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Article ; Online: Leveraging Health Linkage Data From the UK Biobank-With Great Power Comes Great Responsibility-Reply.

Amin, Najaf / Kaddurah-Daouk, Rima / van Duijn, Cornelia M

2023 Volume 80, Issue 10, Page(s) 1077–1078

Language	English
Publishing date	2023-08-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	2701203-7
ISSN	2168-6238 ; 2168-622X
ISSN (online)	2168-6238
ISSN	2168-622X
DOI	10.1001/jamapsychiatry.2023.2969
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Article: Current Concepts in Pharmacometabolomics, Biomarker Discovery, and Precision Medicine.

Beger, Richard D / Schmidt, Michael A / Kaddurah-Daouk, Rima

Metabolites

2020 Volume 10, Issue 4

Abstract: Pharmacometabolomics (PMx) studies use information contained in metabolic profiles (or metabolome) to inform about how a subject will respond to drug treatment. Genome, gut microbiome, sex, nutrition, age, stress, health status, and other factors can ... ...

Abstract	Pharmacometabolomics (PMx) studies use information contained in metabolic profiles (or metabolome) to inform about how a subject will respond to drug treatment. Genome, gut microbiome, sex, nutrition, age, stress, health status, and other factors can impact the metabolic profile of an individual. Some of these factors are known to influence the individual response to pharmaceutical compounds. An individual's metabolic profile has been referred to as his or her "metabotype." As such, metabolomic profiles obtained prior to, during, or after drug treatment could provide insights about drug mechanism of action and variation of response to treatment. Furthermore, there are several types of PMx studies that are used to discover and inform patterns associated with varied drug responses (i.e., responders vs. non-responders; slow or fast metabolizers). The PMx efforts could simultaneously provide information related to an individual's pharmacokinetic response during clinical trials and be used to predict patient response to drugs making pharmacometabolomic clinical research valuable for precision medicine. PMx biomarkers can also be discovered and validated during FDA clinical trials. Using biomarkers during medical development is described in US Law under the 21st Century Cures Act. Information on how to submit biomarkers to the FDA and their context of use is defined herein.
Language	English
Publishing date	2020-03-27
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662251-8
ISSN	2218-1989
ISSN	2218-1989
DOI	10.3390/metabo10040129
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Article ; Online: Gut microbial molecules in behavioural and neurodegenerative conditions.

Needham, Brittany D / Kaddurah-Daouk, Rima / Mazmanian, Sarkis K

Nature reviews. Neuroscience

2020 Volume 21, Issue 12, Page(s) 717–731

Abstract: Mounting evidence suggests that the gut microbiome impacts brain development and function. Gut-brain connections may be mediated by an assortment of microbial molecules that are produced in the gastrointestinal tract, which can subsequently permeate many ...

Abstract	Mounting evidence suggests that the gut microbiome impacts brain development and function. Gut-brain connections may be mediated by an assortment of microbial molecules that are produced in the gastrointestinal tract, which can subsequently permeate many organs, including sometimes the brain. Studies in animal models have identified molecular cues propagated from intestinal bacteria to the brain that can affect neurological function and/or neurodevelopmental and neurodegenerative conditions. Herein, we describe bacterial metabolites with known or suspected neuromodulatory activity, define mechanisms of signalling pathways from the gut microbiota to the brain and discuss direct effects that gut bacterial molecules are likely exerting on specific brain cells. Many discoveries are recent, and the findings described in this Perspective are largely novel and yet to be extensively validated. However, expanding research into the dynamic molecular communications between gut microorganisms and the CNS continues to uncover critical and previously unappreciated clues in understanding the pathophysiology of behavioural, psychiatric and neurodegenerative diseases.
MeSH term(s)	Animals ; Bacteria/metabolism ; Brain/physiopathology ; Gastrointestinal Microbiome ; Humans ; Mental Disorders/microbiology ; Mental Disorders/psychology ; Neurodegenerative Diseases/microbiology ; Neurodegenerative Diseases/psychology
Language	English
Publishing date	2020-10-16
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2034150-7
ISSN	1471-0048 ; 1471-0048 ; 1471-003X
ISSN (online)	1471-0048
ISSN	1471-0048 ; 1471-003X
DOI	10.1038/s41583-020-00381-0
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Article ; Online: Oxylipin transport by lipoprotein particles and its functional implications for cardiometabolic and neurological disorders.

Liang, Nuanyi / Harsch, Brian A / Zhou, Sitong / Borkowska, Alison / Shearer, Gregory C / Kaddurah-Daouk, Rima / Newman, John W / Borkowski, Kamil

Progress in lipid research

2023 Volume 93, Page(s) 101265

Abstract: Lipoprotein metabolism is critical to inflammation. While the periphery and central nervous system (CNS) have separate yet connected lipoprotein systems, impaired lipoprotein metabolism is implicated in both cardiometabolic and neurological disorders. ... ...

Abstract	Lipoprotein metabolism is critical to inflammation. While the periphery and central nervous system (CNS) have separate yet connected lipoprotein systems, impaired lipoprotein metabolism is implicated in both cardiometabolic and neurological disorders. Despite the substantial investigation into the composition, structure and function of lipoproteins, the lipoprotein oxylipin profiles, their influence on lipoprotein functions, and their potential biological implications are unclear. Lipoproteins carry most of the circulating oxylipins. Importantly, lipoprotein-mediated oxylipin transport allows for endocrine signaling by these lipid mediators, long considered to have only autocrine and paracrine functions. Alterations in plasma lipoprotein oxylipin composition can directly impact inflammatory responses of lipoprotein metabolizing cells. Similar investigations of CNS lipoprotein oxylipins are non-existent to date. However, as APOE4 is associated with Alzheimer's disease-related microglia dysfunction and oxylipin dysregulation, ApoE4-dependent lipoprotein oxylipin modulation in neurological pathologies is suggested. Such investigations are crucial to bridge knowledge gaps linking oxylipin- and lipoprotein-related disorders in both periphery and CNS. Here, after providing a summary of existent literatures on lipoprotein oxylipin analysis methods, we emphasize the importance of lipoproteins in oxylipin transport and argue that understanding the compartmentalization and distribution of lipoprotein oxylipins may fundamentally alter our consideration of the roles of lipoprotein in cardiometabolic and neurological disorders.
MeSH term(s)	Humans ; Oxylipins/metabolism ; Apolipoprotein E4/metabolism ; Lipoproteins/metabolism ; Nervous System Diseases ; Cardiovascular Diseases/metabolism
Chemical Substances	Oxylipins ; Apolipoprotein E4 ; Lipoproteins
Language	English
Publishing date	2023-11-17
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	282560-0
ISSN	1873-2194 ; 0079-6832 ; 0163-7827
ISSN (online)	1873-2194
ISSN	0079-6832 ; 0163-7827
DOI	10.1016/j.plipres.2023.101265
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Article: Acylcarnitines metabolism in depression: association with diagnostic status, depression severity and symptom profile in the NESDA cohort.

Montanari, Silvia / Jansen, Rick / Schranner, Daniela / Kastenmüller, Gabi / Arnold, Matthias / Janiri, Delfina / Sani, Gabriele / Bhattacharyya, Sudeepa / Dehkordi, Siamak Mahmoudian / Dunlop, Boadie W / Rush, A John / Penninx, Brenda W H J / Kaddurah-Daouk, Rima / Milaneschi, Yuri

medRxiv : the preprint server for health sciences

2024

Abstract: Background: Acylcarnitines (ACs) are involved in bioenergetics processes that may play a role in the pathophysiology of depression. Studies linking AC levels to depression are few and provide mixed findings. We examined the association of circulating ... ...

Abstract	Background: Acylcarnitines (ACs) are involved in bioenergetics processes that may play a role in the pathophysiology of depression. Studies linking AC levels to depression are few and provide mixed findings. We examined the association of circulating ACs levels with Major Depressive Disorder (MDD) diagnosis, overall depression severity and specific symptom profiles. Methods: The sample from the Netherlands Study of Depression and Anxiety included participants with current (n=1035) or remitted (n=739) MDD and healthy controls (n=800). Plasma levels of four ACs (short-chain: acetylcarnitine C2 and propionylcarnitine C3; medium-chain: octanoylcarnitine C8 and decanoylcarnitine C10) were measured. Overall depression severity as well as atypical/energy-related (AES), anhedonic and melancholic symptom profiles were derived from the Inventory of Depressive Symptomatology. Results: As compared to healthy controls, subjects with current or remitted MDD presented similarly lower mean C2 levels (Cohen's d=0.2, p≤1e-4). Higher overall depression severity was significantly associated with higher C3 levels (ß=0.06, SE=0.02, p=1.21e-3). No associations were found for C8 and C10. Focusing on symptom profiles, only higher AES scores were linked to lower C2 (ß=-0.05, SE=0.02, p=1.85e-2) and higher C3 (ß=0.08, SE=0.02, p=3.41e-5) levels. Results were confirmed in analyses pooling data with an additional internal replication sample from the same subjects measured at 6-year follow-up (totaling 4195 observations). Conclusions: Small alterations in levels of short-chain acylcarnitine levels were related to the presence and severity of depression, especially for symptoms reflecting altered energy homeostasis. Cellular metabolic dysfunctions may represent a key pathway in depression pathophysiology potentially accessible through AC metabolism.
Language	English
Publishing date	2024-02-15
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.14.24302813
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Article: Metabolomics Signatures of serotonin reuptake inhibitor (Escitalopram), serotonin norepinephrine reuptake inhibitor (Duloxetine) and Cognitive Behavior Therapy on Key Neurotransmitter Pathways in Major Depressive Disorder.

Bhattacharyya, Sudeepa / MahmoudianDehkordi, Siamak / Sniatynski, Matthew J / Belenky, Marina / Marur, Vasant R / Rush, A John / Craighead, W Edward / Mayberg, Helen S / Dunlop, Boadie W / Kristal, Bruce S / Kaddurah-Daouk, Rima

medRxiv : the preprint server for health sciences

2024

Abstract: Metabolomics provides powerful tools that can inform about heterogeneity in disease and response to treatments. In this study, we employed an electrochemistry-based targeted metabolomics platform to assess the metabolic effects of three randomly-assigned ...

Abstract	Metabolomics provides powerful tools that can inform about heterogeneity in disease and response to treatments. In this study, we employed an electrochemistry-based targeted metabolomics platform to assess the metabolic effects of three randomly-assigned treatments: escitalopram, duloxetine, and Cognitive Behavior Therapy (CBT) in 163 treatment-naïve outpatients with major depressive disorder. Serum samples from baseline and 12 weeks post-treatment were analyzed using targeted liquid chromatography-electrochemistry for metabolites related to tryptophan, tyrosine metabolism and related pathways. Changes in metabolite concentrations related to each treatment arm were identified and compared to define metabolic signatures of exposure. In addition, association between metabolites and depressive symptom severity (assessed with the 17-item Hamilton Rating Scale for Depression [HRSD
Language	English
Publishing date	2024-04-03
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.02.24304677
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Article ; Online: Metabolomics profiling reveals distinct, sex-specific signatures in serum and brain metabolomes in mouse models of Alzheimer's disease.

Pandey, Ravi S / Arnold, Mattias / Batra, Richa / Krumsiek, Jan / Kotredes, Kevin P / Garceau, Dylan / Williams, Harriet / Sasner, Michael / Howell, Gareth R / Kaddurah-Daouk, Rima / Carter, Gregory W

Alzheimer's & dementia : the journal of the Alzheimer's Association

2024

Abstract: Introduction: Increasing evidence suggests that metabolic impairments contribute to early Alzheimer's disease (AD) mechanisms and subsequent dementia. Signals in metabolic pathways conserved across species can facilitate translation.: Methods: We ... ...

Abstract	Introduction: Increasing evidence suggests that metabolic impairments contribute to early Alzheimer's disease (AD) mechanisms and subsequent dementia. Signals in metabolic pathways conserved across species can facilitate translation. Methods: We investigated differences in serum and brain metabolites between the early-onset 5XFAD and late-onset LOAD1 (APOE4.Trem2R47H) mouse models of AD to C57BL/6J controls at 6 months of age. Results:* We identified sex differences for several classes of metabolites, such as glycerophospholipids, sphingolipids, and amino acids. Metabolic signatures were notably different between brain and serum in both mouse models. The 5XFAD mice exhibited stronger differences in brain metabolites, whereas LOAD1 mice showed more pronounced differences in serum. Discussion: Several of our findings were consistent with results in humans, showing glycerophospholipids reduction in serum of apolipoprotein E (apoE) ε4 carriers and replicating the serum metabolic imprint of the APOE ε4 genotype. Our work thus represents a significant step toward translating metabolic dysregulation from model organisms to human AD. Highlights: This was a metabolomic assessment of two mouse models relevant to Alzheimer's disease. Mouse models exhibit broad sex-specific metabolic differences, similar to human study cohorts. The early-onset 5XFAD mouse model primarily alters brain metabolites while the late-onset LOAD1 model primarily changes serum metabolites. Apolipoprotein E (apoE) ε4 mice recapitulate glycerophospolipid signatures of human APOE ε4 carriers in both brain and serum.
Language	English
Publishing date	2024-04-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.13851
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Article: Gut Microbiome-Linked Metabolites in the Pathobiology of Major Depression With or Without Anxiety-A Role for Bile Acids.

MahmoudianDehkordi, Siamak / Bhattacharyya, Sudeepa / Brydges, Christopher R / Jia, Wei / Fiehn, Oliver / Rush, A John / Dunlop, Boadie W / Kaddurah-Daouk, Rima

Frontiers in neuroscience

2022 Volume 16, Page(s) 937906

Abstract: Background: The gut microbiome may play a role in the pathogenesis of neuropsychiatric diseases including major depressive disorder (MDD). Bile acids (BAs) are steroid acids that are synthesized in the liver from cholesterol and further processed by gut- ...

Abstract	Background: The gut microbiome may play a role in the pathogenesis of neuropsychiatric diseases including major depressive disorder (MDD). Bile acids (BAs) are steroid acids that are synthesized in the liver from cholesterol and further processed by gut-bacterial enzymes, thus requiring both human and gut microbiome enzymatic processes in their metabolism. BAs participate in a range of important host functions such as lipid transport and metabolism, cellular signaling and regulation of energy homeostasis. BAs have recently been implicated in the pathophysiology of Alzheimer's and several other neuropsychiatric diseases, but the biochemical underpinnings of these gut microbiome-linked metabolites in the pathophysiology of depression and anxiety remains largely unknown. Method: Using targeted metabolomics, we profiled primary and secondary BAs in the baseline serum samples of 208 untreated outpatients with MDD. We assessed the relationship of BA concentrations and the severity of depressive and anxiety symptoms as defined by the 17-item Hamilton Depression Rating Scale (HRSD Results: The concentration of the primary BA chenodeoxycholic acid (CDCA) was significantly lower at baseline in both severely depressed (log Conclusion: In patients with MDD, BA profiles representing changes in gut microbiome compositions are associated with higher levels of anxiety and increased probability of first-line treatment failure. If confirmed, these findings suggest the possibility of developing gut microbiome-directed therapies for MDD characterized by gut dysbiosis.
Language	English
Publishing date	2022-07-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2022.937906
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Article ; Online: Metabolomic signatures of intravenous racemic ketamine associated remission in treatment-resistant depression: A pilot hypothesis generating study.

Singh, Balwinder / MahmoudianDehkordi, Siamak / Voort, Jennifer L Vande / Han, Xianlin / Port, John D / Frye, Mark A / Kaddurah-Daouk, Rima

Psychiatry research

2022 Volume 314, Page(s) 114655

Abstract: In this pilot study (N = 9), we highlight new insights gained on ketamine's mechanism of action where we have mapped biochemical processes that are affected within 40 min of intravenous ketamine exposure. Targeting acylcarnitines, we demonstrated rapid ... ...

Abstract	In this pilot study (N = 9), we highlight new insights gained on ketamine's mechanism of action where we have mapped biochemical processes that are affected within 40 min of intravenous ketamine exposure. Targeting acylcarnitines, we demonstrated rapid utilization of short-chain acylcarnitines within 40 min of ketamine treatment followed by restoration within 24 h; this change in short chain acylcarnitine with rapid-acting antidepressant treatment is consistent with previous work identifying similar change but at 8-weeks with slower-acting SSRI treatment. Using a non-targeted metabolomics platform, we defined broader effects of ketamine on lipid metabolism and identified changes in triglyceride that correlate with ketamine response. This study provides novel insights into ketamine's action and highlighting a possible role for mitochondrial function and energy metabolism in ketamine's mechanism of action.
MeSH term(s)	Antidepressive Agents/pharmacology ; Antidepressive Agents/therapeutic use ; Depression ; Depressive Disorder, Treatment-Resistant/drug therapy ; Humans ; Ketamine/pharmacology ; Ketamine/therapeutic use ; Pilot Projects
Chemical Substances	Antidepressive Agents ; Ketamine (690G0D6V8H)
Language	English
Publishing date	2022-05-28
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	445361-x
ISSN	1872-7123 ; 1872-7506 ; 0925-4927 ; 0165-1781
ISSN (online)	1872-7123 ; 1872-7506
ISSN	0925-4927 ; 0165-1781
DOI	10.1016/j.psychres.2022.114655
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Article ; Online: Expert insights: The potential role of the gut microbiome-bile acid-brain axis in the development and progression of Alzheimer's disease and hepatic encephalopathy.

Jia, Wei / Rajani, Cynthia / Kaddurah-Daouk, Rima / Li, Houkai

Medicinal research reviews

2019 Volume 40, Issue 4, Page(s) 1496–1507

Abstract: Recent epidemiological and molecular studies have linked the disruption of cholesterol homeostasis to increased risk for developing Alzheimer's disease (AD). Emerging evidence also suggests that brain cholesterol accumulation contributes to the ... ...

Abstract	Recent epidemiological and molecular studies have linked the disruption of cholesterol homeostasis to increased risk for developing Alzheimer's disease (AD). Emerging evidence also suggests that brain cholesterol accumulation contributes to the progression of hepatic encephalopathy (HE) via bile acid (BA)-mediated effects on the farnesoid X receptor. In this perspective paper, we reviewed several recently published studies that suggested a role for the gut microbiota transformation of BAs as a factor in AD and HE development/progression. We hypothesize that in addition to cholesterol elimination pathways, alteration of the gut microbiota and subsequent changes in both the serum and brain BA profiles are mechanistically involved in the development of both AD and HE, and thus, are a potential target for the prevention and treatment of the two diseases. Our understanding of the microbiome-BAs-brain axis in central nervous system disease is still evolving, and critical questions regarding the emerging links among central, peripheral, and intestinal metabolic failures contributing to brain health and disease during aging have yet to be addressed.
MeSH term(s)	Alzheimer Disease/microbiology ; Alzheimer Disease/pathology ; Bile Acids and Salts/metabolism ; Brain/metabolism ; Disease Progression ; Gastrointestinal Microbiome ; Hepatic Encephalopathy/microbiology ; Hepatic Encephalopathy/pathology ; Humans ; Models, Biological
Chemical Substances	Bile Acids and Salts
Language	English
Publishing date	2019-12-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	603210-2
ISSN	1098-1128 ; 0198-6325
ISSN (online)	1098-1128
ISSN	0198-6325
DOI	10.1002/med.21653
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