Nutritional psychoneuroimmunology: Is the inflammasome a critical convergence point for stress and nutritional dysregulation?

Abstract

Psychoneuroimmunology (PNI) aims to elucidate mechanisms by which the immune system can influence behavior. Given the complexity of the brain, studies using inbred rodents have shed critical insight into the presumed vagaries of the human condition. This is particularly true for stress modeling where adverse stimuli, conditions and/or interactions elicit patterned behavioral reactions that can translate across species. As example, sickness behaviors are as easily recognized in mice as they are in humans, and a family pet. Recently, nutrition has gained prominence as a regulator of brain function. Once perceived as mostly a peripheral player, except when manifest at extremes like starvation or gluttony, nutritional and/or metabolic stress is now recognized as a worrisome contributor to poor mental health especially in those who suffer from food insecurity or overnutrition. In this review, we will explore emerging areas of rodent research that demonstrate the impact of nutritional status on the stressed brain. Our overall goal is to implicate inflammasome activation as a critical convergence point for stress and nutritional dysregulation. In doing so, we will present results from studies focused on macronutrient, micronutrient and dietary bioactives so as to encourage innovative investigation into the emerging field of nutritional PNI.

Introduction

A dysregulated nutritional and/or metabolic status negatively impacts almost all types of illness [1] and can tip an otherwise stable patient into a confusional or demented state [2]. While correlational studies show that an extensive list of foodstuff appear to impact brain function [3], specific pathways delineating how nutrients mechanistically regulate behavior are, for the most part, lacking. Stress whether physical, mental or emotional is generally bad for health [4]. Rodent models are particularly adept at revealing the consequences of stress because most rodent-based research employs inbreed strains of mice that generally subsist in standardized microcommunities that inherently limit genetic and epigenetic variation. Therefore, the study of behavior and nutritional status are inherently simplified given the consistency of elicited responses. Nutritional stress is generally defined as times in which creatures go hungry [5]. However this unidirectional definition appears to underappreciate the stressful consequences of overnutrition [6] and the salutary effects of fasting [7]. Given that stress commonly changes food intake, stress and nutrition are intrinsically linked, yet whether this metaphorical quid pro quo is adaptive or maladaptive is shockingly uncertain. Even the age old proverb feed a cold, starve a fever remains an enigmatic scientific conundrum that continues to be researched nearly half a millennium from its purported coining [8]. Since feeding behavior is crucial to organismal survival, elucidating brain-based pathways common to both food intake and stress should likely aid in the mechanistic understanding of some of our most difficult to treat health issues namely mental illness and addiction. As such, the discovery that what is eaten can influence the immune system vis-a-vis the inflammasome [9] provides a critical nexus point for nutrient to brain communication.

Macronutrients

The discovery that overnutrition and its consequence, metabolic stress, can activate the immune system [10] provided a logical framework to extend the we are what we eat concept from physical health to mental health. PNI researchers had already discerned that proinflammatory cytokines, especially tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) generated during infectious illness, are responsible for most of the sickness symptoms observed [11]. Identification that IL-1β maturing inflammasomes are sensors of non-infectious danger signals that can be triggered by macronutrients like free fatty acids (FFAs) conceptually-solidified foodstuff-associated immune system activation, particularly with regard to innate immunity [9]. Finally, more recent realization that the ligand-binding component of inflammasomes, i.e. NOD-like receptors (NLRs), are generously distributed throughout cells types of the CNS (including neurons) [12], made practical the theory that nutrients can commutate directly with the brain and that this communication can alter behavior. Not surprisingly, the effect of obesogenic diets on the brain and behavior are now aggressively explored.

Obesogenic diets used in rodent research often contain 60% kcal from fat. Mice fed such high fat diets (HFDs) for 12 weeks exhibit anxiety- and depressive-like behaviors [13]. When these animals are exposed to restraint stress, they show a much greater corticosterone response than control mice a fed low-fat diet (LFDs) [13]. These results illustrate a connection between macronutrient composition and behavior along with a logical causative pathway, dysregulation within the sympatho-adrenomeduallary (SAM) axis. In addition to acute stress like restraint, HFDs also interact with experimental chronic mild stressor paradigms. These mice tend to demonstrate profound depressive-like behavior, and very poor Morris water maze performance indicative of significant hippocampal dysfunction [14]. At lower levels of dietary lipid, such as the “Western style” diet equivalent of 45% kcal from fat, mouse memory is impaired [15]. Furthermore, layered on pressures like “intruder” stress prior to behavioral testing additionally worsens memory performance [15]. HFD feeding even exerts intergenerational effects on behavior through epigenetic programming. Mice born to dams fed a HFD show markedly worse behavioral responses to chronic unpredictable mild stress (CUMS), exhibiting increased anxiety-like and depressive-like behavior [16]. These behavioral interactions are also apparent when treatments are reversed, that is, dams are stressed via the dexamethasone administration and offspring are fed a HFD [17].

In general, overnutrition appears detrimental to mental performance in that high carbohydrate diets (66% kcal from sugar) can impair memory and increases anxiety-like and depressive-like behaviors [18]. Fructose appears especially problematic, as it prompts behavioral deficits akin to psychological stress [19]. The propensity for calorie-rich diets to adversely impact brain function suggests that systemic energy homeostasis is tightly intertwined with mental health. Additional support for this hypothesis is seen in studies where energy intake is curtailed. As example, acute fasting reduces trait anxiety-like behaviors and improves learning in some strains of mice [20]. Importantly, rodent models that pattern human cognitive decline secondary to aging or type 2 diabetes show amelioration with calorie restriction [21]. Ketosis, an essential element of the starvation response, induced by feeding specialized diets, improves learning and reduce anxiety-like behavior caused by once-daily exposure to variable stressors [22].

Micronutrients & Dietary Bioactives

Micronutrients frequently denoted as vitamins and minerals are critical to organismal health, but they are usually required and/or available to body in low concentrations. Vitamin B deficiencies have well-known neurological consequences that can be quite deleterious, but only recently has the supplementation of such vitamins during stress shown potential as a therapeutic. Specifically, supplementation of thiamine (vitamin B1) improves learning in contextual and avoidance-based tasks degraded by predator stress [23] while improving spatial memory and brain BDNF levels after repeat bouts of immobilization [24]. Vitamin B6, in turn, extinguishes dexamethasone-induced depressive-like behaviors if administered as a pretreatment [25]. Vitamins B9 and B12 also mitigate depressive-like behaviors if instigated by maternal separation [26] or CUMS [27]. Likewise, folate lessens depressive-like behaviors and restores locomotor deficits triggered through restraint stress [28] and corticosterone administration [29]. Interestingly, folate and vitamins B9/12 promote methyl donation which is important in epigenetic regulation. Hence, vitamin-dependent differential gene expression may be an important mechanism by which foodstuff communicates with the brain. Finally, vitamin D appears important to stress responses because its deficiency exacerbates depressive-like behaviors secondary to CUMS, social separation and social defeat [30,31].

Food-derived bioactives are seen by some as mystical restoratives and by others as this century’s “snake oil”. Recently, some polyphenols and flavonoids appear to modulate rodent stress with epigallocatechin gallate (EGCG) from tea and hyperoside from St. John’s Wort protecting against chronic mild stress-induced memory-impairment and depressive-like behaviors [32,33]. Herb/spice-derived bioactives including capsaicin and curcumin [34] appear pro-cognitive and anti-depressive [35] with curcumin likely mitigating memory/learning impairments via its anti-inflammatory properties in the brain [36]. Caffeine, on the other hand, is clearly a food-derived bioactive with a delineated impact on mental health especially in regard to neurodegeneration [37]. Although most effective at pharmacologic doses as a pan-adenosine receptor antagonist where it inhibits adenosine-dependent activation of caspase-1 in the brain and memory impairment caused by oxidative stress [38], it has also been added to Western style diets to prevent memory impairment triggered by chronic psychosocial stress [15].

Nutrients and the inflammasome

As highlighted above, food can modulate stress. How nutrients do this, however, is mostly unknown. Several master regulators and/or sensors of nutrient status exists like mTOR and AMPK, but, although they integrate into inflammasome pathways, these seem to have only minor roles in behavioral pathways [39]. Otherwise, clinically available drugs like the mTOR inhibitor rapamycin (Sirolimus) or the AMPK activator aica ribonucleotide (AICAR) would be standard therapies for mental illness and cognitive impairment. In contrast, anti-inflammatory strategies are frequently examined when exploring innovative ways to combat the sequelae of overnutrition and neurodegeneration [36]. Increasingly, the inflammasome is recognized as a key energy sensor reacting to metabolic stress [40,41]. In the brain, the NLR family, pyrin domain containing 3 (NLRP3) inflammasome is the most plentiful.

Recently, the action of macronutrients on inflammasome function has gained prominence. While hyperglycemia can activate the inflammasome in rats, fatty acids appear to exert a much more direct influence on this process [9]. The dietary saturated fatty acids (SFAs) palmitic and stearic can undergo intracellular crystallization leading to lysosomal dysfunction and NLRP3 inflammasome activation, in contrast to monosaturated oleic acid, which appears to inhibit inflammasomes [42]. Interestingly, palmitic acid alone when administered as an injectable occasions behavioral abnormalities including anxiety-like behaviors [43]. In addition, dietary perturbations like a HFD regulate expression of critical inflammasome components priming cells for the enhanced detection of danger signals [44]. Since this HFD-dependent priming is, in part, mediated by the SAM axis, overnutrition, at least, is strongly linked to innate immune responsivity and behavioral stress pathways [44].

Given the importance of the SAM axis to inflammasome regulation, it is not surprising that chronic stress is tied to inflammasome activation [45]. Importantly, chronic stress as modeled in rats via CUMS not only triggers the NLRP3 inflammasome but also prompts depressive-like behavior [46]. Equally, caspase-1 knockout mice are resistant to anxiety- and depression- inducing task [47], and appear protected from stress-induced anxiety/depressive-like behaviors. In the same vain, therapeutics that block caspase-1 activity [20] and/or IL-1β action, interfere with behavioral manifestations coupled to inflammasome activation [38]. Hence, senegenin, a staple of Chinese herbal medicine that down-regulates inflammasome pathway activity, alleviates depressive-like behavior in mice exposed to CUMS [48]. This action of senegenin appears similar to that of the essential oil, geraniol, which is touted as a neuroprotective that can dampen inflammasome activation and CUMS-induced depressive-like behaviors [49].

Perhaps the clearest link between nutrition, stress and the inflammasome is the impact that calorie restriction has on anxiety-like behavior, learning/memory and caspase-1 activation. As example, acute fasting reduces anxiety-like behavior and improves memory in mice [20]. Importantly, this same acute fasting reduces caspase-1 activity in neurons of the brain. Likewise, intermittent fasting also dampens inflammasome activity and enhances mouse learning and memory [50]. Interestingly, a crucial outcome of caloric restriction, i.e. the generation of ketone bodies from the metabolism of fatty acids, may be key to the benefits of calorie restriction on the brain because β-hydroxybutyrate (BHB) is a potent inhibitor of inflammasomes [51]. Therefore, as theorized, pretreatment of mice with BHB immediately prior to restraint stress prevents depressive-like behaviors, and extended administration of BHB curtails the induction of depressive-like behaviors with chronic stress [52].

Conclusion

As ascribed to Hippocrates, Let food be thy medicine and medicine be thy food. Thus, has the intersection of PNI and nutrition emerged as an exciting and important confluence of established disciplines?: While still in its infancy, nutritional PNI should continue to gain traction because the tools needed to study the impact of foodstuff on the brain appear more widely accessible including: facilitated gene editing, cell-specific next-gen sequencing and high-resolution brain pathway mapping. Hopefully, nutritional PNI will grow from its current rooting in phenomenology to a field supported by mechanistic discernment so that the foods of the future can be tailored to provide personalized nutrition. To that end, identification of the inflammasome as a prospective master regulator of nutritional status and stress responses provides an early glimpse into a cornucopia of likely pathways where food influences both the brain and behavior.

Highlights.

1. Nutrition is a critical regulator of brain function that is being actively investigated for its role in psychoneuroimmunology.

2. Macronutritional trends such as dietary fat, carbohydrate, and protein composition as well as overall energy intake, are essential modifiers of the behavioral response to stress.

3. Although consumed in small quantities, vitamins and dietary bioactives can have large effects on an animals’ response to a variety of stressful stimuli.

4. Nutrition and stress both regulate the inflammasome, which is a mechanistic link between these factors and the behavioral response.

Abbreviations:

PNI

Psychoneuroimmunology

NLR

Nod-like receptor

HFD

High-fat diet

LFD

Low-fat diet

SAM

sympatho-adrenomeduallary

FA

Fatty acids

CUMS

Chronic unpredictable mild stress

BHB

β-hydroxybutyrate