The Metabolomic Mind: Microbial Metabolite Programming of Microglia Open Access

Gut microbes play a critical role in host health by breaking down complex carbohydrates, influencing peripheral immune system development, inhibiting the colonization of harmful pathogens, and producing vitamins and metabolites [1]. The central role of microbes in orchestrating host physiology has led to the emergence of the microbiota as a critical component of the gut-brain-axis, a framework describing how neural function is modulated by gut-derived signals [2]. Foundational evidence for a critical role of microbes in the gut-brain-axis derives from studies utilizing germ-free (GF) mice that are devoid of a microbiome. These investigations demonstrate that the microbiome begins influencing the brain in the prenatal time-period, as evidenced by disrupted thalamocortical neuron axonogenesis in fetuses from GF dams [3]. Postnatally, GF mice display increased synaptic plasticity gene expression [4] and altered neuronal apoptosis in the hippocampus and hypothalamus [5, 6]. As adults, GF mice maintain heightened synaptic plasticity gene expression [7] with increased hippocampal neurogenesis [8] and serotonin [9]. Further, adult GF mice display increased blood-brain barrier permeability [10], disrupted white matter development [11, 12], and decreased brain derived neurotrophic factor across several brain regions [7, 9, 13]. Collectively, these findings underscore the microbiome’s persistent influence on brain function throughout development and the lifespan. The significance of the microbiome’s persistent influence on the brain stems from the fact that its composition and microbial metabolism is shaped by environmental exposures and host physiology, suggesting that these shifts may have lasting implications for neural function. Consequently, dissecting the mechanisms that mediate microbe-brain interactions is fundamental to advancing our understanding of disease and informing novel therapeutic strategies.

Efforts to elucidate the mechanisms by which the microbiome exerts its broad influence on the brain have increasingly focused on microglia as primary mediators of these effects. Microglia are the resident innate immune cells of the central nervous system, where they have a diverse role outside of their canonical immune functions responding to infection and injury. Microglia interact with other glial cells and neurons, resulting in unique neuromodulatory functions during development and adulthood [14]. During development, microglia refine neural circuits by phagocytosing neural precursor cells [15], guiding cortical interneuron migration and inhibitory circuit formation [16, 17], facilitating axonal guidance [16, 18], regulating synapse formation [19, 20], and supporting proper myelination [21]. Their neuromodulatory role extends into adulthood, where they facilitate synaptic remodeling and provide trophic support to other cell types. The critical role of microglia in regulating neural circuit wiring and function has led to their increasingly recognized potential role in the pathogenesis of neuropsychiatric disorders. Because microglial functions also overlap with many processes disrupted in GF mice, current research investigates how the microbiome modulates microglia to shape brain development and function.

Despite the growing recognition of microglia as key regulators of brain development and function, and their emerging roles in the pathogenesis of various psychiatric and neurological disorders, the precise mechanisms linking the microbiota to microglial function remain incompletely understood. GF mouse studies clearly show that the microbiome modulates processes overlapping with key microglial functions, yet it is unclear which microbial signals govern microglial maturation, metabolic adaptations, and functional states. Even more poorly defined is how altering these microbe-microglia signaling pathways influences brain circuit refinement, ultimately contributing to disease susceptibility or resilience. Elucidating these mechanisms will not only deepen our understanding of brain physiology and pathology but may also reveal novel therapeutic targets by harnessing microbial signals to modulate microglial function and improve neurological and psychiatric outcomes. In this review, we first detail how the absence of microbial signals impacts microglial development and function, then highlight the key microbial metabolites implicated in microglial function and their relevance to pathology and the potential for future interventions.

Microglia begin responding to environmental signals early in embryonic development, and the absence of maternal microbial signals perturbs this maturation process [22]. RNA-sequencing of microglia isolated from male fetuses at embryonic day 18 (E18) of GF dams show that nearly all differentially expressed genes compared to male fetuses from specific pathogen-free dams are downregulated. This downregulation coincides with delayed chromatin accessibility between E14.5 and E18.5 [22]. This immature transcriptomic phenotype continues into adulthood [23] and is supported by surface protein markers indicative of immature microglia [24]. Concomitantly, fetal brains from GF dams have increased microglia labeling, with elevated microglial density persisting into the perinatal period [5] and adulthood [24]. In addition to increased proliferation and density of microglia, GF mice have a persistent altered microglial morphology across the lifespan characterized by increased soma size with excessive process length and branching. This perturbed morphology can be induced with antibiotic treatment during development [25] and adulthood [24] and is reversible in GF mice with microbiota colonization [24], suggesting that microbes have a continual influence on microglia. Collectively, the transcriptional, proliferative, and morphological disruptions indicate that microglia fail to mature normally in the absence of microbial signals.

The microbiota is also necessary for microglia to mount a response to environmental signals across the lifespan. Exposure to maternal stress in utero causes increased inflammation in the fetal brain which is absent in offspring from GF dams [26], indicating a blunting of immune reactivity in the GF fetal brain. Normally, microglia have increased inflammatory cytokine expression following birth, but this response does not occur in mice born from GF dams [4, 5]. Further, neonatal GF mice exhibit a ramified microglial morphology, characterized by increased process extension and branching indicative of a quiescent surveillance state, with decreased expression of scavenger receptors and the phagocytic lysosomal marker CD68. These changes are associated with increased functional synapses in the cerebellum suggesting decreased synaptic pruning by GF microglia [4]. This blunted microglial reactivity continues into adulthood in GF mice where microglia continue to have decreased expression of genes involved with cell activation and defense responses [23, 24, 27], with a failure to shift toward an amoeboid morphology during aging [28]. However, the specific pathways disrupted vary across brain regions with neuroinflammatory and complement pathways preferentially perturbed in the hippocampus compared to the prefrontal cortex [27]. Many of the observed disruptions can be reversed with microbial colonization, suggesting that most microbiota influences on microglial function can be manipulated later in life, although there is likely key developmental programming windows for some of these alterations [25].

The functional consequences of this blunted response in GF microglia are shown in their response to infectious stimuli. Adult GF microglia have an attenuated cytokine response and fail to adapt an amoeboid morphology to the bacterial endotoxin lipopolysaccharide (LPS) and lymphocytic choriomeningitis virus infection [24]. This impaired response to infectious stimuli in GF mice results in worsened virus-induced neurologic damage, which is primarily driven by a failure of microglia to express necessary components for antigen presentation to T cells [29]. Overall, this blunted response with exacerbated pathology demonstrates that microbial signals are integral for microglia to respond appropriately to their environment, facilitating proper cytokine expression, phagocytic function, antigen presentation, and morphological adaptations to environmental challenges.

The microbiome is also essential for normal metabolic function in microglia across the lifespan. When comparing GF microglia to specific pathogen-free microglia, metabolic function and translation are central pathways enriched among the differentially expressed genes during both embryonic [22] and adult [27] stages. Metabolomic analysis of microglia in adult GF mice show a significant disruption in metabolites involved in the TCA cycle and purine metabolism [30]. Further, GF microglia show increased mitochondrial density with decreased membrane potential and increased mitochondrial superoxide caused by a defect in the respiratory chain. This mitochondrial deficit is reversible with microbial colonization [30], further suggesting that normal metabolic function of microglia is maintained by the microbiota. However, disruptions to mitochondrial function and metabolism are not unique to microglia in the brain of GF mice. Single-cell RNA-sequencing of both the prefrontal cortex and hippocampus has shown all of the neural and glial cell types in these regions have disruptions to energy metabolism pathways which are reversed with microbial colonization [27], suggesting microbial metabolites provide a necessary substrate for normal cell metabolic function in the brain.

The microbiome is responsible for the production of a number of bioactive metabolites that reach the brain [31]. An emerging body of evidence points to microbial metabolites as critical intermediaries that link the microbiota to microglial function. By modulating metabolic processes and signaling pathways within microglia, these metabolites help define cellular phenotypes and responsiveness. In the following sections, we will examine the specific metabolite-driven mechanisms that underlie this intricate gut-microglia communication.

Short-chain fatty acids (SCFAs) are derived from microbial fermentation of dietary fibers in the colon and primarily consist of acetate, propionate, and butyrate in a ratio of around 3:1:1 in circulation, respectively [32]. They can regulate different host functions as a substrate for energy production or by signaling through several receptors, FFAR2 (GPR43), FFAR3 (GPR41), GPR109a, OLFR78 and by modulating histone deacetylase activity [33]. SCFAs can reach the central nervous system and are increasingly recognized for their capacity to modulate CNS-immune interactions, positioning them as key mediators of the microbiota’s influence on microglia and other neural cell types Figure 1. While SCFAs can modulate inflammation in the periphery through their receptors, this likely does not occur in homeostatic microglia, as they do not express free-fatty acid receptors. Instead, microglia express SCFA transporters, and SCFAs are able to diffuse into microglia where they modulate gene expression through inhibition of histone deacetylases [34].

The role of SCFAs in mediating effects of the microbiome on microglia is evident in their ability to reverse several disruptions to microglia found in GF mice. Supplementation of GF mice with SCFAs largely rescues their perturbed microglial proliferation, density, and morphology, although they do not reverse the immature microglial phenotype [24]. Further, acetate supplementation alone is sufficient to recapitulate this amelioration of microglia density and morphology and also restores normal mitochondrial function and reverses most of the differentially expressed genes seen in GF microglia [30]. Together, this suggests that SCFAs, and especially acetate, are key mediators through which the microbiome exerts its regulatory effects on microglial function. However, it remains unclear how SCFAs interact with microglia to regulate proliferation and morphology, and to what extent SCFAs other than acetate can rescue microglial perturbations in GF mice.

SCFAs also play a critical role in modulating the microglial inflammatory response through inhibiting histone deacetylase and by targeting the transcription factor NF-κB, a key transcription factor driving pro-inflammatory gene expression. In vitro, SCFAs attenuate the production of pro-inflammatory cytokines and chemokines triggered by LPS-stimulation [34‒38]. Treatment with SCFAs also prevent microglia from adopting an amoeboid morphology associated with heightened inflammatory responses and instead promotes a more ramified, anti-inflammatory state, marked by increased IL-10 expression, decreased phagocytic capacity, and decreased toxicity toward co-cultured neurons [36‒38]. The inhibition of NF-κB nuclear translocation and DNA binding by SCFA treatment provides a direct molecular mechanism in their ability to reduce inflammatory gene expression [34, 35]. Moreover, SCFA-induced histone deacetylase inhibition increases histone acetylation at the Il10 promoter [36] and induces a ramified microglial morphology [37], reinforcing their anti-inflammatory and homeostatic phenotypes.

Consistent with in vitro findings, animal models of SCFA supplementation mirrors these anti-inflammatory and neuroprotective effects. In rodent models of inflammation induced by LPS administration, supplementation with acetate or butyrate causes reduced microglia density, increased ramified morphology, and diminished expression of pro-inflammatory cytokines [37, 39‒41]. The observed SCFA-driven changes in microglial phenotype are accompanied by preservation of cholinergic neuronal populations vulnerable to LPS-stimulation [39] and the mitigation of behavioral deficits, including sickness-induced depressive-like behavior [37, 41]. Indeed, the anti-inflammatory and neuroprotective effects of SCFAs extend to models of neuronal damage and degeneration. In models of ischemic stroke or experimental autoimmune encephalomyelitis (EAE), SCFA supplementation decreases the burden of neuroinflammatory mediators, modulates microglial morphology toward a less reactive phenotype, and ultimately mitigates the extent of CNS damage [36, 42].

Beyond models of significant inflammatory induction in the central nervous system, SCFAs also ameliorate microglial and synaptic alterations in models of chronic low-grade neuroinflammatory states induced by dietary perturbations. In mice consuming a fructose-enriched diet, SCFA supplementation reduces microglial density in the hippocampus and dampens the expression of inflammatory mediators, thereby restoring a more homeostatic neuroimmune environment [43]. Similarly, long-term consumption of a high-fat diet, which induces a state of low-grade chronic neuroinflammation in the hippocampus and prefrontal cortex, is mitigated by butyrate supplementation. In these animals, butyrate attenuates the high-fat diet-induced increases in microglial density in both regions, promotes a ramified microglial morphology, and normalizes spine densities in the prefrontal cortex. These cellular changes further correlate with improved social and anxiety-related behaviors [44].

Dietary interventions that increase endogenous SCFA production also support their role in modulating microglia. High-fiber diets elevate cecal [45] and circulating levels of SCFAs [46], recapitulating the in vivo anti-inflammatory effects observed with direct supplementation. Such diets reduce expression of inflammatory cytokines and increase brain derived neurotrophic factor in the hippocampus of healthy mice [46], as well as attenuate LPS-induced neuroinflammation and social withdrawal [45]. Conversely, fiber-deficient diets increase microglial density in the hippocampus, promote an amoeboid morphology with elevated CD68 and pro-inflammatory cytokine expression, and are associated with synaptic disruptions and cognitive impairment – deficits that are reversed by restoring SCFAs [47]. Taken together, these findings demonstrate that SCFAs are critical for maintaining a balanced neuroimmune environment, modulating neural function, and behavior. This understanding highlights potential dietary and therapeutic strategies to harness SCFAs for promoting homeostatic microglial activity and reducing aberrant neuroinflammation.

Tryptophan is an essential amino acid acquired through the diet, serving as a substrate for protein synthesis and as a precursor for the production of serotonin and melatonin. While most tryptophan is metabolized by the host through the kynurenine pathway to produce kynurenic acid, quinolinic acid, picolinic acid, 3-hydroxykynurenine, and nicotinamide adenine dinucleotide and various intermediates, gut microbes further expand the range of tryptophan metabolites by converting it into an array of indole metabolites. These metabolites are absorbed by the host and reach the brain [31] and are also capable of crossing the placental barrier to reach the fetal brain [48].

Bacterial-derived indole metabolites exert their influence on microglia largely through the aryl hydrocarbon receptor (AhR), a transcription factor expressed in immune cells that modulates inflammatory responses in part by regulating NF-κB signaling [49]. Evidence suggests that bacterial tryptophan metabolites begin influencing microglial activation early in life. In a rodent model of intrauterine growth restriction, adolescent offspring display increased microglial density, an amoeboid microglial morphology, heightened inflammatory cytokine expression, and reduced hippocampal spine density [50]. These neuroimmune and synaptic disruptions correlate with reduced sociability and increased anxiety-like behavior. Notably, hippocampal concentrations of the bacterial-derived tryptophan metabolite indole-3-propionic acid (IPA) are decreased in offspring exposed to intrauterine growth restriction, and IPA supplementation rescues both the behavioral deficits and hippocampal inflammation [50]. These findings underscore the capacity of microbial tryptophan metabolites to shape microglial phenotypes to potentially influence brain function early in life. Still, the precise roles of bacterial indole metabolites in shaping microglial function both in utero and during early postnatal development remain unclear. Moreover, it remains to be determined whether these metabolites can mitigate other inflammatory prenatal insults, such as maternal immune activation or chronic stress. This is particularly important in prenatal stress where the abundance of tryptophan metabolizing bacteria are decreased [51, 52] with supplementation having the potential to increase fetal indole metabolites [53].

Bacterial-derived tryptophan metabolites continue to shape microglia function and behavior into adulthood in healthy mice. The bacterial-derived metabolite indole-3-acetic acid (IAA) can be methylated by the host to produce methyl-IAA, whose serum concentrations correlate with reduced anxiety-like behavior, whereas IAA itself shows no such association [54]. Dietary supplementation with methyl-IAA further supports this observation by decreasing anxiety-like behavior and reducing inflammatory cytokine expression in the prefrontal cortex and hippocampus. However, unlike IAA which can influence immune responses through AhR-dependent mechanisms, methyl-IAA exerts its effects without activating AhR in microglia [54]. This shift from an AhR-dependent to an AhR-independent mechanism underscores how subtle host-driven biochemical alterations can redirect a bacterial metabolite’s immunomodulatory potential, ultimately influencing behavioral outcomes. Elucidating the pathways outside of AhR through which indole metabolites influence microglia is essential for a comprehensive understanding of their immunomodulatory capacity.

Beyond early life and homeostatic contexts, bacterial-derived tryptophan metabolites also attenuate microglial inflammatory responses in models of neurodegeneration. In EAE, conditional AhR knockout in microglia exacerbates disease severity, increasing spinal cord demyelination and enhancing NF-κB nuclear localization, which elevates pro-inflammatory gene expression [55]. Additionally, microglial AhR signaling shapes astrocyte inflammation by modulating the balance between VEGF-B and TGFα signaling. In the absence of microglial AhR, VEGF-B expression is elevated, promoting astrocyte inflammatory responses, whereas the anti-inflammatory mediator TGFα is diminished [55]. Consequently, loss of AhR in microglia not only heightens microglial inflammation but also promotes a more pathological state in astrocytes, contributing to overall disease severity in EAE. The critical role of microbial tryptophan metabolites in AhR-dependent processes is evident from altering their availability through dietary manipulation. EAE animals fed a tryptophan-depleted diet show a similar exacerbation of inflammation that can be reversed by supplementation with the bacterial-dependent tryptophan metabolite indoxyl-3-sulfate (I3S). I3S supplementation has no additional effect in microglial AhR knockout mice [55], confirming its dependence on AhR signaling to mediate its effects.

Additional evidence from neurodegenerative models supports the broader relevance of tryptophan metabolites in regulating microglia. Direct supplementation with IAA or IPA reduces hippocampal microglial density and inflammatory cytokine expression in a mouse model of aging, which is associated with decreased neuronal degeneration [56]. Similarly, supplementing indole-3-lactic acid [57] or a mixture of bacterial-derived indoles [58] in a mouse model of Alzheimer’s disease mitigates microglial pro-inflammatory cytokine expression, ultimately rescuing hippocampal synaptic density and cognitive deficits. Collectively, these findings underscore the versatility and impact of microbial tryptophan metabolites in modulating microglial activity across a range of pathological conditions with the potential to alter the course of disease.

Bile acids are cholesterol-derived molecules produced by the liver to facilitate fat emulsification and absorption in the small intestine. The primary bile acids cholic acid and chenodeoxycholic acid are synthesized in the liver and can be conjugated with taurine or glycine [59]. Although most bile acids are reabsorbed, a small fraction escapes reabsorption and is metabolized by gut bacteria to produce secondary bile acids, which can enter circulation and the CNS [60, 61]. Particular attention has focused on ursodeoxycholic acid (UDCA) and its taurine conjugate tauroursodeoxycholic acid (TUDCA) since UDCA is already approved by the FDA to treat primary biliary cirrhosis [62], and emerging evidence suggests that these molecules may confer neuroprotective benefits against inflammatory conditions.

Studies in a variety of models consistently show UDCA and TUDCA to exert potent anti-inflammatory effects on microglia under pathological conditions. In vitro experiments show that both compounds attenuate nitric oxide production and pro-inflammatory cytokine release (e.g., IL-1β, TNF-α, IFN-γ), and reduce the migratory capacity of microglia exposed to LPS or amyloid beta – all while having little to no effect on these mediators at baseline [63‒66]. Similar findings are reported in vivo, where TUDCA attenuates LPS-induced increases in hippocampal microglial density, inflammatory cytokine expression, as well as iNOS and VCAM-1 expression [65, 67]. Furthermore, TUDCA elevates TGF-β and IL-10 levels, along with the density of ARG1+ microglia in the hippocampus of LPS-stimulated animals [68, 69]. This anti-inflammatory effect extends to other models of heightened neuroinflammation, as TUDCA reduces inflammatory cytokine expression and improves functional outcomes in chronic stress [70], spinal cord injury [66, 71, 72], stroke [61, 73, 74], and neurodegenerative disease models [75‒78], although the direct influence on microglial function in these contexts remains to be elucidated.

Mechanistically, TUDCA’s protective role is tightly linked to its capacity to inhibit NF-κB signaling under inflammatory conditions. This inhibition is initiated by TUDCA binding to the bile acid receptor TGR5 (GPBAR1) in LPS-treated animals, as blockade of TGR5 prevents NF-κB inhibition and the downstream anti-inflammatory effects of TUDCA [69]. Upon ligand activation, TGR5 triggers adenylate cyclase, thereby elevating cAMP levels in microglia. The rise in cAMP is at least partially responsible for suppressing NF-κB activity and promoting an anti-inflammatory phenotype [69]. TUDCA also exerts effects through induction of TGF-β signaling (predominantly TGF-β3), as blocking TGF-β prevents TUDCA-induced attenuation of increased hippocampal microglial density in LPS-treated mice [68]. Collectively, these findings underscore the therapeutic potential of secondary bile acids to modulate microglial function and mitigate neuroinflammation across multiple disease models.

Trimethylamine oxide (TMAO) is generated through gut bacteria metabolizing l-carnitine and choline into trimethylamine, which then enters circulation and is converted by the liver into TMAO. The consistent correlation between serum and brain TMAO levels suggests that TMAO readily crosses the blood-brain barrier, and there is also evidence that it traverses the placental barrier to influence fetal brain development [3]. Circulating TMAO levels rise with age in both humans and mice, independently associating with cognitive decline [79]. In microglia, TMAO stimulation elevates expression of inflammatory markers and increases phagocytosis [80]. Moreover, dietary TMAO supplementation induces cognitive deficits, elevates NF-κB activation, and upregulates inflammatory gene expression in the brain [79]. TMAO also exacerbates neurodegeneration and neuroinflammation in ischemic stroke [81] and in a Parkinson’s disease model [82], further supporting the inflammatory effects of TMAO.

Although the precise mechanisms by which TMAO modulates microglial function remain to be fully elucidated, evidence suggests that activation of the nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a key pathway. The NLRP3 inflammasome is a cytosolic protein complex that detects diverse environmental signals and acts as a convergence point for cellular danger signals, initiating an inflammatory cascade via caspase-1 activation and the subsequent release of IL-1β and IL-18. Studies on TMAO-induced endothelial cell inflammation indicate that mitochondrial reactive oxygen species mediate NLRP3 activation and inflammatory cytokine expression [83, 84], with evidence that NLRP3 is activated by TMAO independently of reactive oxygen species in microglia following ischemic stroke [81].

Beyond TMAO, there are other gut microbiota-derived metabolites that accumulate with age, such as isoamylamine [85] and N⁶-carboxymethyllysine (CML) [28] that also disrupt microglial function. Isoamylamine promotes microglial apoptosis by binding to the S100A8 promoter and recruiting p53, and its supplementation in mice induces cognitive deficits. Conversely, reducing isoamylamine production alleviates age-related cognitive decline, linking its effects on microglia to the cognitive impairments observed in aging [85]. N⁶-CML, unlike TMAO, triggers mitochondrial dysfunction in microglia, increasing reactive oxygen species and reducing ATP levels [28]. The proportion of CML-containing microglia rises with age in both mice and humans, suggesting that CML contributes to the mitochondrial deficits associated with aging microglia. However, this accumulation of CML results from aging-related disruptions in gut permeability dependent on the gut microbiota rather than direct bacterial metabolism. Together, these studies reveal that multiple gut-derived metabolites, including TMAO, CML, and isoamylamine, contribute to the dysregulation of microglial function to promote inflammation and neurodegeneration. However, the roles of these metabolites in shaping microglial activity outside of aging and neurodegenerative contexts remain unclear. Their capacity to perturb microglial function suggests that they could also contribute to the pathophysiology of other conditions linked to microbiota-microglia interactions, including mood and neurodevelopmental disorders.

Despite the significant advances in our understanding of microbiome-microglia interactions, critical knowledge gaps persist. It remains unclear how the microbiome facilitates microglia maturation during development and whether changes in bacterial-derived metabolites can shape microglial regulation of brain development. Similarly, we do not fully understand how differences in these metabolite profiles may either predispose or protect against the development of neurological or psychiatric disorders. A limited understanding of the molecular mechanisms driving the complex interactions between metabolites and microglia, and of how these changes in microglial function directly affect other brain cell types, necessitates future work that moves beyond correlational studies to dissect causal mechanisms and identify critical developmental windows of susceptibility. Unraveling these metabolite-driven pathways and their temporal dynamics may ultimately enable the design of prebiotic, probiotic, and direct metabolite interventions to protect against neurodevelopmental disorders, improve therapeutic outcomes in CNS disorders, and confer resilience against neurodegenerative processes.

Collectively, the existing evidence establishes the microbiome as a critical regulator of microglial development, metabolic homeostasis, and immunomodulatory functions, shaping the brain’s cellular landscape from fetal development into adulthood. Through the production of bioactive metabolites including SCFAs, tryptophan derivatives, secondary bile acids, and inflammatory compounds, the gut microbiota exerts a persistent influence on microglial phenotypes, impacting synaptic refinement, neuronal viability, and neuroinflammatory signaling. These findings highlight that changes in microbiota composition and metabolite availability are closely intertwined with microglial-mediated processes underlying both typical neural development and the pathophysiology of neuropsychiatric and neurodegenerative disorders.

Dr. Michael Bailey is a Scientific Cofounder and owns stock options in Scioto Biosciences. Dr. Michael Bailey was a member of the Journal’s Editorial Board at the time of submission. The remaining authors have no conflicts to declare.

1R01HD116839-01 to MB, 5R01MH129589-03 to TG, and R01MH129589-01 to TG. The funder had no role in the design, data collection, data analysis, and reporting of this study. The remaining authors received no funding.

B.G.V. conceptualized the review, performed the literature review, and wrote the manuscript. M.T.B. edited and reviewed the manuscript; T.L.G. conceptualized, reviewed, and edited the manuscript.