test - working memory (List sorting Test), episodic memory (Picture sequence memory test), processing speed (Pattern Comparison processing speed Test), executive function (Flanker inhibitory control and attention test; Dimensional change card sort test), and language (Picture vocabulary test; Oral reading recognition test).	• With aging, the plasma and brain concentrations of TMAO increased.
8	Feng et al., 2011⁸	SAMP8 and SAMR1, 8-month-old (M).	Electro-acupuncture (EA) treatment.	¹H NMR	Plasma.	Morris water maze.	• Lower levels of TMAO were measured in SAMP8 as compared to SAMR1. • EA treatment improved the TMAO and spatial memory.
9	Meng et al., 2019⁹.	Aged F344xBN F1 rats (M).	Laparotomy surgery. TMAO (120 mg/kg) in drinking water for 3 weeks	LC coupled with triple-quadrupole MS	Plasma.	Fear conditioning and open-field test.	• Cognitive dysfunction was exacerbated in the laparotomy group following TMAO treatment. . • In the hippocampus, TMAO treatment increased microglia-mediated neuroinflammation and the production of reactive oxygen species (ROS), and decreased the production of the antioxidant enzyme methionine sulfoxide reductase (Msr) A.
				Others
10	Guo et al., 2021¹⁰	SAMP8 mice, 5-month-old (M); Adult KM mice (M and F); Sprague-Dawley rats (M).	High sugar and high fat diet (HSHF). trimethylamine (TMA)- 2 mL/kg/d of 2.5% TMA.	LC-MS.	Serum and brain.	None.	• HSHF diet-induced gut-dysbiosis, intestinal inflammation, altered neurotransmitter metabolism in brain and gut, and also affected brain function and circRNA profiles. The gut metabolite TMAO may responsible for degradation of brain cirRNAs.
11	Zhao et al., 2019¹¹.	Sprague-Dawley rats, 20-month-old, (M).	TMAO, 120 mg/kg in drinking water for 3 weeks. Sevoflurane 2.6% exposure for 4 h.	LC coupled with triple-quadrupole MS.	Plasma.	Fear conditioning test and open field test.	• In the context of contextual fear conditioning, TMAO and sevoflurane significantly reduced freezing responses. • TMAO treatment and sevoflurane exposure lead to increased microglia activity, proinflammatory cytokines, NADPH oxidase-dependent reactive oxygen species, and decreased methionine sulfoxide reductase A antioxidant enzymes in the hippocampus. Cognitive impairment results from pre-existing high levels of TMAO circulating in aged rats after exposure to sevofurane.
12	Romano et al., 2017¹².	C57BL/6 germ-free mice (M and F)), (WT and Apoe ^−/−).	1% choline diet for two weeks.	LC-MS/MS Agilent 6410 Triple Quadrupole LC/MS instrument.	Serum.	Marble-burying assay.	• Choline-consuming animals had higher levels of serum TMAO.. Babies born to mothers who consumed choline buried more marbles, suggesting anxiety or depression.
13	Luo et al., 2021¹³.	ICR mice, 8-week-old (M and F).	TMAO (0.5% and 1.5%) dissolved in drinking water. TMAO intra-hippocampal infusion 0.2, 1.0 μmol.	LC-MS.	Serum.	Social dominance test, Social interaction test, bedding preference test, sexual preference test.	• TMAO administered centeral and peripheral level lowerd the social rank and reduced sexual preference. • Central TMAO infusion induced a total 207 differential metabolites belonging to metabolic or signaling pathways.
14	Mao et al., 2021¹⁴.	ICR mice, 8-weeks old (M and F)	0.2% and 1.0% of 3,3-dimethyl-1-butanol (DMB, indirect inhibitors of TMAO) in drinking water for 21 days.	LC-ESI-MS/MS on Agilent 1290 series LC and 6410 triple, quadruple MS.	Serum.	Social dominance test, bedding preference test, sexual preference test, social interaction test, open field test, tail suspension test, forced swimming test, novelty-suppressed feeding test and novel object recognition task.	• Despite no effects on sexual preference, anxiety, depression-like phenotype or memory formation, DMB exposure significantly influences social dominance of adult mice. • Highlights the TMAO effects on social behaviors.

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Abbreviations: Alzheimer’s disease (AD), chronic unpredictable stress (CUMS), 3,3-dimethyl-1-butanol (DMB), ), electro-acupuncture (EA), electrospray ionization (ESI), female (F), High sugar and high fat diet (HSHF), liquid chromatography–mass spectrometry (LC/MS), mass spectrometry (MS), male (M), middle cerebral artery occlusion/reperfusion (MCAO), nuclear magnetic resonance (NMR), reactive oxygen species (ROS), senescence-accelerated mouse-prone-8 (SAMP8), senescence-accelerated mouse resistant 1 (SAMR1), trimethylamine N-oxide (TMAO).

4.1. Alzheimer’s disease.

Alzheimer’s disease is a highly devastating disease marked by intracellular tangles and extracellular plaques [54]. This heterogeneous disease involves multiple phenotypes and includes genetic factors, environmental factors, and also dysfunction in the gut microbiome as its etiopathophysiology [55,56]. Related to the microbiota, TMAO has been related with AD pathology in clinically-relevant samples and animal models [57]. It was reported that CSF-TMAO concentrations in individuals with mild cognitive impairment (MCI), AD dementia were higher than those without dementia.. Importantly, these increased CSF-TMAOconcentrations were positively correlated with p-tau, p-tau/Aβ42, total tau, and neurofilament light chain protein concentrations [32]. However, an equivalent study described no differences in CSF-TMAO levels in specimens collected from individuals afflicted by AD dementia, non-AD dementia, and other neurological disorders [9]. The large-scale, non-overlapping genome-wide association studies were performed to understand the relationship between gut metabolites such as TMAO, carnitine, choline, or betaine and the risk of AD with the sample size of 455,258. The outcome from this study revealed that, TMAO or its precursors, play no causal roles in the development of AD [10].

In a triple-transgenic mice model of AD, 3xTg-AD elevated plasma and brain TMAO levels was observed as compared with age-matched control mice [39]. The levels of TMAO further elevated with increased age in these mice. In ex vivo studies, when TMAO incubated with hippocampal brain slices results loss of synaptic transmission. In both in vivo and ex vivo studies, TMAO activated the PERK-EIF2a-ER stress-signaling axis, resulting in endoplasmic reticulum stress and decreased synaptic plasticity [39]. In APP/PS1 mice, the association of TMAO with cognitive deterioration of choline-treated mice in presence or absence of probiotics (Lactobacillus plantarum) was evaluated. Treatment with memantine and probiotics significantly improved cognitive function, declined Aβ levels in the hippocampus, and preserved neuronal integrity and plasticity in choline-treated mice. There was a simultaneous reduction in TMAO synthesis and neuroinflammation, evidencing the role of TMAO in cognitive improvement [58]. This study used APP/PS1 mice of varying ages to understand how TMAO influences aging-induced cognition. Further, the use of 3,3-dimethyl-1-butanol (DMB; indirect inhibitor of TMAO) significantly reduced TMAO levels and decreased amyloid patholgy in the hippocampus. These molecular changes were linked with cognitive and long-term potentiation (LTP) improvements [59].

Among the different clinical studies that investigated the role of TMAO on AD pathology and cognitive process, it was observed that both had positive and no effect of TMAO on AD pathology when CSF-TMAO levels were measured. However, in preclinical studies using an AD mouse model, plasma or serum TMAO levels showed a strong influence on cognitive function and AD pathology. Furthermore, intervention to reduce TMAO levels measurably ameliorated cognitive deterioration, neuroinflammation, and AD pathology.

4.2. Parkinson’s disease.

In PD and control patients, no difference in TMAO levels was observed in either plasma or CSF. A subset of PD patients with motor fluctuations had significantly higher elevated plasma- and CSF-TMAO levels [60]. The saliva-TMAO of patients with early-stage PD was significantly more than that of the controls. . Modulation in TMAO profile correlated with levodopa equivalent daily dose [61]. Conversely, another study demonstrated decreased plasma-TMAO levels in PD patients than control. Moreover, PD patients with lower TMAO levels exhibited faster increases in levodopa equivalent dose. Further the risk of PD-dementia increased when plasma- TMAO level was low (<6.92 mmol/L) also had a higher risk for PD-dementia conversion as compared with the high TMAO level group counterpart [60]. Similarly, reduced fecal-TMAO levels were observed in PD group as compared to controls. This result supports the notion that TMAO is associated with the proper folding of proteins and thereby prevents the formation of pathological insoluble fibrils [62]. Interestingly, one study reports that early-stage PD patients show significantly increased levels of saliva-TMAO[61]. However, the plasma and feces TMAO levels were significantly decreased in PD patients as that of control group [60,62].

At present, there are no preclinical studies reporting the association between PD and TMAO concentrations in biological tissues. Given the significant role of the gut microbiome in PD, future studies may unveil the potential biological significance of this gut metabolite using controlled experimental conditions.

4.3. Amyotrophic lateral sclerosis.

In ALS patients, one study found decreased plasma-TMAO levels which was inversely correlated with the severity of upper motor neuron impairments. Interestingly, plasma-TMAO metabolic pathway alteration was also observed in their spouse [63]. This finding leads to the notion that alteration in gut microbiome started at earlier stage in in ALS patients. In another clinical study, the plasma-TMAO levels were not altered in ALS group. However, TMAO concentrations were greater when formic acid (neurotoxic compound) levels were up, showing that the presence of TMAO was positively correlated with formic acid levels [64].

4.4. Autism spectrum disorder (ASD).

In a cross-sectional study, ASD patients demonstrated higher plasma-TMAO which wascorrelated with severity of disease [65].

4.5. Stroke.

Increased serum TMAO concentrations of first acute ischemic stroke were associated with worse neurological deficit in a Chinese patient population [23]. Similarly, Patients with post-carotid artery stenting had an increased risk of new ischemic brain lesions if their TMAO levels were higher [66] and first stroke in hypertensive patients [67]. On the contrary, large-artery atherosclerotic (LAA) stroke or transient ischemic attack patients reported to have lower blood-TMAO levels [68]. In a similar model of LAA, Xu et al. reported elevated plasma TMAO levels in LAA stroke patients [69]. This study investigated the association between TMAO levels and cardiovascular malfunctions, including stroke. Plasma-TMAO were significantly reduced after antibiotics treatment and then regained after the withdrawal of antibiotics. Elevated plasmaTMAO were associated with an higher risk of a major cardiovascular malfunctions [70].

This study by Hou et al. verfied the effect of, TMAO, on neurological dysfunction at earlier stage after acute ischemic stroke. The results confirmed the “dose-response” relationship between TMAO concentration and neurological dysfunction at earler stage [71]. Association of TMAO with post-stroke cognitive impairment was evaluated. It was found that plasma-TMAO levels were more in patients with cognitive decline but not altered in patients with no cognitive loss [72]. This study analyzed the temporal effects of TMAO levels in stroke patients, i.e., at admission, after 2-days, and at 90-days. The plasma TMAO levels were higher at admission, decreased at 2-days, and again increased at 90-days after stroke in stroke patients than that of control subjects [73]. A study by Sun et al. demonstrated elevated plasma-TMAO levelsin patients with stroke, suggesting a positive correlation between plasma-TMAO and ischemic stroke [74]. This study explored the dynamic changes of TMAO in acute ischemic stroke patients. Elevated TMAO levels at initial period (before or less than24 h of acute ischemic stroke) increases the risk of poor stroke outcomes.. However, the level of TMAO decreased with the onset of stroke [75]. A study by Su et al. assessed the association between TMAO levels and neurological function after ischemic stroke. Rats subjected to experimental stroke by middle cerebral artery occlusion/reperfusion (MCAO/R) when treated with TMAO led to neuroinflammation, increased proliferation of reactive astrocytes and formation of glial scar and neurological dysfunction [60].

4.6. Depression.

A comparison of serum-TMAO levels in depression patients having carbohydrate malabsorption (CMA) and not reported to have CMA was conducted.The serum TMAO levels were shown to have positive correlation with depressive symptoms. Among the tested 251 study participants, the significant correlations were notes in 87 females and 49 males with no CMA, and 115 patients with CMA showed no significant correlations. TMAO, depression, and CMA are associated with sex differences in serum levels [76].

Plasma-TMAO levels were declined after chronic unpredictable stress (CUMS) in ratswhich further associates the TMAO with depression[77].

4.7. Bipolar disorder.

The metabolic profiling in bipolar disorder (BD) revealed that the level of TMAO was diminished in BD population during depressive episodes [78].

4.8. Schizophrenia.

Investigating the gut microbiome profile in schizophrenia patients reveals that TMAO reductase level was reduced in schizophrenia patients. Decreased TMAO reductase in schizophrenia patients may explain the reduced TMAO clearance in these group. [79].

4.9. Post-traumatic stress disorder (PTSD).

TMAO levels were assessed in patients with and without acute myocardial infarction (AMI)-induced PTSD symptoms.. TMAO levels were significantly higher in participants with PTSD symptomatology than in the group without PTSD symptoms shortly after AMI. This relationship reflects an association of elevated TMAO levels with PTSD vulnerability [80].

4.10. Others.

The effect of high sugar and fat diet on host gut microbiome was investigated. Elevated serum-TMAO levels were observed after high sugar and high-fat diet. The gut microbiota byproduct TMAO tends to alter some brain circRNAs. Additionally, the basal level of gut microbiota determined the conversion rate of choline to TMAO [81]. This study examined whether pre-existing elevated TMAO levels affect cognitive function after anesthetic sevoflurane exposure in aged rats. As expected, pre-existing higher circulating TMAO significantly reduced associative learning. The increased TMAO level was also associated with microglia activity, inflammatory cytokine expression, and NADPH oxidase-dependent ROS production in the hippocampus in rats exposed to sevoflurane. The data also suggest that downregulation of the antioxidant enzyme methionine sulfoxide reductase A (MSrA) by TMAO may lead to neuroinflammation mediated cognitive impairment in aged rats [82].

A study by Romano et al. examined the impact of gut microbial choline metabolism on bacteria and hosts. . The mice colonized with wild-type E. coli MS 200-1 strain, also called choline consuming community, accumulated more TMAO. An increase of anxiety was found in offspring colonized with choline consuming bacteria containing high TMAO levels (marble burying test), indicating an association between higher anxiety and TMAO levels [83]. The role of TMAO on social behaviors was also tested in this study, and the results demonstrated that TMAO exposure reduced social rank and declined sexual preference in adult mice. Of note, TMAO may influence social behaviors by altering metabolites in the hippocampus and signaling pathways such as FoxO and retrograde endocannabinoid signaling [84]. The elevated of TMAO concentrations were correlated with fear-conditioning, anxiety, and social behavior in preclinical models.

5. Role of TMAO in aging.

A study by Li et al. investigated on the association between TMAO and brain aging brain in both humans and mice, they observed increased plasma-TMAO levels in both clinical subjects and preclinical population[85]. Characteristics of the brain aging phenotype, such as senescent cell accumulation and cognitive decline, were evaluated in aging mouse model SAMP8 and its control SAMR1. In both SAMR1 and SAMP8 mice, TMAO enhanced synaptic damage by inhibiting the mTOR pathway, resulting in a reduction in synaptic plasticity-related proteins.. Based on these findings, TMAO may be associated with brain aging and cognitive dysfunction in SAMR1 mice and worsen the process of cerebral aging in SAMP8 mice. [85]. On evaluating the effect of TMAO on central inflammation and memory . Increase in age shown to have elevated plasma-TMAO levels which was negatiely associated with cognition [52]. These results suggest that TMAO enter brain parenchyma by crossing BBB in aged mice were where it increases the inflammatory state and glial cell activation. [52]. The study by Meng et al. showed that treatment with TMAO negatively affected cognition and exaggerated the neuroinflammation in aged rats [37].

In contrast to the above studies, the levels of plasma-TMAO in SAMP8 were decreased as compared to age-matched SAMR1. Following electro-acupuncture treatment, cognitive function improved, and TMAO levels declined in SAMP8 mice [86].

6. Role of TMAO as an osmolyte in the conformational harmony of protein folding.

Compounds involved in osmosis are known as osmolytes and are essentially involved in maintaining cell volume and fluid balance. Physiologically, when a cell swells due to external osmotic pressure, the efflux of osmolytes that carry water with them restores to normal cell volume. Among others, TMAO is one of these natural osmolytes. These compounds possess osmoprotective properties and are essential for all aspects of protein biochemistry, including folding, function, and stability. [87,88]. Studies have documented that some osmolytes act as neuroprotectors, but few promote neurodegeneration; the former is achieved by maintaining cell volume without compromising the cell function in the brain. The role of TMAO in regulating protein folding in intrinsically disordered proteins such as α-synuclein, tau, and amyloid-beta has been documented in different studies [89,90].

It is known that deposition of misfolded and aggregated forms of α-synuclein in neurons and glia is a hallmark of synucleinopathy disease [91]. The effect of TMAO on α–synuclein protein foldin was studied in vitro, and results revealed that depending on TMAO concentration the folding of α-synuclein differs[91]. The tau protein regulates the microtubule homeostasis in the CNS. The hyperphosphorylation and oligomerization of tau protein are some of the pathological hallmarks of tauopathies, including AD [92]. TMAO, in an in vitro study, promotes the formation of helical oligomers by distributing water around the perimeter of this peptide [93], In the case of Aβ, TMAO enhanced the Aβ aggregation, as demonstrated by a increased signal in thioflavin (ThT) assay as shown TMAO+Aβ group. At the same time, TMAO promotes the redistribution of water leading to stable Aβ peptideformation [94]. Regardless of the clear effect of TMAO in protein aggregation in vitro, it is possible that indirect effects triggered by this metabolite in vivo may also participate in the aggregation of these disease-associated proteins in the brain. As mentioned previously, the above studies explain the roles of TMAO wherein it can act as both neuroprotective and neurodegenerative in different conditions.

7. Therapeutic significance.

Among the different therapeutic targets emerging from gut microbiota, TMAO is gaining importance as a metabolite that can influence systemic inflammation and vascular-related pathways. Many approaches are discussed to target TMAO levels. 1) Changing the gut microbiota composition by prebiotics and probiotics, for example, by means of methanogenic bacteria depleting TMA and TMAO production [95,96]. 2) Reducing the predecessors of TMAO such as choline, betaine, and L-carnitine. It is still not possible to use this approach as choline is one of the precursors that plays a crucial role in neurotransmitters’ production [97]. 3) Although antibiotics treatment leads to gut dysbiosis, they also suppress the levels of TMAO. Treatment with metronidazole and ciprofloxacin significantly reduces TMAO levels. The effect was not for long-term withdrawal of antibiotics, but demonstrated reduced TMAO levels to an undetectable amount [98]. Reducing TMAO concentrations by the continuous use of antibiotics has the disadvantage of gut dysbiosis affecting beneficial bacterial populations in the gut. 4) Inhibiting TMAO by pharmacological means involves preventing formation of lysophosphatidylcholine from choline and lysophosphatidic acid via the phospholipase-autotaxin pathway [99]. Another approach is via DMB, a drug that inhibits choline TMA lyase activity[100]. Natural products such as Gynostemma pentaphyllum, Glycyrrhiza uralensis co-administered with Aconitum carmichaelii were also reported to reduce TMAO levels in animal models [70,101]. The natural antioxidant, resveratrol, has also been shown to decline plasma TMAO levels by elevating Lactobacillus and Bifidobacterium levels and decreasing TMA-forming bacteria [102]. Treatment with enalapril was also shown to have an association with lowering TMAO levels in rodents by elevating excretion of TMAO [103]. However, most of the discussed studies show evidence in the preclinical model.

Conclusion and future perspectives.

Eubiosis is a condition where the gut microbiome lives in a harmonic relationship with the host. Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and Verrucomicrobia make up the gut milieu of healthy individuals. . Altered microbiota composition causes increased levels of TMAO, resulting in several pathological conditions such as oxidative stress, microglial activation, and ER stress. These deleterious conditions may develop into CVD, renal disease, diabetic conditions, metabolic syndrome, colon cancers, NDDs, etc. Through the enteric nervous system, the gut communicates with the brain, and the gut microbiota is also regulated.. This bidirectional relationship via the gut-brain axis provides the mechanistic basis for TMAO levels can be used as a biomarker. This relationship provides the foundation for new target paths in various brain pathologies. Different approaches such as probiotics, prebiotics, antibiotics, antioxidants and enzymes have shown significant evidence of reducing TMAO levels in the preclinical models. Further research is warranted to corroborate these intense experimental studies in clinical populations.

Acknowledgment

This work was supported by The University of Texas Health Science Center at Houston. The Alzheimer’s Association^® AARGDNTF-19-619645 to TB. The authors also acknowledge the funding support from the USA National Institute of Health/National Institute on Aging (NIA) grant (1RF1AG072491-01) to TB and RM.

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PERMALINK

Clinical Significance and Potential Role of Trimethylamine N-Oxide in Neurological and Neuropsychiatric Disorders

Sowjanya Mudimela

Narahari Koppa Vishwanath

Anilkumar Pillai

Rodrigo Morales

Sean P Marrelli

Tatiana Barichello

Vijayasree V Giridharan

Abstract

1. Introduction

2. TMAO production and metabolism.

2.1. Gut microbiota-derived TMAO.

2.2. TMAO metabolism and binding.

Figure 1.

2.3. Potential gut microbiota associated with TMAO levels and disease condition.

3. Significance of TMAO in the central nervous system.

Figure 2.

3.1. Oxidative stress

3.2. Blood-brain barrier (BBB).

3.3. Glial cells.

4. Role of TMAO in neurological and neurodegenerative disorders.

Table 1:

Table 2:

4.1. Alzheimer’s disease.

4.2. Parkinson’s disease.

4.3. Amyotrophic lateral sclerosis.

4.4. Autism spectrum disorder (ASD).

4.5. Stroke.

4.6. Depression.

4.7. Bipolar disorder.

4.8. Schizophrenia.

4.9. Post-traumatic stress disorder (PTSD).

4.10. Others.

5. Role of TMAO in aging.

6. Role of TMAO as an osmolyte in the conformational harmony of protein folding.

7. Therapeutic significance.

Conclusion and future perspectives.

Acknowledgment

References

ACTIONS

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