Stress, depression, diet, and the gut microbiota: human–bacteria interactions at the core of psychoneuroimmunology and nutrition

Stress and depression facilitate dysbiosis and a leaky gut

Stress can affect health through its impact on gut bacteria. The autonomic and circulatory systems carry distress signals to the gut. Additionally, a new bone marrowmediated pathway was recently discovered [4], highlighting the role that immune cells play as messengers that convey psychological stress to the gut. The heightened inflammation that frequently accompanies stress and depression triggers blooms of pathogenic bacteria that encourage dysbiosis and a leaky gut [5].

Both chronic and acute stressors can shift the gut bacteria in multiple regions and habitats — both the inside (lumen) and border (mucosal lining) of the gut [6–8]. Rodent research demonstrates that stress can rapidly affect the gut bacteria’s composition [7,9]. Furthermore, an in vitro work shows that catecholamines can elevate certain bacterial levels 10 000-fold and intensify their infectiousness in 14 hours [10]. These pathogenic species may crowd out beneficial species. In line with an early work linking academic stress with immune dysregulation [11], Knowles et al. found that as university students’ stress increased throughout the semester, certain health-promoting bacteria decreased [12]. Even so, people under stress have unpredictable patterns of dysbiosis [13]. Gut bacteria can regulate the immune system, but dysbiosis can increase risk for infection or autoimmune disease [14].

Stress and mood disorders compound one another. Several studies show differences in the gut microbiota’s composition and function in individuals with major depressive disorder, compared to healthy controls. Some data suggest that proinflammatory species can dominate at the expense of health-promoting species in depressed individuals [15]. Comparison of depressed and non-depressed individuals revealed 279 different bacteria-synthesized proteins, primarily related to glucose and amino acid metabolism [16], possible inflammatory correlates.

Stress and depression can increase gut barrier permeability. The result, a ‘leaky gut,’ allows bacteria to seep into circulation, producing an inflammatory response. Indeed, both depression and stress can provoke heightened inflammation [17,18] and gut leakiness [19^••,20]. For example, a troubled marriage is a chronic stressor. Most hostile couples had greater gut permeability than their less hostile counterparts [19^••]. Even a laboratory speech stressor increased intestinal permeability in healthy adults, and subgroup analysis revealed that this effect was only present in those who had elevated cortisol [21]. Along with cortisol, mast cells helped to weaken stressed participants’ gut barriers. Bacteria can leak through the stress-remodeled gut barrier, thereby boosting inflammation — illustrating stress’s multifaceted physiological assault (Figure 1).

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Figure 1

Gut environment’s hypothesized role in psychoneuroimmunology. Depression and stress get under the skin via behavioral and physiological changes, including altered immune function. These adverse changes promote the survival and replication of pathogenic gut bacteria and weaken the gut barrier. Gut dysbiosis itself increases gut permeability, and it may also influence health behaviors like diet. These physiological and behavioral changes can ultimately further dysregulate key stress-responsive systems, including the immune, endocrine, and autonomic nervous systems, thereby fueling the chronicity of depression and stress.

Stress and depression prompt unhealthy food choices and poor metabolic responses

Diet functions as a major pathway from stress to gut dysbiosis. Even mild stressors can encourage unhealthy eating. For example, saturated fat and caloric intake rose on Monday in cities whose NFL football team lost on Sunday, compared to declines in cities whose team won; intake remained stable in those cities whose NFL team did not play, or those without an NFL team. Furthermore, cities with the most committed fans showed the greatest change [22]. Relatedly, in a recent ecological momentary assessment study, emotional eaters’ hedonic, taste-based eating increased with negative emotion [23]. Functional neuroimaging evidence suggests that stress deactivates executive function in response to food cues and elicits a bias toward comfort foods [24]. As discussed below, stress-related microbiota shifts may also impact food cravings.

Stress and depression not only influence food choices, they can also alter metabolic responses to food. Following a fast-food type meal, women who reported prior day stressors had lower fat oxidation, higher insulin, and lower resting energy expenditure than those reporting no prior day stressors — with lower caloric expenditure that could potentially fuel 7–11 pounds of weight gain per year [25^•]. Similarly, women with a history of depression had higher postprandial cortisol and fat oxidation, compared to women without a depression history [25^•]. These kinds of metabolic changes could have downstream effects on the gut microbiota, and the reverse is also possible.

Diet shapes the gut bacteria

Diet has emerged as one of the most powerful predictors of gut bacteria composition — above and beyond one’s genotype [26]. Diet determines which bacteria will thrive in the gut, and the gut bacteria in turn aid digestion. Although long-term diets form the gut community’s structure, dietary modification can produce detectible shifts in some bacterial species within 24 hours [27].

Macronutrient profiles predict unique gut microbiota populations. A recent systematic review highlighted the emerging convergence in the field of nutrition that is facilitated by a focus on macronutrients’ impact on the gut microbiota [28]. Broadly speaking, plant protein, unsaturated fats, and fiber support a pro-health gut microbiota — in contrast to excessive consumption of animal protein, saturated fats, and simple or artificial sugars.

The Western diet, high in saturated fat, processed foods, and refined sugar, starkly contrasts with fiber-rich, plantbased diets of indigenous cultures. The Western diet fosters a distinct gut microbiota signature with low gut microbiota diversity and greater gut leakiness, which may contribute to metabolic syndrome and chronic disease onset [29]. In particular, imbalanced macronutrient intake may be to blame. For instance, low fiber consumption may dysregulate immune function, as short-chain fatty acids (SCFAs) resulting from bacterial fermentation of complex carbohydrates are important for healthy immune function [30].

Likely due in part to the Western diet, 60–70 million Americans suffer from digestive disorders, costing $100 billion annually [31]. Importantly, some digestive medications impact the gut bacteria. For example, proton pump inhibitors (e.g. omeprazole), widely used to treat acid reflux, reduce diversity and affect 20% of species, creating an unhealthy gut microbiota that may predispose to gastrointestinal infection [32]. Indeed, PPIs may negatively impact the gut bacteria population even more so than do antibiotics [32].

The gut bacteria impact food cravings and eating behaviors

The number of bacterial cells in the human body parallels the number of human cells [33], and thus, whether they support or undermine health is of critical importance. In many instances, bacteria are clearly beneficial, but they can also compete with each other as well as their human host for resources. Thus, microbiota diversity ensures that one species’ interests do not eclipse the human’s. However, it has been hypothesized that dysbiosis and low diversity may prompt dysregulated eating behavior in line with the dominant bacterial species’ needs [34].

Mechanistic data support the notion that the gut bacteria influence food choices. The gut bacteria produce molecules that mimic or interfere with human appetite-regulating peptides and hormones [35,36]. Also, the gut bacteria can modify reward pathways [37], communicate with the appetite-modulating vagus nerve [38], and may even influence the expression of taste receptors [39]. Lastly, through their release of neurotransmitters, such as serotonin, acetylcholine, and norepinephrine, the gut bacteria may indirectly influence eating behavior through mood changes [40].

Evidence for this bottom-up pathway from gut bacteria to eating behavior has recently emerged. In the stool samples of healthy adults, specific microbiota abundances tracked with eating behaviors, including eating frequency and overnight-fast duration [41^••]. Targeted delivery of a bacteria-produced SCFA, propionate, to the colon over 24 weeks reduced meal size, weight gain, belly fat, and increased postprandial satiety signals, but did not reduce subjective appetite in overweight adults [42]. Thus, there is accumulating evidence that the gut bacteria and their products affect appetite.

Diet modulates stress reactivity and depression

Clinical investigation of the role of macronutrient intake in stress reactivity remains largely inconclusive. Much of the relevant research is cross-sectional, assessing stress levels and food consumption at a single time point. An exception: following a dietary intervention, in which women were assigned to drink either sugar-sweetened or aspartame-sweetened beverages three times a day for two weeks, sugar consumption was associated with higher activity in the left hippocampus and reduced cortisol in response to stress [43]. If sugar indeed attenuates physiological stress responding, stressed individuals may preferentially consume sugar. In contrast, fat intake may enhance stress reactivity; healthy, normotensive individuals had greater cardiovascular reactivity to stress following a high-fat meal than they did after a low-fat meal [44].

Healthier diets can reduce the risk of depression. A metaanalysis showed that adherence to high-quality diets such as the Mediterranean diet was associated with a lower risk of depressive symptoms over time [45]. Inflammation elevates risk for depression, and the Mediterranean diet’s anti-inflammatory benefits have been demonstrated across multiple studies [46,47]. Mounting evidence suggests that these anti-inflammatory effects are mediated by the microbiome. Although multiple components of the Mediterranean diet have synergistic effects on inflammation, high dietary fiber and low levels of saturated fat sculpt the gut microbiota’s composition and its production of metabolites that reinforce the gut barrier [46–48]. Thus, fewer gut bacteria leak into the bloodstream, lessening inflammatory burden and depression risk.

The gut microbiota can influence stress reactivity and mood

Through their communication with the vagus nerve and neurotransmitter release, the gut microbiota may play a role in stress responding. In a functional neuroimaging study of 40 women, certain bacterial profiles tracked with patterns of brain activation following exposure to emotional stimuli [48]. Randomized controlled trials featuring probiotics suggest a causal link between the gut microbiota and stress responding. Probiotic supplementation improved sleep, autonomic balance, and bowel habits and reduced stress and cortisol levels in Japanese medical students [49]. Moreover, after one month of drinking a probiotic-containing fermented milk product, healthy women had less activity in emotion and sensation brain loci when exposed to emotional stimuli [50^••].

Relatedly, the gut microbiota may contribute to depressive symptoms. In an elegant experimental design, the transfer of fecal matter from depressed humans to microbe-depleted rats induced depressive-like behavior in the rats [51]. Moreover, a large epidemiological study in the United Kingdom revealed that one course of antibiotics, which reliably destabilize the gut microbiota, increased risk for anxiety or depression by about 20%, while multiple courses increased risk by almost 50% [52]. Antibiotic use may program a new ‘set point’ of gut bacteria that is relatively stable — even though it may facilitate poorer mental and physical health [53]. In contrast, probiotic supplementation may reduce inflammation [54] and have positive effects on depression, anxiety, and stress, although some studies have not found this effect [55].

Work on this project was supported in part by National Institutes of Health grants CA172296, CA186251, CA186720, and AG057032.