Therapeutic Implications of the Microbial Hypothesis of Mental Illness

Savitz, Jonathan; Yolken, Robert H.

doi:10.1007/7854_2022_368

Cited by 9 publications

(5 citation statements)

References 252 publications

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“…For instance, the Detroit Neighborhood Health Study showed that for every one unit increase in CMV IgG antibody titer, the odds of incident depression increased by 26% so that individuals with IgG antibody titers in the highest quartile had four times greater odds of depression compared to participants in the lower three quartiles 41 . In the case of schizophrenia, results have been more equivocal 14 which may explain the negative ndings of this study. Although some early papers reported a higher frequency of CMV seropositivity in schizophrenia [49][50][51] , these ndings proved challenging to replicate and several meta-analyses or systematic reviews have failed to detect a statistical association between CMV serostatus and schizophrenia [52][53][54] .…”

Section: Discussioncontrasting

confidence: 70%

“…CMV has attracted the attention of the psychiatric eld because CMV (a) is neurotrophic and may cause neurological disease 1,2 , (b) it can be reactivated by psychological stress which is linked with the onset and exacerbation of many psychiatric disorders 3,4 , and (c) it can be reactivated by in ammation [4][5][6] which is linked with multiple psychiatric disorders including mood disorders and schizophrenia [7][8][9][10][11] . Importantly, lytic CMV replication can in turn worsen in ammation 12,13 , raising the possibility that poorly-controlled CMV infections may be one source of the systemic or neuroin ammation underlying the development of some cases of mental illness 14,15 .…”

Section: Introductionmentioning

confidence: 99%

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Cytomegalovirus antibodies are associated with mood disorders, suicide, markers of neuroinflammation, and microglia activation in postmortem brain samples

Zheng

Webster

Weickert

et al. 2023

Preprint

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Cytomegalovirus (CMV) is a common, neurotrophic herpesvirus that can be reactivated by inflammation and cause neurological disease. CMV replication can in turn worsen inflammation, raising the possibility that poorly controlled CMV infections may contribute to the neuroinflammation underlying some psychiatric disorders. We investigated whether the presence of anti-CMV antibodies in blood were associated with mental illness, suicide, neuroinflammation, and microglial density in the dorsolateral prefrontal cortex in postmortem samples. Data (n = 114 with schizophrenia; n = 78 with bipolar disorder; n = 87 with depression; n = 85 controls) were obtained from the Stanley Medical Research Institute. Gene expression data from a subset of 82 cases were categorized into “high” (n = 30), and “low” (n = 52) inflammation groups based on a recursive two-step cluster analysis using expression data for four inflammation-related genes. Measurements of the density of non-ramified and ramified microglia were available for an independent subset of 51 samples. All analyses controlled for age, sex, ethnicity, postmortem interval, and pH. CMV seropositivity significantly increased the odds of a mood disorder diagnosis (bipolar disorder: OR = 2.49; major depression: OR = 2.62) and among the psychiatric cases, of suicide (OR = 2.21). Samples in the upper tercile of anti-CMV antibody titers were more likely to be members of the “high” inflammation group (OR = 4.41). CMV positive cases also showed an increased ratio of non-ramified to ramified microglia in layer I of the dorsolateral prefrontal cortex (Cohen’s d = 0.81). The results raise the possibility that the reactivation of CMV contributes to the neuroinflammation that underlies some cases of psychiatric disorders.

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Section: Discussioncontrasting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Cytomegalovirus antibodies are associated with mood disorders, suicide, markers of neuroinflammation, and microglia activation in postmortem brain samples

Zheng

Webster

Weickert

et al. 2023

Preprint

Self Cite

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“…The bacterial flagellin and type III secretion system (T3SS) is known to activate the NLRC4 inflammasome 68 , and interestingly, a flagellin-TLR5 interaction allows us to differentiate between commensal-derived flagellin and pathogen-derived flagellin originating from the gut 69 . The gut microbiome has been implicated in MDD 70 , 71 and it is conceivable that NLRC4 inflammasomes activated by gut bacterial flagellin may play an unrecognized role in this relationship. In addition, the increase in NLRC4 expression raises the possibility of a viral etiology as we have previously hypothesized 72 – 75 , but it is also possible that the effect is driven by ER stress.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of ER stress, inflammasome activation, and mitochondrial biogenesis-related genes in peripheral blood mononuclear cells in major depressive disorder

Munshi,

Alarbi,

Zheng

et al. 2024

Preprint

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A subset of major depressive disorder (MDD) is characterized by immune system dysfunction, but the intracellular origin of these immune changes remains unclear. Here we tested the hypothesis that abnormalities in the endoplasmic reticulum (ER) stress, inflammasome activity and mitochondrial biogenesis contribute to the development of systemic inflammation in MDD. RT-qPCR was used to measure mRNA expression of key organellar genes from peripheral blood mononuclear cells (PBMCs) isolated from 186 MDD and 67 healthy control (HC) subjects. The comparative CT (2−ΔΔCT) method was applied to quantify mRNA expression using GAPDH as the reference gene. After controlling for age, sex, BMI, and medication status using linear regression models, expression of the inflammasome (NLRC4 and NLRP3) and the ER stress (XBP1u, XBP1s, and ATF4) genes was found to be significantly increased in the MDD versus the HC group. After excluding outliers, expression of the inflammasome genes was no longer statistically significant but expression of the ER stress genes (XBP1u, XBP1s, and ATF4) and the mitochondrial biogenesis gene, MFN2, was significantly increased in the MDD group. ASC and MFN2 were positively correlated with serum C-reactive protein concentrations. The altered expression of inflammasome activation, ER stress, and mitochondrial biogenesis pathway components suggest that dysfunction of these organelles may play a role in the pathogenesis of MDD.

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“…One additional limitation applies to phage therapeutics in a microbiome setting, namely the vital emerging roles of non-bacterial drivers of dysbiosis. These include viruses other than phages, which are increasingly recognized as important in maintaining gut ecological balance and contributors to dysbiosis in disease [ 109 , 110 , 111 , 112 ], as well as fungi and protozoa [ 113 , 114 , 115 , 116 , 117 ]. Phages targeting bacteria exclusively are unable to directly affect these organisms of emerging importance.…”

Section: Targeted Microbiome Therapeutics: Opportunities and Challengesmentioning

confidence: 99%

A Taxonomy-Agnostic Approach to Targeted Microbiome Therapeutics—Leveraging Principles of Systems Biology

et al. 2023

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The study of human microbiomes has yielded insights into basic science, and applied therapeutics are emerging. However, conflicting definitions of what microbiomes are and how they affect the health of the “host” are less understood. A major impediment towards systematic design, discovery, and implementation of targeted microbiome therapeutics is the continued reliance on taxonomic indicators to define microbiomes in health and disease. Such reliance often confounds analyses, potentially suggesting associations where there are none, and conversely failing to identify significant, causal relationships. This review article discusses recent discoveries pointing towards a molecular understanding of microbiome “dysbiosis” and away from a purely taxonomic approach. We highlight the growing role of systems biological principles in the complex interrelationships between the gut microbiome and host cells, and review current approaches commonly used in targeted microbiome therapeutics, including fecal microbial transplant, bacteriophage therapies, and the use of metabolic toxins to selectively eliminate specific taxa from dysbiotic microbiomes. These approaches, however, remain wholly or partially dependent on the bacterial taxa involved in dysbiosis, and therefore may not capitalize fully on many therapeutic opportunities presented at the bioactive molecular level. New technologies capable of addressing microbiome-associated diseases as molecular problems, if solved, will open possibilities of new classes and categories of targeted microbiome therapeutics aimed, in principle, at all dysbiosis-driven disorders.

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Therapeutic Implications of the Microbial Hypothesis of Mental Illness

Cited by 9 publications

References 252 publications

Cytomegalovirus antibodies are associated with mood disorders, suicide, markers of neuroinflammation, and microglia activation in postmortem brain samples

Cytomegalovirus antibodies are associated with mood disorders, suicide, markers of neuroinflammation, and microglia activation in postmortem brain samples

Increased expression of ER stress, inflammasome activation, and mitochondrial biogenesis-related genes in peripheral blood mononuclear cells in major depressive disorder

A Taxonomy-Agnostic Approach to Targeted Microbiome Therapeutics—Leveraging Principles of Systems Biology

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