Anthocyanin-rich fruits and mental health outcomes in an Italian cohort

1 Introduction

In recent years, following the increased life expectancy, aging-related health conditions are becoming urgently relevant, especially concerning mental health [1]. The global population living with depression in 2015 was estimated to be over 300 million people while anxiety disorders were estimated to affect more than 260 million people (4.4% and 3.6% of the global population, respectively) [2]. According to the Global Burden of Disease 2019 estimates, depressive and anxiety disorders are among leading contributors to disability-adjusted life-years (DALYs) [3]. In addition, nowadays sleep disorders represent one of the most discussed topics in literature; this growing interest is probably due to the possible link between inadequate sleep quality and the onset of negative health conditions which may precede neurodegenerative diseases [4]. In fact, factors such as inflammation and oxidative stress seem to arise at the same time as inadequate sleep quality [5]. There is no direct mechanism clearly explaining the observed trends, although there is a general agreement that environmental factors may trigger neuroinflammation, which in turn may affect the human brain until the development of the aforementioned conditions [6]. Modern lifestyles, including excess of stress, loss of sleep, and poor diet have been investigated as potential determinants of subclinical chronic inflammation [7]. On this matter, it is noteworthy to note that all these disorders are thought to be interconnected and may share similar pathways, probably representing various clinical expressions of a univocal pathophysiological condition.

Emerging evidence suggests that diet may play a much bigger role than previously hypothesized when considering mental health disorders [5]. There are a number of pathways that may explain how diet affects mental health: the correct intake of macro and micronutrients, the circadian rhythm and the feeding time are just some aspects considered [8]. The process of neuroinflammation exerted for example by the alteration of hormonal homeostasis in the context of glucose metabolism and adiponectin regulation is crucial [5]. Therefore, the dietary intake of anti-inflammatory and antioxidant compounds (i.e. omega-3 fatty acids and polyphenols) has a positive impact on the neurogenesis and on the gut-brain axis [9,10, 9,10]. Encouraging the consumption of plant-based foods is widely considered an effective dietary advice, since fruit and vegetables, but also legumes, whole grains, nuts and seeds are valuable sources of vitamins, fiber, healthy fats, and phytochemicals, such as polyphenols [11]. This group of compounds have been the focus of recent attention due to their marked variety of chemical structures and functions in humans [12] including brain-related outcomes [13]. Among the most consumed, anthocyanins are certainly among the most studied for their antioxidants and anti-inflammatory properties as well as the interaction with gut microbiota [14]. Anthocyanins represent a class of flavonoids produced when anthocyanidins are glycosylated, which are responsible for the characteristic coloring of fruits of different plants [15]. Chemically, anthocyanins represent the main group of water-soluble plant pigments and the color they determine depends on the pH [16]. Berries represent an important natural source of anthocyanins, such as bilberry (Vaccinium myrtillus), blueberry (species such as Vaccinium angustifolium or Vaccinium corybosum), and maqui berry (Aristotelia chilensis), as well as tart cherry (Prunus cerasus) and blackcurrant (Ribes nigrum) [17]. The most abundant dietary anthocyanins are cyanidin, delphinidin, malvidin, peonidin, pelargonidin and petunidin [18]. The biological activity of anthocyanins depends on the chemical structure of the molecules [19], but most of them have been shown to exert antioxidant and anti-inflammatory activities, which may explain their neuroprotective effects [13,20, 13,20]. Anthocyanins may also protect neurons, modulate cell signaling pathways, improve memory functions, and exert anti-apoptotic effects [21,22, 21,22]. Moreover, anthocyanins are demonstrated to improve endothelial health and potentially resulting in better blood flow and function of brain cells and neurotransmission [23].

Although the current results are promising, the vast majority of studies are conducted in vitro and laboratory settings, while studies on humans are limited. Moreover, most scientific literature focuses on berries, which are commonly consumed in Northern-European populations and only a minority of the general global population [24]. Concerning Southern Italian islands, only few types of berry-fruits are easily accessible, such as strawberries and cherries, while other anthocyanin-rich fruits, such as red oranges and prickly pears, are quite peculiarly consumed in those areas and not common in other European countries [25]. The aim of this study was to examine the association between anthocyanin-rich fruits consumption and mental health outcomes, including sleep quality, perceived stress, and depressive symptoms in the Mediterranean healthy Eating, Aging and Lifestyle (MEAL) study, a cohort of Southern Italian individuals developed to investigate the relation between dietary and behavioral factors and health. The role of specific fruits was also investigated in order to explore whether any differences would occur in the association with mental health outcomes.

2 Methods

3 Results

The sample comprised 1572 individuals of mean age of 46.6 years (range 18–92 years). There was no significant different distribution of anthocyanin-rich fruit consumption across categories of background variables, with exception for age group, being middle-aged individuals resulting as higher consumers of anthocyanin-rich fruits (Table 1). Additionally, intake of major macronutrients has been explored in relation to consumption of anthocyanin-rich fruit resulting in substantial no differences across tertiles of intake (Supplementary Table 1). Overall, these results suggest a limited role of potential demographic, socio-economic, and nutritional confounding factors.

Table 2 shows the association between anthocyanin-rich fruits intake and mental health outcomes. All models resulted in a significant inverse association between increasing anthocyanin-rich fruits and occurrence of poor sleep quality, high perceived stress, and depressive symptoms: in the most adjusted model, individuals in the highest tertile of anthocyanin-rich fruits were less likely to have poor sleep quality (OR = 0.63, 95% CI: 0.47–0.86), high perceived stress (OR = 0.68, 95% CI: 0.51–0.92), and depressive symptoms (OR = 0.67, 95% CI: 0.49–0.90). A subgroup analysis considering individual anthocyanin-rich fruits is presented in Table 3. All individual fruits, to a various extent, resulted significantly (or nearly) associated to the outcomes investigated: higher intake of berries was inversely associated with poor sleep quality and depressive symptoms; there was an inverse significant association between cherry, prickly pear, and grape consumption and poor sleep quality, while blood oranges were also associated with perceived stress (Table 3).

The present study investigated the relationship between anthocyanin-rich fruit consumption and mental health outcomes of sleep quality, perceived stress and depressive symptoms. The results suggest that individuals reporting the highest intake of anthocyanin-rich fruit consumption were associated with best outcomes, such as being less likely to experience poor sleep quality, high perceived stress, and symptoms of depression. Additionally, the study investigated the association between specific anthocyanin-rich fruits and mental health outcomes with results suggesting that higher intake of berries was inversely associated with both poor sleep quality and symptoms of depression and strawberries with the latter one, consumption of cherries, prickly pears, and grapes was inversely associated with better sleep quality, and consumption of blood oranges was inversely associated with perceived stress.

The present findings are in line with other investigations examining the effects of anthocyanin ingestion and mental health outcomes and our previous studies demonstrating the association between dietary polyphenols and brain outcomes [39–41]. There have been several animal studies performed exploring the effect of anthocyanin ingestion on mental performance reporting promising results potentially applicable to dietary interventions. For example, rats fed with a high anthocyanin diet performed better in memory and problem solving-based tasks (Morris water maze) additionally finding a positive correlation between performance and anthocyanin compounds in the cortex [42]. Others suggested that anthocyanin was a protective factor against the effects of psychological stress and the subsequent process of oxidative stress-reducing the number of dopaminergic neurons resulting in degenerative pathogenesis [43]. The positive effects of anthocyanin were also observed in post-stroke mice when examining results of despair swimming and tail suspension tests [44]. While animal model tests are not free of certain limitations, in particular how these effects would translate to humans, the connection between the antioxidative protective effects of anthocyanin are universally pointed towards. The available literature on the effects of anthocyanins, beyond the reduction of oxidative stress, on particular human behavioral and psychological manifestations of affective disorders is growing [45,46, 45,46]; however, the detrimental role of oxidative stress in individuals expressing depression symptoms is already well established [47,48, 47,48]. Anthocyanin-rich foods like cherries have been previously shown to decrease oxidative stress and inflammation in humans [49]. Several studies examined specific effects of anthocyanins on human mental health. For example, a placebo-controlled study of tart cherry juice consumption showed beneficial effects when treating elderly insomnia patients with reported results suggesting improved sleep time and sleep efficiency [50]. The present findings support the notion that anthocyanin protective effects extend beyond depressive symptoms and additionally suggest improved sleep quality and lower perceived stress among individuals who consume fruits rich in anthocyanins. This partially aligns with a previous meta-analytic examination of blueberry interventions finding mixed results when examining the effects of blueberry interventions on mood [51,52, 51,52]. The effectiveness of anthocyanin-rich grape juice was previously described, in an acute supplementation randomized control trial, as increasing the feelings of calm in healthy young adult populations [53] and this effect might explain lowered perceived stress and depressive symptoms observed in the present study. The present results have to also be considered while taking into account that individuals suffering from depressive symptoms are often also affected by high perceived stress while experiencing sleep disturbance is well-established comorbidity of major depressive disorder [54,55, 54,55]. This suggests the effects observed might be partially attributable to a symptom network effect.

The study also observed differential significant beneficial effects for different types of anthocyanin-rich fruits. These effects might be attributable to other bioactive compounds present in certain fruits (i.e., vitamin C may play some role in the central nervous system) [56]. However, another hypothesis relies on the different types of anthocyanins found within each type of food that may have different bioavailability [57]. For instance, while some studies reported relatively poor bioavailability (>1%) of some anthocyanins, certain other forms, such as cyanidin-3-glucoside, showed bioavailability in the order of 12.4%, suggesting wide disparities [58–60]. Furthermore, it has to be taken into consideration that the per 100 g contents of different types of fruits provide different levels and kinds of structurally distinct anthocyanin derivatives [61]. Therefore, the differential effects the consumption of different kinds of fruits observed in the present study has to be interpreted with these qualities in mind as long-term beneficial mental health effects of anthocyanins might be dependent on concentration, bioavailability, and synergistic effects between different types of anthocyanins.

Recent years have seen an increased interest in anthocyanins and their potential health benefits concerning diseases resulting from aging, obesity, neurological diseases, diabetes, inflammation, and even bacterial infections [62–64]. While more research is needed, the findings provided in this study might be explained by an overall positive effect that anthocyanins have for brain health. There are several proposed mechanisms of how anthocyanins may influence the physiological function and promote brain health. The health-promoting properties of fruit-derived anthocyanins has been attributed to their potent-anti-inflammatory properties, which have been reported to be comparable, to a certain extent, to the effects of non-steroidal anti-inflammatory drugs [65]. In addition, the anti-inflammatory properties of anthocyanins found in cherries, resultant from higher concentrations of gallic acid, cyanidin 3-glucoside, cyanidin and peonidin derivatives as well as hydroxycinnamic acids (e.g., neochlorogenic acid, chlorogenic acid), and p-coumaric acid derivatives have been found to effectively protect neuronal cells from damaging effects of oxidative stress in a dose-dependent manner [65]. The neuroprotective activities of anthocyanins have been also proposed to be beneficial in protecting against brain diseases [66], including psychiatric disorders [67]. Anthocyanins promote the activity of endogenous antioxidant defenses and redox homeostasis by reducing formation of free radicals and reducing oxidative stress. Additionally, anthocyanins may also modulate neuronal cell death signaling pathways [68], regulate mitochondrial function [69], inhibit protein aggregation [70], and potentiate autophagy [71], as well as prevent cell death induced by disrupted calcium homeostasis [72]. Furthermore, anthocyanins though increasing neuronal signaling and reducing in brain structures oxidative and inflammatory mediators may delay negative effects of brain aging [73]. In addition, administration of anthocyanin-rich plant extracts has been shown to efficiently abolish microglia and astrocyte activation and abrogate neuroinflammatory response by suppressing NF-κB activation, thereby leading to the reduction of iNOS and TNF-α levels in the hippocampal and cortical regions [74], as well as production of pro-inflammatory mediators, including IL-1β, TNF-α, IL-6, and PGE2 in whole brain. Anthocyanins acting as a source of melatonin [75] have been proposed to play an important role in promoting a good quality sleep [76]. In particular, cherry fruit can influence certain physiological properties that act on sleep pathways, such as helping to modulate the sleep–wake cycle via their melatonin and anthocyanin content [49]. It has been shown that melatonin obtained from cherries, through binding to clock-related genes receptors (melatonin receptor (MT)-1 and MT2) found in the suprachiasmatic nucleus, can upregulate their activity. In turn, an increased actions of MT1 and MT2 can inhibit certain molecular pathways controlled by actions of c-response element binding protein (cAMP) and protein kinases (PKA), what may promote the release of neurotransmitters, such as gamma-aminobutyric acid (GABA), which have been implicated in the sleep cycle induction [77–79].

The results of the present study should be interpreted with certain limitations in mind. First, the analysis was conducted on a relatively small number of individuals recruited from a restricted geographical area, which may limit the generalizability of the findings. Second, the cross-sectional design can only inform about associations and not causality. Third, although there was only little influence of background variables on the associations between the main variable of exposure and the outcomes investigated, we cannot rule out the possibility of potential unexplored confounding factors.

5 Conclusions

In conclusion, the results of the present study support the hypothesis that diets including fruits rich in anthocyanin may result in positive mental health outcomes. Furthermore, the results suggest that different fruit types influence mental health outcomes differentially which warrants further exploration aimed at examining these outcomes in light of anthocyanin bioavailability.