Stressed to the Core: Inflammation and Intestinal Permeability Link Stress-Related Gut Microbiota Shifts to Mental Health Outcomes

Abstract

Stress levels are surging, alongside the incidence of stress-related psychiatric disorders. Perhaps a related phenomenon, especially in urban areas, the human gut contains fewer bacterial species than ever before. Although the functional implications of this absence is unclear, one consequence may be reduced stress resilience. Preclinical and clinical evidence has shown how stress exposure can alter the gut microbiota and their metabolites, affecting host physiology. Also, stress-related shifts in the gut microbiota jeopardize tight junctions of the gut barrier. In this context, bacteria and bacterial products can translocate from the gut to the bloodstream, lymph nodes, and other organs, thereby modifying systemic inflammatory responses. Heightened circulating inflammation can be an etiological factor in stress-related psychiatric disorders, including some cases of depression. In this review, we detail preclinical and clinical evidence that traces these brain-to-gut-to-brain pathways that underlie stress-related psychiatric disorders and potentially affect their responsivity to conventional psychiatric medications. We also review evidence for interventions that modulate the gut microbiota (e.g., antibiotics, probiotics, prebiotics) to reduce stress responses and psychiatric symptoms. Lastly, we discuss challenges to translation and opportunities for innovations that could impact future psychiatric clinical practice.

Introduction: Stress and Stress-Related Psychiatric Disorders

Worldwide, perceived stress continues to tick higher and higher, setting new records (1). Stress is inevitable, and therefore resilience is critical. Chronic and repetitive stressors increase the likelihood of psychiatric disorder onset in susceptible individuals, and yet many people successfully adapt to ongoing stressors (2). There are many reasons why people are unable to adapt, and for those who cannot adapt, psychiatric disorders can generate more stressors (e.g., conflict with people who do not understand the disorder) and can prolong the stressor’s psychological and physiological impact via anticipatory worry or post-event rumination (3–5) – core cognitive features of anxiety and depression. Although prior research conceptualized and measured stress differently, chronic or repetitive stressors that accumulate and uniquely interact with the individual’s context or history are most psychologically and physiologically detrimental (6). The stress response system, including the sympathetic-adrenal medullary (SAM) and hypothalamic-pituitary adrenal (HPA) axes, facilitates a functional response to time-limited threats that require a physical response (i.e., the classic fight-or-flight response), but the same response is potentially detrimental when the stressor is long-lasting and does not require a physical response. Stress-responsive systems are dysregulated in psychiatric disorders and may be possible etiological factors (7).

Both acute and chronic stress impact the immune system, which, over time, can result in psychological and behavioral changes. In humans, a 20-minute speech stressor increased inflammatory and antiviral gene expression via beta-adrenergic signaling (8). In contrast, chronic stress tracks with upregulated proinflammatory and downregulated anti-viral gene expression (9). Acute inflammatory rises can provoke a plethora of sickness behaviors – such as anhedonia, lack of appetite, and fatigue – paralleling depression symptoms (10). Indeed, higher basal inflammation may set the stage for depression, and vice versa (11). The transition from acute to chronic stress is not entirely clear (12), but acute stress that is repetitive may not allow for full recovery.

Social threats, especially those involving conflict, may be some of the most potent stressors (13). In humans, a speech for a panel of judges is a leading stress paradigm due to reproducible, steep endocrine and cytokine responses (14). We recently reported that those who had heightened inflammatory responses to this social-evaluative stressor had the greatest depressive symptom increases over time, especially if they reported frequent social stress in their daily lives (15). Although exaggerated inflammatory responses likely promoted survival during stressful situations throughout evolution, they are perhaps unnecessary and depressogenic in modern populations (16). Indeed, at least 25% of depression cases feature clinically elevated inflammation, evidenced by C-reactive protein (CRP, an acute phase protein produced during inflammation) of >3mg/L (17), with evidence of an anhedonia-prominent immune-mediated depression subtype (18). Moreover, circulating inflammatory markers have moderate to strong relationships with central nervous system (CNS) inflammatory markers in depressed patients (19). Although we primarily focus on depression in this review, stress and inflammation are also risk factors for the onset of other psychiatric disorders (e.g., schizophrenia) (20).

Failure to account for immune dysfunction as an etiological factor in some cases of depression may partially explain the high rates of treatment-resistant depression (21). Recognizing this etiological factor has led to novel therapeutic strategies, such as tumor necrosis factor-α antagonists for treatment-resistant depression, which are effective among those with elevated baseline inflammation (22). However, a newer frontier of immunopsychiatry involves the manipulation of the gut microbiota – comprised of fungi, archaea, viruses, yeast, and bacteria, the latter of which has received the most focus. The gut microbiota shape, and are shaped by immune function and psychological states (23). Emerging evidence implicates inflammation – locally in the gastrointestinal mucosa as well as systemically – and reduced integrity of the gut’s epithelial and mucosal lining (i.e., intestinal permeability, gut leakiness) as primary culprits connecting stress-induced gut microbiota shifts to psychiatric symptoms. In the Supplemental Material, we outline foundational stress-responsive pathways linking the gut, brain, and immune systems; the vagus nerve is particularly notable for its importance in both upstream and downstream signaling. Here we review key translational findings, first among animals and then humans, that (1) psychological stress impacts the gut microbiota, gut barrier integrity, metabolites, and systemic inflammation; and (2) these stress-related consequences contribute to poorer mental health.

Preclinical Findings: Downstream Effects from the Brain to the Gut

Over fifty years ago, stress’s effect on the gut microbiota emerged with the observation that rehoused mice had a lower abundance of beneficial Lactobacillus (24). Later, ex vivo and in vivo experiments demonstrated that stress hormones, particularly noradrenaline, could stimulate the growth of pathogenic bacteria (e.g., Escherichia coli) (25,26) and enhance adherence to mucosal tissue (27). One of the first systematic, culture-based in vivo studies investigated why infant rhesus monkeys often developed diarrhea after being weaned from their mothers (28). Infants showed significant declines in Lactobacillus three days after maternal separation. However, Lactobacillus abundance returned to baseline at the end of the week—an early indication of the microbiota’s resilience observed in other animal and human studies(29,30). Although this drop was not correlated with cortisol secretion, it was related to a more stressed behavioral phenotype, which itself predicted a higher risk of opportunistic infections (28). Lactobacillus reduction during stress is often reported in the literature, and it is consequential for immune function (31,32).

Subsequent research showed that stress could even affect the gut microbiota across generations. For example, in a culture-based study, an acoustic startle paradigm (10 minutes per day with three bursts of noise, five days per week for six weeks) led to lower abundances of Lactobacillus and Bifidobacterium in infants of prenatally-stressed rhesus monkey mothers versus non-stressed mothers for six months after birth (33). Again, there was a greater incidence of opportunistic microbial infection among infants of prenatally stressed mothers (40%) compared to those of non-stressed mothers (0%). These intergenerational stress effects on the gut microbiota, which have been replicated using more advanced 16S rRNA gene sequencing, may influence offspring colonic innervation and motility, HPA-axis stress responses, social behavior in males, and anxiety-like behavior in females (34–36). Intriguingly, germ-free mice that were separated from their mothers earlier in development, showed anxiety- and depressive-like behavior when their gut microbiome was reconstituted in adulthood. Importantly, anxiety- or depressive-like behavior did not develop after colonizing adult germ-free mice that were not separated from their mothers during development (37); thus, maternal separation may induce an intestinal environment that is more conducive to the growth or activity of bacteria associated with depression and anxiety. We discuss whether gut microbiota composition can be a biomarker of stress in the Supplemental Material.

Stress not only affects bacterial communities in the interior lumen of the intestine, but also in communities that are more closely associated with mucosal tissue. In mice exposed to a single two-hour social disruption (i.e., a dominant male intruder into a pre-established social cohort), diversity and relative abundances of mucosa-associated bacteria in the genera Parabacteroides and Lactobacillus, including L. reuteri, declined (38). These differences in mucosa-associated bacteria appear to be more consistent than differences in luminal bacteria, since exposure to a prolonged restraint stressor also affected mucosa-associated, but not luminal, diversity and Lactobacillus abundance (39).

These stress-induced alterations in the microbiome were accompanied by upregulated intestinal epithelial cell antimicrobial, proinflammatory, pro-oxidative gene expression (40). This is a common host response to bacterial contact with the intestinal epithelium. Indeed, in situ hybridization and a lectin-based mucus stain, showed that social defeat stress reduces the mucus barrier allowing bacteria to come into close contact with the epithelium (40,41). Reductions in intestinal mucus, and bacterial contact with the epithelium can lead to the translocation of intestinal bacteria (and bacterial products) to the interior of the body where they can exacerbate intestinal inflammation and/or trigger inflammatory responses throughout the body. The ensuing inflammatory response, which is often a low-grade inflammatory response, disrupts host physiology, including brain physiology, and is likely a key mechanism by which the gut microbiota can impact the brain and behavior responses to stress (41).

Translation to Humans: Downstream Effects from the Brain to the Gut

One of the first indications of brain-gut interactions in humans came from the clinical observation that stress seemed to trigger inflammatory bowel disease (IBD) flare-ups (42). Prospective evidence later showed that perceived stress, negative affect, and major life events, and not NSAIDs, antibiotics, or infections, predicted IBD flare-ups (43). Stress plays a major role in functional gastrointestinal disorders as well (44). Intestinal permeability¹, low-grade systemic inflammation, and most notably mucosal inflammation characterize IBD, and intestinal epithelial cell shedding may foreshadow relapse (46). In one study, UC and Crohn’s disease patients had disproportionate abundance (up to 100-fold higher than healthy controls) of certain mucolytic bacteria (47). Psychological states are connected with these gastrointestinal manifestations: Compared to IBD patients without anxiety, depression, or high perceived stress, distressed patients have lower gut microbiota richness and diversity, as well as higher levels of potentially pathogenic bacteria (e.g., the genera Enterococcus, Streptococcus) and lower levels of beneficial microbes (e.g., Bifidobacterium) (48–50). Interestingly, transferring the gut microbiota of IBD patients with depression to specific pathogen free mice caused more severe colitis, endotoxin in the bloodstream, and depressive-like behavior, compared to those who received the microbiota of IBD patients without depression (49), showing that the gut microbiota play a central role in comorbid IBD and depression. In a multi-omics study of patients with ulcerative colitis, not only were distressed patients’ gut microbiota less diverse and rich, but microbiome differences were related to bile acid profiles and immune function (48). This correspondence between the gut microbiota and metabolome evident among mice (51) was also evident in another human IBD sample, which also showed differences in the metabolome related to bile acid secretion (52). Bile acids play a large role in shaping the gut microbiome (53), thus stress-associated alterations in bile acid profiles may have important effects on microbial community composition.

Even among healthy people, stress is associated with changes in the gut environment. To date, most human studies show non-experimental brain-to-gut associations – at best longitudinally. One line of research involved military-related stressors that are mostly physical in nature (e.g., four weeks of combat training) (54–56). These studies generally show increases in inflammation, gastrointestinal symptoms, stress, anxiety, depression, intestinal permeability, and even blood-brain-barrier (BBB) permeability in response to short-term military training (54–56). In one study, intestinal permeability increased in tandem with markers of inflammation, changes in gut microbiota composition, and metabolism following an extreme four-day hike through the Arctic (54). It is difficult to tease apart the unique roles of psychological versus physical stress in these studies because soldiers report heightened stress, anxiety, and depressive symptoms during these physical stressors; yet, those who report more gastrointestinal symptoms report the most distress during the physical challenge (55).

Outside the military paradigm, undergraduates’ levels of certain lactic acid-producing bacteria, such as Lactobacillus, decreased as academic stress mounted toward the end of the semester (57). Also, maternal prenatal stress tracks with offspring gut microbiota composition (58), similarly to animal studies (28). Although we are unaware of head-to-head comparisons between different stressor types and their effects on the gut-brain axis, early life stress and trauma, especially in relation to attachment figures, may canalize unhealthier trajectories because the microbiome is intimately involved in brain development (59). Interestingly, stressor-induced changes in the microbiome may be offset by parasympathetic activity. A recent report found that parasympathetic activity, as indexed by heart rate variability – indicative of vagal tone – was positively associated with human gut microbiota diversity and composition in women (60). Health behaviors and social relationships also affect the gut-brain axis (Supplemental Material).

Intestinal permeability, and associated translocation of bacteria or bacterial products, has emerged as a common finding in stress studies that assess the brain-gut axis. In addition to observational studies reviewed in the Supplemental Material, a handful of human studies have manipulated stress and measured intestinal permeability. For example, after immersing their hands in cold water, healthy women with moderate life stress, but not low stress, were more distressed, had decreased epithelial secretory ability, and greater intestinal permeability; however, there were no differences in the autonomic or hormonal response (61). A follow-up study showed that cold stress-induced intestinal permeability may be specific to women (62). In a more ecologically valid paradigm, healthy undergraduates who had significant salivary cortisol increases when they presented a bachelors or master’s thesis to an examination committee showed significant increases in intestinal permeability in a mast cell-dependent manner (63). This effect could be mimicked by administering corticotropin-releasing hormone (63), translating rodent findings of the centrality of mast cells and stress hormones in stress-induced gut leakiness (64–67).

Preclinical Evidence: Upstream Effects from the Gut to the Brain

Early findings that stress can alter gut bacteria led to studies examining whether these effects are bi-directional (i.e., whether gut bacteria could affect the stress response). Observations in germ-free mice helped to identify the importance of gut microbes for stress and anxiety. Compared to their conventional counterparts, germ-free mice have lower levels of anxiety-like behavior in basal conditions and following acute stress, even though they have exaggerated HPA-axis stress responses (68–71). Reconstitution with Bifidobacterium infantis can normalize, whereas Escherichia coli can enhance, plasma adrenocorticotropic hormone and corticosterone responses (68). However, reconstitution is not able to restore all aspects of CNS neurotransmission. For example, hippocampal serotonin remained low after recolonization even though serotonin is influenced by the gut microbiota and serotonin’s precursor tryptophan returned to baseline in the periphery of reconstituted mice (69). Other research also shows a tryptophan-serotonin imbalance in germ-free mice (51), illustrating the important role of gut bacteria in tryptophan metabolism and serotonin homeostasis. In addition, gut bacteria shape the adrenal and pituitary gland’s stress response, attenuating genetic expression of a glucocorticoid receptor sensitivity modulator in the pituitary and of steroidogenesis and catecholamine synthesis in the adrenal gland (72).

Germ-free mice have also been useful for illustrating the impact that stress-induced changes to the microbiome can have on host physiology. For example, compared to dominant mice, submissive mice have significantly lower gut microbiota diversity, a different bacterial composition, lower body weight, less white adipose tissue, and greater inflammation (73). When the submissive microbiome was transplanted into germ-free mice, recipients developed the submissive behavioral profile (i.e., anti-social, depressive-like behavior) and physiological phenotype (e.g., smaller adipocytes). One step further, on the cusp of translational research were the findings by Kelly et al. showing that transferring gut microbiota from depressed humans, which were less diverse than that of non-depressed humans, to germ-free mice initiated depressive-like behavior (74), confirming the behavioral impact of the microbiome.

The mechanisms by which the microbiome may impact behavior during stress are complex and multifactorial but can involve the immune system. In mice, repeated social defeat leads to anxiety-like behavior and cognitive deficits, which are dependent upon immune activation (75). Neuronal release of interleukin (IL)-1β leads to microglial activation and subsequent recruitment of inflammatory monocytes to the brain (75). We have found social defeat fails to increase inflammatory cytokines, as well as hippocampal neuronal and microglial activation, when mice are treated with an antibiotic cocktail to affect the microbiota (41). Social defeat led to mucus depletion and increased lipopolysaccharide (LPS) binding protein (LBP) (41), which can occur when intestinal bacteria (or bacterial components like LPS) translocate from the intestinal lumen to the interior of the body through a leaky gut. LBP binding to CD14, a receptor on the surface of leukocytes which leads to increased inflammatory cytokines, was necessary for social defeat-induced increases in hippocampal neuronal and microglial activation (41). Although this study focused on the dorsal hippocampus, others have found that the microbiota from stressed mice drive increases in Il-1β in the ventral hippocampus and increased depressive-like behavior (76). These studies illustrate that during stress, the microbiota contribute to hippocampal neuroinflammation related to anxiety and depressive-like behavior.

Findings that the microbiota contribute to stressor-induced behavioral changes have led to translational studies testing whether targeting the microbiome can improve behavioral responses. Pre-stress gut microbiota modulation via probiotics, prebiotics, and antibiotics can alter the behavioral response to stress, including stress resilience. In mice exposed to chronic social defeat stress, about one-third are resilient (i.e., do not develop depressive-like behavior). These resilient mice have higher abundances of Bifidobacterium compared to non-resilient mice. Interestingly, Bifidobacterium supplementation leads to increased resilience (77). Multiple studies have demonstrated that pre-stress antibiotic treatment can block stress-related depressive- and anxiety-like behavior (78,79). Similarly, prebiotic fiber can modify behavioral responses to stress. Among male mice, three weeks of fructooligosaccharide and galactooligosaccharide supplementation increased short-chain fatty acid (SCFA) concentration, boosted serotonin levels in the prefrontal cortex, changed gene expression in the hippocampus and hypothalamus, and reduced chronic social stress-related increases in glucocorticoids and depressive- and anxiety-like behavior (80). Human milk oligosaccharides have also been tested in mice, and after two weeks of supplementation, the colonic mucosa-associated microbiota community structure was resilient to social disruption stress. Consistent with this observation, the supplemented mice had normalized anxiety-like behavior and even improved neuronal maturation in the dentate gyrus (81) – a brain structure implicated in depression and anxiety. See (82) for a comprehensive review of probiotic and prebiotic supplementation.

Translation to Humans: Upstream Effects from the Gut to Brain

It is now well recognized that gut microbiota and metabolites are associated with human mood and behavioral differences. For example, in a gut microbiome-wide association study of depressive symptoms, developed with the Rotterdam Study cohort (N=1,054) and validated in the Amsterdam HELIUS cohort (N=1,539), not only was microbiota diversity lower, but depressed individuals had significantly different abundances of bacteria that synthesize glutamate, butyrate, serotonin, and GABA, compared to healthy controls (83). Indeed, evidence has accumulated that key features of the metabolome, including pathways involved in neurotransmission, glutamatergic and energy metabolism, reliably distinguish patients with unipolar and bipolar depression from each other and from healthy controls (84). These depression-related metabolome signatures interact with the immune system. For example, glutamate via NMDA receptors can increase neuronal proinflammatory cytokine expression (85), and SCFAs like butyrate dampen inflammatory responses (86).

Perhaps not surprisingly, findings that the microbiome is associated with mood have led to studies testing whether probiotics and prebiotics can improve mood. Multiple meta-analyses suggest that probiotic administration, especially multispecies supplementation, may modestly reduce depressive symptoms among those with mild to moderate depression, but not among healthy people (87,88). However, despite supportive animal studies, to date, the evidence is not strong for probiotic anxiolytic effects in humans (89–91). The reasons for the discrepant findings are not exactly clear, but the laboratory animal microbiome is significantly different than the human microbiome (92). Thus, microbiome contributions to probiotic beneficial effects likely differ in laboratory animals and humans. Moreover, probiotic dosing in laboratory animals is often similar to dosing used in humans, even though laboratory animals are much smaller (93). Fewer studies have focused on prebiotics, but when pooling effects from the small number of extant human studies – most of them not psychiatric samples – there is not overwhelming support for the idea that prebiotics can improve clinical depression or anxiety (94).

Probiotics, prebiotics, or synbiotics (the combination of probiotics and prebiotics) may have more beneficial effects when administered as adjunctive treatments to conventional medication (e.g., SSRIs). The small number of trials to date have shown that these interventions are more effective than first-line treatment alone or with placebo in generalized anxiety disorder and major depressive disorder (95). In contrast, adjunctive probiotic treatment increased tolerability of first-line treatments in schizophrenia but had no effect on clinical outcomes (95). Interestingly, a recent meta-analysis of three randomized, placebo-controlled trials in humans showed that the tetracycline antibiotic minocycline reduced depressive symptoms (effect size = −0.78) (96); however, it is not yet clear whether shifts in the gut microbiota mediate this antidepressant effect, as minocycline easily crosses the BBB and reduces the proinflammatory potential of microglia (97).

There is accumulating evidence that gut leakiness is evident in stress-related psychiatric disorders. Several cross-sectional studies have found evidence for greater intestinal permeability among depressed patients, compared to healthy controls (98–101). In fact, intestinal permeability may be especially elevated in persistent and severe depression (100,102). Further, metagenome sequencing showed that anxious and depressed patients have increased abundance of bacterial genes related to mucus degradation, as well as endotoxin biosynthesis, compared to their peers without a psychiatric disorder (98). Gut leakiness, however, may not be unique to depression: Meta-analytic evidence indicates that a wide range of leaky gut markers are higher among those with severe mental illness and chronic fatigue, compared to healthy controls, and that these markers positively track with sickness behaviors (103). Thus, intestinal permeability may be a transdiagnostic risk factor for sickness behaviors. In terms of prospective risk, we found that LBP predicted depressive symptoms one and two years later among 315 women, but the reverse relationship was non-significant. Leaky gut’s relationship with future depressive symptoms was particularly strong among those with high levels of circulating inflammation at baseline (104), indicating that gut leakiness could be a unique risk factor for development of inflammation-driven depressive symptoms.

There are a few notable studies for administering probiotics to healthy humans, manipulating stress exposure, and measuring resultant gut leakiness as well as self-reported and physiological stress. In one small, randomized double-blind, placebo-controlled trial, healthy young males and females who received twice-daily Lactobacillus rhamnosus milk for one month prior to a thesis defense showed lower intestinal permeability, anxiety, and perceived stress in comparison to individuals that received acidified milk as a control. Interestingly, there were no differences in cortisol, suggesting the probiotics may affect permeability independently from effects on the endocrine response to stress (105). These results contrast with another RCT among healthy young males, which showed that eight weeks of L. rhamnosus did not impact mood, anxiety, stress, sleep quality, cognitive performance, inflammation, or salivary cortisol responses to a socially-evaluated cold pressor test (106). This lack of effects in males suggest that future work should examine sex as a potential moderator. Additionally, probiotic strain specificity is critical, as there is considerable variability.

Conclusion

Preclinical and clinical evidence demonstrate that chronic and repetitive stressors – particularly social stressors — reduce the diversity and the relative abundance of beneficial bacteria in the intestine. These stressors also lead to altered metabolomic profiles that are associated with dysregulation of whole-body energy dynamics, greater intestinal permeability and translocation of bacteria and bacterial products across the gut barrier, and enhanced mucosal and circulating inflammation. The heightened circulating inflammation is particularly relevant for stress-related psychiatric disorders, which often coincide with enhanced inflammatory responses. Thus, targeting the gut microbiota is a promising approach to promote physiological stress resilience that may in turn foster psychological resilience and reduce the incidence of stress-related psychiatric disorders.

That said, experimental evidence in humans is nascent, and there are several challenges to translating preclinical findings. It is currently not clear what constitutes a healthy human gut microbiome, as it is highly variable between individuals (107,108), and many microbial genes and functions are not yet characterized (109). In addition, the type and “dose” of stress exposure that affects the gut microbiota remains unclear, as preclinical stress paradigms (e.g., social defeat) do not precisely parallel clinical stress paradigms. Moreover, during stressful periods, human dietary patterns change and it is difficult to account for dietary variation in humans when stressed (unlike preclinical studies utilizing standardized chow). Finally, there are substantial cross-cultural differences in human physiological responses to stress (110), which deserve further consideration in the gut-brain axis literature as most studies have focused on Western populations. The Supplemental Material outlines future directions.

Overall, the gut microbiota is a critical element in stress-related psychiatric disorders, as microbial genes in the human body outnumber human genes by 150-fold(111). The prevalence of psychiatric disorders that do not respond to conventional treatments calls for a more nuanced and in-depth understanding into how peripheral physiology, including non-human cells in the gut, may drive certain psychiatric symptoms and treatment responses in the context of stress.

Figure 1.

Stress-related changes in the gut affect the immune system, peripheral organs, and brain. (A) Psychological stress has downstream consequences for the gut (e.g., communicated via the vagus nerve [depicted in yellow] hypothalamic-pituitary adrenal [HPA] axis, and sympathetic nervous system). Notably, environmental stress, such as lower environmental biodiversity and poor dietary habits, can directly impact the gut. (B) During stress, the relative abundance of beneficial bacteria in the lumen often decrease, as does overall richness and diversity. Mucosal mast cell degranulation can damage the epithelial cell lining and compromise barrier integrity. (C) Gut bacteria and bacterial products (like lipopolysaccharide) can then translocate into the bloodstream, spleen, and lymph nodes (lymphatic system depicted in green), priming monocytes and triggering a systemic inflammatory response. (D) Higher levels of peripheral inflammation can also affect blood brain barrier permeability and increase neuroinflammation. These stress-related physiological changes can, in turn, enhance the harmful effects of subsequent stressors, decrease resilience, and heighten risk for psychiatric disorders.