Rinnakkaistallenteet Terveystieteiden tiedekunta
2021
Possible use of fermented foods in
rehabilitation of anorexia nervosa: the gut microbiota as a modulator
Rocks, Tetyana
Elsevier BV
Tieteelliset aikakauslehtiartikkelit
© 2020 Elsevier Inc.
CC BY-NC-ND https://creativecommons.org/licenses/by-nc-nd/4.0/
http://dx.doi.org/10.1016/j.pnpbp.2020.110201
https://erepo.uef.fi/handle/123456789/24918
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Possible use of fermented foods in rehabilitation of anorexia nervosa: the gut microbiota as a modulator
Tetyana Rocks, Madeline West, Meghan Hockey, Hajara Aslam, Melissa Lane, Amy Loughman, Felice N. Jacka, Anu Ruusunen
PII: S0278-5846(20)30517-0
DOI: https://doi.org/10.1016/j.pnpbp.2020.110201 Reference: PNP 110201
To appear in: Progress in Neuropsychopharmacology & Biological Psychiatry Received date: 28 June 2020
Revised date: 23 November 2020 Accepted date: 2 December 2020
Please cite this article as: T. Rocks, M. West, M. Hockey, et al., Possible use of fermented foods in rehabilitation of anorexia nervosa: the gut microbiota as a modulator, Progress in Neuropsychopharmacology & Biological Psychiatry (2019), https://doi.org/10.1016/
j.pnpbp.2020.110201
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© 2019 Published by Elsevier.
Possible use of fermented foods in rehabilitation of anorexia nervosa: the gut microbiota as a modulator
Tetyana Rocks1,* Tetyana.rocks@deakin.edu.au,Madeline West1, Meghan Hockey1, Hajara Aslam1, Melissa Lane1, Amy Loughman1, Felice N. Jacka1,2,3,4, Anu Ruusunen1,5,6
1Deakin University, IMPACT – the Institute for Mental and Physical Health and Clinical Translation, Food & Mood Centre, School of Medicine, Barwon Health, Geelong, Australia.
2Centre for Adolescent Health, Murdoch Children’s Research Institute, VIC; Australia
3Black Dog Institute, NSW; Australia
4James Cook University, QLD; Australia
5Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
6Department of Psychiatry, Kuopio University Hospital, Kuopio, Finland
*Corresponding author at: PO BOX 280, Geelong 3220, Victoria, Australia.
Abstract
Anorexia nervosa is a serious psychiatric disorder with high morbidity and mortality rate.
Evidence for the optimal psychopharmacological approach to managing the disorder remains limited, with nutritional treatment, focused on weight restoration through the consumption of high energy diet, regarded as one of the fundamental steps in treatment. The human gut microbiome is increasingly recognised for its proposed role in gastrointestinal, metabolic, immune and mental health, all of which may be compromised in individuals with anorexia nervosa. Dietary intake plays an important role in shaping gut microbiota composition, whilst the use of fermented foods, foods with potential psychobiotic properties that deliver live bacteria, bacterial metabolites, prebiotics and energy, have been discussed to a lesser extent.
However, fermented foods are of increasing interest due to their potential capacity to affect gut microbiota composition, provide beneficial bacterial metabolites, and confer beneficial outcomes to host health. This review provides an overview of the role of the gut microbiota in relation to the disease pathology in anorexia nervosa and especially focuses on the therapeutic potential of fermented foods, proposed here as a recommended addition to the current nutritional treatment protocols warranting further investigation.
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Keywords
eating disorder; gut health; nutrition; probiotic; treatment.
1.
I
ntroductionAnorexia nervosa (AN) is a psychiatric condition with high morbidity and mortality rates.
The lifetime prevalence of AN is relatively low, approximately 1% in women and even lower in men (Smink et al., 2012; Zipfel et al., 2015). However, the severity of symptoms, great individual and societal burden, and low recovery rate demand continuous efforts in improving the therapeutic approaches in treatment (Himmerich et al., 2019; Zipfel et al., 2015). Despite promising advances in the psychopharmacological treatments of some psychiatric disorders in recent decades (Keith, 2006; Millan et al., 2015), the options for individuals with AN remain limited, with no well-established evidence (Himmerich and Treasure, 2018; Zipfel et al., 2015). Furthermore, although psychotherapies constitute key therapeutic components in AN, nutritional treatment, which leads to weight restoration, is an integral step in treatment (Resmark et al., 2019). Thus, developing a better understanding of the underlying mechanisms that could support effective nutritional management is essential in advancing treatment approaches.
The human gastrointestinal (GI) microbiome (the collection of all microorganisms and their genomes) is gaining considerable recognition with current evidence suggesting that it plays a pivotal role in an individual’s state of health (Gilbert et al., 2018). Furthermore, the gut microbiota (specific microorganisms, including bacteria or archaea) has been implicated in metabolic (Mithieux, 2018), immune (Fung et al., 2017) and GI systems (Pittayanon et al., 2020), as well as mood and cognitive states (Smith and Wissel, 2019), all of which are commonly impaired in individuals with AN. Indeed, the investigations conducted in this population have shown significant perturbations in the gut microbiota composition of those with AN compared to normal and overweight controls (Ruusunen et al., 2019). Some research has also demonstrated that the gut microbiota of patients with AN remains
significantly altered in comparison to healthy individuals following nutritional rehabilitation treatment (Mack et al., 2016). These findings suggest the gut microbiota may be involved in both development and progression of AN and should be considered in its treatment.
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Gut microbiota composition and function have been the target of proposed novel
management approaches for numerous conditions, including Irritable Bowel Syndrome (IBS), obesity, depression, anxiety and AN (Biesiekierski et al., 2019; Larroya-Garcia et al., 2019).
Psychobiotics, or live bacteria that, when consumed in adequate amounts, could modulate the gut microbiota and confer biotherapeutic potential, provide an appealing adjunct avenue for treatment of psychiatric conditions (Long-Smith et al., 2020). For instance, a recent
systematic review showed various pro- and prebiotics might be safe options for improving symptomology and metabolic outcomes in major depressive disorder, bipolar disorder, and Alzheimer’s disease (Barbosa and Vieira-Coelho, 2019). Food-based options, such as fermented foods, have gained recognition due to their potential synbiotic capacity as these usually contain probiotics (e.g., yoghurt or miso) and prebiotics (e.g., tempeh or sauerkraut) in various combinations, as well as beneficial bacterial metabolites (Aslam et al., 2018).
Furthermore, plant-based fermented foods, such as fermented vegetables and grains, are also an important source of dietary fibre (Swain et al., 2014), the consumption of which comes with well-established broad health benefits. Therefore, for individuals with AN, food-based sources of psychobiotics, such as fermented foods, could confer mental health benefits and deliver a synergistic boost with an additional nutrient-rich food option conforming to the objectives of treatment – increasing energy and nutrient intake and normalising eating behaviour. This review provides an overview of the role of the gut microbiota in relation to the disease pathology in AN with a particular focus on the mechanisms of action and therapeutical potential of fermented foods (Figure 1).
2. Nutritional treatment in anorexia nervosa
Nutritional rehabilitation has been recognised as a core component in the treatment of AN (Resmark et al., 2019). Weight restoration through the gradually increased energy
consumption is the primary focus, with the overall goals of increasing food intake, restoring nutritional status, improving eating behaviours and eating patterns, education about nutrition and challenging misconceptions and rigid thinking about foods, and, ultimately, reversing the effects of malnutrition (Cuerda et al., 2019; Hay et al., 2014). Treatments must also consider the health status of the patient, including both physical and psychiatric comorbidities
(Resmark et al., 2019; Zipfel et al., 2015). The specific composition of dietary regimens may vary between patients and across settings; however, the overall focus of nutritional treatment is regular consumption of energy-dense meals and snacks that promote weight restoration and
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normalise eating behaviours, including consuming foods that are often avoided, for instance, desserts and sweets. Although essential in therapy, it is unclear what influence the current nutritional treatments of AN may have on a less considered aspect of the disorder’s aetiology – the gut microbiome.
Clinical guidelines for nutritional treatment of AN are predominantly focused on the
provision of a high energy diet and weekly weight gain targets. In medically stable patients, delivering high energy diets through oral feeding is preferred; however, the use of high energy liquid supplements, nasogastric or parenteral feeding may be necessary to supplement food intake (Resmark et al., 2019; Rocks et al., 2014). The nutritional protocols used in this patient group are not well defined in the literature, thus the quality of these high energy nutritional treatments is challenging to assess from the perspective of their influence on the gut microbiota composition.
3. Gut microbiota and host health
The human gut microbiome is a highly evolved and complex system encompassing trillions of bacteria, archaea, viruses, fungi, parasites and their genomes. The gut microbiome co- develops with its human host and plays a critical role in its health and disease (Gilbert et al., 2018). The term “microbiota” specifies bacterial taxa within the microbiome and is often mapped out in relation to its composition (presence) and diversity (range) (Cani, 2018;
Gilbert et al., 2018). The gut microbiome is highly dynamic, with multiple factors
demonstrated to affect its microbial composition and functions. Research in humans suggests that genetics, environment, age, diseases, and medications all influence gut microbial
composition and have been associated with its function (Gilbert et al., 2018; Jackson et al., 2018). Among lifestyle factors such as food intake, physical activity, sleep, and habitat, both diet quantity and quality have been regarded as prominent determinants (Gilbert et al., 2018;
Singh et al., 2017). Gut microbiota composition and function are thought to be implicated in many aspects of host health, including physiology, psychology and cognition (Cani, 2018;
Gilbert et al., 2018; Rea et al., 2020). Increasingly, the gut microbiome is linked to digestive, endocrine and immune functions (Gilbert et al., 2018; Mithieux, 2018; Zmora et al., 2019), all of which are often compromised in AN (Norris et al., 2016; Roubalova et al., 2019; Zipfel et al., 2015).
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Recent advances in our understanding of the gut-brain axis – the bidirectional communication between the gut and the brain – indicate that the gut microbiome may potentially be an
important pathway for mental and cognitive health (Bastiaanssen et al., 2020; Smith and Wissel, 2019). It is hypothesised that this communication occurs directly, via stimulation of the vagus nerve and modulation of hypothalamic-pituitary-adrenal axis (HPA), as well as peripherally through the production of short-chain fatty acids (SCFAs), neurotransmitters, and immune metabolites (Cryan et al., 2020; Rea et al., 2020). Animal studies provide
evidence that perturbations to gut microbiota homeostasis can result in psychological distress and impaired cognitive function. For example, transplantation of gut microbiota from humans with major depression to germ-free rodents induces depressive- and anxiety-like behaviours (Kelly et al., 2016). As metabolic, psychiatric and cognitive disturbances are all involved in AN, the role of gut microbiota and their modifications warrant further consideration.
4. Nutrition and gut microbiota
The gut microbiota is highly responsive to the nutritional content of an individual’s dietary intake as well as specific nutrients therein (Singh et al., 2017; Zmora et al., 2019). Broadly, traditional dietary patterns (e.g., Mediterranean-style diets) that are largely based on the consumption of minimally processed foods, with high intake of plants and plant-based foods (e.g., grains, vegetable, fruit, legumes, nuts and seeds) and with a lower intake of animal- origin foods, influence the diversity and function of the microbiota in a manner that is associated with positive health states. Conversely, Western-styles of eating characterised by the consumption of highly processed foods, with high sugar intake, has been shown to reduce the diversity of the gut bacteria and hinder microbiota-mediated health effects (Makki et al., 2018; Singh et al., 2017).
Major food components, i.e., carbohydrates, proteins, fats, and fibres, are all important determinants in the gut microbiota – host health nexus; however, dietary fibre appears to be critical to GI, metabolic, and immune health (Makki et al., 2018). Dietary fibre provides an important source of energy for the gut microbiota allowing for production of health-
conferring metabolites, including SCFAs (Koh et al., 2016). Diets with high fibre intake that promote proliferation of bacterial producers of SCFAs have been associated with enhanced gut epithelium integrity, and gut-related immune, and inflammatory responses (Makki et al., 2018). For instance, a meta-analysis of 64 human studies showed that compared to groups
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that consumed low fibre or control condition diets, healthy adults in high dietary fibre intervention groups had increased abundance of beneficial Bifidobacterium spp. and
Lactobacillus spp., and greater concentrations of SCFA butyrate after the interventions (So et al., 2018). Notably, along with containing potentially health promoting probiotics (discussed below), plant-based fermented foods, such as fermented vegetables, are also high in dietary fibre (Swain et al., 2014). Therefore, high fibre fermented foods should be considered for their additional significance for the gut microbiota composition.
There is emerging interest in investigating the effect of macronutrients, such as fat and protein, on gut microbiota composition. In the general population and in various patient- groups, it has been clearly demonstrated that dietary fat intake strongly influences gut
microbial composition (Paoli et al., 2019; Singh et al., 2017). However, the effect of high-fat diets on gut microbiota may also vary according to the quality of the dietary fat; for example, in mice models high unsaturated-fat diet increased the levels of Verrucomicrobia
(Akkermansia muciniphila) and the apparently beneficial Bifidobacteria (Singh et al., 2017).
Evidence also suggests that dietary proteins affect the composition and metabolic activity of the gut microbiota (Ma et al., 2017). Generally, lower dietary protein intake has been shown to shift microbial composition toward elevated levels of putatively beneficial bacteria that have demonstrated capacity for carbohydrate fermentation, whereas higher protein intake has been associated with microbial metabolite alterations, for example reduced faecal levels of SCFAs (De Filippo et al., 2010). In addition, decreased levels of the butyrate-producing Roseburia and stool levels of butyrate were demonstrated after a high-protein/low- carbohydrate diet (Russell et al., 2011).
Additionally, artificial substances, such as emulsifiers, preservative, artificial sweeteners and other food additives, widely used in commercial food production, may also have an impact on the gut microbiota composition. Current evidence from preclinical and human studies
suggests that consumption of these substances influence the gut microbiota and impact metabolic or immune health of its host (Cao et al., 2020). For example, in an ex vivo model, dietary emulsifiers polysorbate and carboxymethylcellulose were shown to impact human gut microbiota composition and gene expression, increasing its proinflammatory capacity
(Chassaing et al., 2017). Although the majority of the existing evidence comes from cell or animal studies with scarce human research, the use of foods and supplements containing
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artificial additives during the nutritional treatment of patients with AN should be carefully considered in terms of their possible impact on the gut and the overall health.
5. Gut microbiota in anorexia nervosa
The roles of gut microbiome composition and function have been recently discussed in eating disorders, especially AN (Mack et al., 2018); however, the evidence remains limited
(Ruusunen et al., 2019). Several cross-sectional studies have investigated gut microbiota composition in individuals with AN, all noting dissimilarities in the composition to various control groups (Borgo et al., 2017; Hanachi et al., 2019; Kleiman et al., 2015; Mack et al., 2016; Million et al., 2013; Morita et al., 2015). These studies reported heterogenous outcomes with some noting a lower total count of bacteria, reduced diversity, and reduced abundance of bacterial species previously associated with beneficial health outcomes. In particular, individuals with AN tended to have a decreased abundance of SCFA producing bacteria, Firmicutes Eubacterium, Roseburia, and Ruminococcus (Borgo et al., 2017;
Hanachi et al., 2019; Mack et al., 2016), as well as decreased abundance of Lactobacillus spp. (Million et al., 2013; Morita et al., 2015). However, some gram-negative bacteria with high pro-inflammatory potential from Enterobacteriaceae family (such as Salmonella, Escherichia coli, and Klebsiella) were more abundant in those with AN (Borgo et al., 2017;
Hanachi et al., 2019; Million et al., 2013). A recently conducted systematic review that provided a summary of nine studies with a total of 180 patients with AN also reported highly heterogenous microbial findings (Di Lodovico et al., 2020). For example, a qualitative synthesis of the studies showed similar alpha-diversity (richness or evenness of the detected species) of individuals with AN in comparison to control groups. In contrast, the review reported a reduced presence of SCFA producers (such as Roseburia) and a higher presence of mucine-degrading species and Enterobacteriaceae in AN groups (Di Lodovico et al., 2020).
Notwithstanding the absence of a consistent gut microbiota profile (heterogeneity which is seen in studies across other psychiatric conditions (e.g., see (Nguyen et al., 2019)), these outcomes indicate that gut microbiota composition perturbation in those with AN may have significant implications for the treatment of eating disorders.
Despite the potential significance of observed differences in microbiota composition, only two studies to date have considered the role of nutritional treatment in eating disorders on gut
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microbiota (Kleiman et al., 2015; Mack et al., 2016). Some changes were observed during nutritional treatment: a post-treatment increase in the levels of carbohydrate-utilising taxa (especially Roseburia, a well-known butyrate producing bacterial genus) and decrease in relative abundances of protein and mucin-degrading taxa (Mack et al., 2016). Levels of Ruminococcus increased following weight restoration in both of these studies, potentially reflecting the increased intake of fibre and resistant starch (Kleiman et al., 2015; Mack et al., 2016). Moreover, after nutritional treatment, both studies reported that the gut microbiota composition of patients remained different to that of healthy control individuals.
Interestingly, although changes in microbial composition were measured following treatment, the overall composition in those with AN had greater resemblance to their own baseline than to that of healthy controls (Mack et al., 2016). The reasons for the relative stability of the microbiome in AN despite treatment are not yet clear, but may include the genetic makeup of individuals predisposed to developing AN, comorbid GI issues, altered dietary intake and eating behaviour, and other treatment procedures, such as medications, or a combination of these.
6. Gastrointestinal symptoms in anorexia nervosa
Despite increases in weight and relative normalisation of behaviour achieved by nutritional rehabilitation, persistent GI symptoms that are present during and following recovery have been reported in the majority of individuals with AN (Salvioli et al., 2013). GI disturbances can range from mild discomfort to severe medical emergencies (Norris et al., 2016) and have been identified as possible determinants of the disorder’s manifestation and management (Norris et al., 2016; Santonicola et al., 2019; Schalla and Stengel, 2019). Over 90% of individuals with AN report such experiences (Salvioli et al., 2013), with high rates of constipation (Boyd et al., 2005; Sileri et al., 2014), symptoms of postprandial fullness, abdominal distension (Salvioli et al., 2013), and IBS (Boyd et al., 2005). Previous research also reported worsening of GI symptoms with both severity and duration of the eating disorder (Sileri et al., 2014). Additionally, treatment adherence may be hindered by these uncomfortable GI disturbances by further driving engagement in disordered eating behaviours (Riedlinger et al., 2020).
The pathogenesis of GI symptoms can be varied, at times unknown, and can depend on the individual’s engagement with eating disorder behaviours and medical history, such as
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starvation, purging, laxative or diuretic misuse, or presence of cormobid disorders (Riedlinger et al., 2020). Further, it appears that current nutritional treatment might not aid in alleviating GI symptoms. Studies reporting changes in GI symptoms following nutritional treatments are limited and results are inconsistent, varying in which symptoms change and improve
(Riedlinger et al., 2020). Even though overall GI symptoms may decline over the course of treatment, many debilitating symptoms persist (Heruc et al., 2018; Mack et al., 2016). For example, the provision of a high-fat, high-fibre and high-energy diet was found to improve some symptoms mainly due to improvements in lower GI symptoms related to slow colonic transit time. However, many symptoms, including abdominal bloating, fullness or distension, persisted without significant improvement following a mean inpatient treatment length of three months (Mack et al., 2016). Similarly, two weeks of a high-energy diet was shown to have no effect on nausea and bloating in adolescents with restricting-type AN (Heruc et al., 2018). As current treatments do not adequately alleviate these common GI symptoms that may complicate treatment and are often long-standing, innovative approaches are needed.
7. Psychiatric comorbidities in anorexia nervosa
Perturbations in the gut microbiota composition and impaired GI functions in individuals with AN might be linked to poorly regulated immune reactivity (Roubalova et al., 2019) and the associated inflammatory state (Solmi et al., 2015) often reported in this group. The gut microbiome plays a role in the regulation of the immune system through the production of metabolites such as SCFAs and other neuroactive compounds (Cryan et al., 2020).
Furthermore, the gut microbiota contributes to gut mucus production, regulation of tight junctions, and anti-microbial proteins, all of which are implicated in chronic activation of the immune system (Makki et al., 2018; Roubalova et al., 2019). Additionally, SCFAs and other metabolites of microbial origin downregulate luminal oxygen level, reducing gut-related inflammation (Makki et al., 2018). In AN, both the innate gut microbiota composition and its changes due to suboptimal dietary intake might be responsible for impaired immune and anti- inflammatory responses.
Changes in the gut microbiota composition and its function could also provide another possible explanation for a high psychiatric comorbidity reported in individuals with AN (Himmerich et al., 2019; Zipfel et al., 2015). Notably, comorbid psychiatric disorders have also shown to be a barrier to recovery (Keshishian et al., 2019), and a risk factor for mortality
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in those with AN (Himmerich et al., 2019). Preclinical research has identified the potential of the gut microbiota as a contributor to the development and progression of several disorders, including those prevalent in AN, such as depression and anxiety (Rea et al., 2020). A recent systematic review of human and animal studies also demonstrated the links between gut microbiota composition, GI state (specifically, IBS symptomology), and depression and anxiety symptomology (Simpson et al., 2020). Specifically, it showed that individuals with comorbid GI and psychiatric disorders also presented with decreased alpha diversity (species richness and evenness) and higher abundance of some bacterial species, including
Proteobacteria and Prevotella, than those without comorbidities (Simpson et al., 2020). These differences between individuals with and without GI and psychiatric symptoms could be explained by gut microbiota dysbiosis, characterised by increased intestinal permeability and upregulated pro-inflammatory communication (Simpson et al., 2020). However, the research is yet to establish a clear clinical presentation of dysbiosis or to provide a coherent
explanation on whether dysbiosis is the cause or the consequence of physical and mental impairment. Nevertheless, nutritional interventions based on whole-food dietary styles and eating patterns, such as the Mediterranean diet, have been increasingly suggested as a suitable adjunctive treatment in psychiatric disorders due to their potential to alter gut microbiome composition, which may in turn, confer benefits for mental outcomes (Morkl et al., 2018;
Sandhu et al., 2017).
A lack of adequate nutrition and prolonged starvation can deprive the brain of essential nutrients and correlates with grey and white matter reduction in patients with AN (Scharner and Stengel, 2019). This loss of brain matter may explain some of the poorer cognitive outcomes observed in patients with AN compared to healthy women (Hay and Sachdev, 2011), such as increased impairments in decision making, tasks measuring abstract thinking and visuospatial abilities (Tenconi et al., 2016). Although several aspects of cognitive
inflexibility related to attention, executive functioning, and non-verbal thinking have shown to improve post remediation therapy, some aspects of neurocognitive function remain impaired following weight recovery (Kucharska et al., 2019).
8. Fermented foods and their therapeutic potential
Fermented foods are consumed across the world owing to their functional and therapeutic properties, although they are not highlighted as a key food category in food guidelines
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(Chilton et al., 2015). Microorganisms (e.g., bacteria and yeast) are the key operators involved in the process of fermentation, which occurs when microorganisms use food or components of food (e.g., glucose, starch) to generate energy by anaerobic respiration, thereby altering the texture, functionality and sensory properties of the food. The microbial respiration is driven by enzymes and consequently yields biologically active molecules that are beneficial to the host (Masood et al., 2011). Fermentation of food can occur naturally or by the deliberate addition of starter cultures (lactic acid bacteria), such as Lactobacillus spp.
and Lactococcus, and Streptococcus or Bifidobacterium spp. (Stiemsma et al., 2020). Most of the lactic acid bacterial strains are considered probiotics; live microorganisms that render health benefits to host when administered in adequate quantities (Yin, 2016). It is speculated that the probiotic cultures and the biochemical metabolites that are produced as the result of fermentation synergistically contribute to the physiological benefits that are associated with fermented food consumption (Aslam et al., 2018; Dimidi et al., 2019; Stiemsma et al., 2020).
Although not all, various commercially and home-produced fermented foods contain live probiotics, prebiotics and bacterial metabolites at the point of consumption.
Fermented foods were highlighted by the 1908 Nobel prize winner in Medicine, Elie
Metchnikoff, who suggested that microorganisms found in fermented dairy may play a role in improving psychiatric symptoms (Bested et al., 2013). There are an array of fermented foods produced by fermenting dairy, such as kefir and yogurt, and plant foods, for example
sauerkraut, tempeh, pickles, fruits, and tea (kombucha). Many fermented foods contain microorganisms that could be considered probiotics; however, specific strains and their number can vary depending on a food product (Dimidi et al., 2019; Tamang et al., 2020). The diversity of fermented foods implies their availability and cultural acceptance across broad populations. Over the last century, the therapeutic role of fermented foods has been studied in relation to a broad range of physical and psychiatric conditions, such as IBS, Inflammatory Bowel Disease (IBD), obesity, and depression and anxiety, in both observational studies and clinical trials (Aslam et al., 2018; Dimidi et al., 2019; Stiemsma et al., 2020). Fermented milk and whole grain products may lower the risk of heart diseases (Anderson, 2003; Seppo, 2001) and certain fermented soybean can reduce cholesterol levels (Hermosilla et al., 1993; Lee, 2004). Moreover, another study utilising both cellular and animal models demonstrated the antimutagenic and anticarcinogenic properties of lactic acid bacteria (Lee et al., 2004).
Finally, fermented foods possess immunomodulatory properties and have been shown to aid in alleviating the severity of GI disorders (Lim et al., 2011).
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8.1 Gut health and gastrointestinal symptoms
Studies assessing the impact of fermented foods on GI symptomology and function have suggested the therapeutic potential of edible ferments, including high tolerability and capacity to decrease both subjective and objective measures of GI dysfunction (Dimidi et al., 2019).
The high tolerability of fermented foods is an important consideration particularly if
considering their use in food-avoidant or restrictive populations, such as individuals with AN.
In addition to compelling animal data (Dimidi et al., 2019), outcomes of investigations in humans suggest that consumption of fermented foods, for example fermented dairy,
modulates human gut microbiota with reported increases in so-called beneficial bacteria and decreases in potentially pathogenic species (González et al., 2019; Stiemsma et al., 2020;
Yılmaz et al., 2019). Two studies specifically focused on gut microbiota composition reported subtle differences in the gut microbiota profiles of frequent fermented food consumers and nonconsumers (Taylor et al., 2020; Zhernakova et al., 2016). An
observational study on a subset of healthy Human Microbiome Project participants showed that while overall microbial diversity was not significantly different between consumers and nonconsumers of fermented foods (mostly, beer, kimchi, kombucha, pickled vegetables, and yoghurt), consumers were found to have a greater number of beneficial bacteria known to be associated with the consumption of fermented foods, such as Lactobacillus strains (Taylor et al., 2020). Similarly, in the Dutch LifeLines-DEEP cohort study, drinking fermented dairy, buttermilk, was associated with a higher microbiome diversity, in contrast to the consumption of other non-fermented dairy products that were associated with a lower diversity
(Zhernakova et al., 2016).
In clinical investigations, one randomized controlled trial (RCT) in 45 patients with IBD reported a significant increase in total bacterial load of Lactobacillus and significant decrease in GI distress (bloating) in the group that consumed 800ml of kefir (fermented dairy drink) daily compared to control group (Yılmaz et al., 2019). Another small non-randomized study in patients with functional constipation reported significant improvements in stool frequency and stool consistency after four weeks of consuming 500ml of kefir daily (Turan et al., 2014).
Additionally, six weeks of lacto-fermented sauerkraut was shown to be effective in reducing symptom severity in patients with IBS (Nielsen et al., 2018).
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In healthy individuals, consumption of fermented dairy foods has been associated with several changes in gut microbiota composition and health-linked biomarkers. For example, habitual consumption of fermented dairy has been linked to increased levels of faecal Akkermansia (in consumers of natural yoghurt) and decreased levels of Bacteroides (in consumers of sweetened variety) (González et al., 2019). These findings were reported along with reduced serum markers of inflammation in habitual consumers. Similarly, 16 days of tempeh (fermented soy bean) consumption has been associated with a greater abundance in Akkermansia (Stephanie et al., 2017), whilst one month consumption of fermented vegetables (210g/day of kimchi daily) has been associated with increased SCFAs production-related bacteria (Kim and Park, 2018). These results highlight the possible beneficial effects of fermented food consumption even in the absence of GI distress.
8.2 Body weight and metabolic health
There is some limited evidence regarding the potential effects of fermented foods (with the most studied ferment being probiotic-containing yoghurt) on body weight or metabolic health. A recent review noted several RCTs across varying clinical populations that reported probiotic versus conventional yoghurt had beneficial effects on some aspects of metabolic health (i.e., improved fasting blood glucose and insulin levels, and antioxidant status);
however, null effects on weight status were observed (Kok and Hutkins, 2018). Clinical trials in both children and adults with malnutrition have also reported no effect of probiotics on weight gain (i.e., Bifidobacterium animalis subsp lactis and Lactobacillus rhamnosus (LGG) in children and Bacillus cereus A 05 in adults) (Grenov et al., 2017; de Castro Soares et al., 2017). In contrast, long-term administration of synbiotics, defined as the combination of probiotics and prebiotics, in a small sample of malnourished patients with refractory
enterocolitis led to accelerated weight gain in all but one patient (Kanamori et al., 2004). In addition, another recent review highlighted the long-known impact of probiotic strains of Gram-positive bacteria in animal and livestock feed to promote weight gain, including Lactobacillus spp., and that these weight gain effects are likely generalisable to humans with probiotics consumed in fermented foods (Angelakis, 2017). Angelakis (2017) also suggested the effect of probiotics on the gut microbiota may be caused by bacteriocin production (i.e., peptides produced by probiotic bacteria that facilitate their colonisation in the competitive gastrointestinal environment). Although limited, current research shows the potential of bacteria, such as Lactobacillus spp., often found in fermented foods, to influence weight
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status, for example in individuals with excess weight (Guazzelli Marques et al., 2020). As weight management is a core aim of treatment in AN, further research is needed to determine the impact of these and other potentially beneficial bacteria on weight gain.
8.3 Immune system and inflammation
Common probiotic microbes in fermented foods can adhere to the intestinal mucosa and colonize in the gut, which contributes to some of the benefits of consumption on the immune system, such as protection against pathogen invasion and modulation of intestinal immune cells (Bermudez-Brito et al., 2012). In particular, specific lactic acid bacteria and
Bifidobacteria species and strains, commonly present in fermented foods, are suggested to be able to modify host metabolism and immunity (Linares et al., 2017).
Promising anti-inflammatory therapeutic properties have been demonstrated from fermented foods, such as yoghurt (Pei et al., 2017). This may be relevant as inflammation plays a central role in many pathophysiological conditions and downregulating inflammation aids in
improving symptoms (Libby, 2007). Pro-inflammatory cytokines in the bloodstream are early indications of infection and inflammation, and can be triggered by local inflammation in the gut and elsewhere (Liu et al., 2017; Maes et al., 2008). The potential for fermented foods to reduce inflammation has been suggested by the results of both preclinical and clinical studies (Agostini et al., 2012; O’Mahony et al., 2005; Veiga et al., 2014). For example, a study that involved individuals with IBS showed that consuming malted milk fermented with probiotic strains Lactobacillus salivarius subsp salivarius UCC4331 and Bifidobacterium infantis 35624 for eight weeks normalized the pro-inflammatory and anti-inflammatory cytokine ratio, and also reduced the pro-inflammatory cytokines with respect to the baseline values (O’Mahony et al., 2005).
Factors localised to the gut (e.g., altered gut microbiota composition, gut inflammation) and peripheral to the gut (e.g., stress-induced inflammation) may compromise gut barrier
integrity, which may in turn exacerbate inflammation (Kelly et al., 2015). Such inflammation is a contributing factor to depression (Berk et al., 2013) and markers of impaired barrier integrity are elevated in clinical depression (Maes et al., 2012). Fermented foods can
contribute to the maintenance of gut epithelial integrity through increased mucous production and upregulation of the production of tight junction proteins, which are critical for
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maintaining gut epithelial integrity (Agostini et al., 2012; Maldonado Galdeano et al., 2015;
Turner, 2009). Moreover, fermented foods have demonstrated potential to enhance the growth of butyrate-producing bacteria in the distal gut. Butyrate is a SCFA that can
potentially improve intestinal epithelial integrity and thereby reduce inflammation (Peng et al., 2009). For example, in a randomized double-blind controlled trial in people with IBS, those who consumed fermented dairy had higher quantities of butyrate producing bacteria in faeces compared to those who consumed acidified milk product (Veiga et al., 2014).
8.4 Psychiatric symptoms
Fermented foods may alter gut microbiota composition and have therefore garnered interest for their potential to modify pathways involved in the aetiology of psychiatric disorders, including AN. A few studies have identified a beneficial effect of fermented foods on
depressive and anxiety symptoms. For example, fermented red ginseng was found to improve depressive symptoms in women (Lee and Ji, 2014) and in chemotherapy patients, when taken as an adjunct to chemotherapy treatment (Jiang et al., 2017). However, two studies that investigated a commercially available probiotic-containing fermented milk drink found no differences in symptoms of depression and/or anxiety between those who consumed the fermented milk or the placebo (Kato-Kataoka et al., 2016; Takada et al., 2016). In our recent review of the mechanisms underpinning fermented foods and health states, we demonstrated the need for clinical trials that directly examine the effects of fermented foods on depressive and anxiety symptoms in humans (Aslam et al., 2018).
Some epidemiological evidence suggests the potential impacts of fermented foods on psychiatric symptoms. Three studies that examined associations between yoghurt
consumption and depressive symptoms reported heterogeneous findings (Perez-Cornago et al., 2016; Stefanska et al., 2014; Yu et al., 2018). In an observational study of women, more frequent consumption of whole-fat yoghurt (≥7 serves/week) was associated with decreased odds of having depressive symptoms when compared to low consumption (< 0.5
serves/week) (Perez-Cornago et al., 2016). Such findings may be noteworthy given the high fat composition of refeeding protocols and reported acceptance of dairy products, including yoghurt, by patients with AN (Segura-García et al., 2014); however, no studies have explored mental health outcomes in relation to fermented dairy consumption in this population. It is theorized that fermented foods may exert benefits on psychiatric symptoms by influencing
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underlying pathways including the gut microbiota, inflammation, HPA-axis and
neurotransmitter production (Aslam et al., 2018). However, these mechanisms are not fully elucidated in humans and current hypotheses are based on animal data. Although the effects of fermented foods on psychiatric symptoms have not been directly studied in AN, it is reasonable to consider the potential beneficial impact of fermented foods as part of nutritional treatment in this disorder given the high comorbidity with depression and anxiety (Furtado and Katzman, 2015).
8.5 Cognition
Despite limited clinical evidence, research points towards the potential role of the gut microbiota in mediating the effects of fermented foods on cognitive function. Cognitive deficits in AN may hinder treatment efficacy and contribute to illness chronicity (Chui et al., 2008); however, evidence from animal studies suggests that changes to gut microbiota composition can modulate oxidative stress and brain-derived neurotrophic factor production;
both of which are implicated in cognitive function (Komanduri et al., 2019; Miranda et al., 2019). Fermented foods have been demonstrated to alter the composition and function of the human gut microbiota (Volokh et al., 2019) and are, therefore, hypothesized to have
neuroprotective benefits. Specifically, live cultures within these foods may influence brain function via changes to the composition of the gut microbiota. Certain microbiota strains have been linked to changes in mitochondria and reactive oxygen species (ROS) (Kumar et al., 2007), including Lactobacillus, which has been shown to produce antioxidant enzymes that protect against host ROS and regulate anti-inflammatory immune responses (LeBlanc et al., 2011). Furthermore, gut bacterial metabolites, such as butyrate, have also shown to reduce oxidative stress (Rose et al., 2018). Oxidative stress markers are higher in patients with AN compared to healthy controls (Solmi et al., 2016). Oxidative stress can induce neuronal cell death and may cause cognitive dysfunction; however, fermented foods may potentially reduce oxidative stress via changes to the microbiota (Kim et al., 2016). Other benefits are proposed to be due to the fermentation process, which enhances the bioavailability of foods, enriching the food product with bioactive peptides and phytochemicals that have anti-inflammatory properties (Kim et al., 2016). Lastly, fermented foods may influence cognitive function via changes to neurotransmitters that are involved in learning and memory processes. Treatment with the probiotic Lactobacillus rhamnosus (JB-1) has been shown to change the expression of gamma-amino butyric acid (GABA) receptors (Bravo et al., 2011), with other studies
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demonstrating that probiotic administration altered serotonin turnover and related metabolites in the brain (Clarke et al., 2013; Desbonnet et al., 2008). The utilisation of Lactobacillus rhamnosus GR-1 as a starter culture in fermented dairy products has been previously
discussed in relation to production of functional foods (Hekmat et al., 2009). Fermented foods may also, via their effects on gut microbiota composition, modulate the production of
neurotransmitters important for cognitive and brain function such as brain-derived
neurotrophic factor, glutamate, GABA and serotonin. Future investigations should establish the impact of fermented foods on cognitive outcomes in patients with AN, for example, fermented dairy products (e.g., kefir or yoghurt), particularly considering that yoghurt is included within refeeding protocols (Peebles et al., 2017; Pettersson et al., 2016) and has been shown to have a positive effect on immunological markers in this patient group (Nova et al., 2006). Furthermore, the potential impact of fermented foods on the production of
neurotransmitters, such as serotonin or GABA, should be further investigated in relation to AN.
9. Fermented foods in anorexia nervosa
Despite the growing understanding of the potential therapeutic benefits of fermented foods, there is a paucity of research on the topic in AN. No studies have explored the direct impact of using fermented foods in nutritional treatment on gut microbiota composition or any other GI-related parameters. One study evaluated the effect of yoghurt, fermented dairy, in
comparison to milk, non-fermented dairy, on immunological outcomes in 30 underweight adolescent females with AN during 10 weeks of nutritional treatment that started in inpatient setting and continued after discharge (Nova et al., 2006). The study introduced 375g of conventional natural yoghurt containing Lactobacillus bulgaricus and Streptococcus
thermophilus daily in the intervention group (n=16); and 400g of semi-skim milk with a close energy and macronutrient value in the control group (n=14). The results showed that in comparison to the milk group, the individuals from the yoghurt group had significantly greater levels of the cytokine IFN-γ, suggesting a positive immunological effect of the intervention (Nova et al., 2006). More recent research reported a beneficial impact of a fermented dairy product on serum insulin-like growth factor-I (IGF-I) measures in 62 females with restricting and binging-purging type AN (Trombetti et al., 2016). This study investigated the effect of protein-enriched fermented cheese on IGF-I as a marker for bone turnover in comparison to an isocaloric fermented preparation with a lower protein content. As expected,
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all of the participants in the both studies gained weight during inpatient treatments, but no significant differences in weight were observed between the fermented and non-fermented dairy groups (Nova et al., 2006; Trombetti et al., 2016).
10. Conclusion
AN is a highly comorbid and treatment resistant disorder with no evidence-based
pharmacological therapies. Recent research indicate that the human gut microbiome might be implicated in AN and opportunities to modulate the gut microbiota should be considered in its treatment, including nutritional treatment. Fermented foods containing psychobiotic candidates with the potential to confer mental health benefits, as well as support favorable metabolic and immune health outcomes, provide an appealing option to be included in nutritional treatment protocols for patients with AN. For this patient group, fermented foods would also deliver an energy- and nutrient-rich option to support weight restoration and nutritional recovery. Therefore, in patients with AN, implementation of pro- and prebiotic containing fermented foods in nutritional treatment protocols, their potential for symptom reduction, as well as the role of the gut microbiota as a potential modulator, should be investigated in randomized controlled trials.We hypothesize that inclusion of fermented foods in nutritional treatment protocols in AN may be beneficial for relevant metabolic, immune-mediated, psychiatric and cognitive symptom reduction.
Figure 1. Fermented foods as a helpful addition to nutritional treatment of anorexia nervosa due to their potential modulating impact on the gut microbiota.
Declaration of interest
TR has received grants, fellowships and research support from University of the Sunshine Coast, Australian Postgraduate Awards, Fernwood Foundation and Be Fit Food. TR received consultancy, honoraria and travel funds from Oxford University Press, the University of Melbourne, the University of Sydney, Bond University, University of Southern Queensland, Dietitians Association of Australia, Nutrition Society of Australia, The Royal Australian and New Zealand College of Psychiatrists, Academy of Nutrition and Dietetics, Black Dog Institute, Australian Rotary Health, Australian Disease Management Association, Department of Health and Human Services, Primary Health Networks, Barwon Health, West Gippsland
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Healthcare Group, Central West Gippsland Primary Care Partnership, Parkdale College, City of Greater Geelong and Global Age. MW is supported by a Deakin University Research Scholarship. MH has received research support from Deakin University, Australian Rotary Health and the A2 Milk Company. HA is supported by Deakin University Postgraduate Industry Research Scholarship. ML is supported by a Deakin University Research
Scholarship and has received research support from Be Fit Foods. AL has received grants, fellowships and research support from the University of New South Wales, the University of Melbourne, RMIT University, Deakin University, the National Health and Medical Research Council (NHMRC), Australian Academy of Science, National Institutes of Health (NIH), and The Jack Brockhoff Foundation. AL has received honoraria and travel funds from Sydney University, the University of Technology Sydney, American Epilepsy Society, Epilepsy Society of Australia, International Human Microbiome Congress, European Society of Neurogastroenterology, Australian and New Zealand College of Anaesthetists, Falk Foundation and Fonds de la Recherche Scientifique (FNRS). FNJ has received
Grant/Research support from the Brain and Behaviour Research Institute, the National Health and Medical Research Council (NHMRC), Australian Rotary Health, the Geelong Medical Research Foundation, the Ian Potter Foundation, Eli Lilly, Meat and Livestock Australia, Woolworths Limited, the Fernwood Foundation, Wilson Foundation, the A2 Milk Company, Be Fit Foods, and The University of Melbourne, and has received speakers honoraria from Sanofi-Synthelabo, Janssen Cilag, Servier, Pfizer, Health Ed, Network Nutrition, Angelini Farmaceutica, Eli Lilly and Metagenics. FNJ has written two books for commercial
publication and has a personal belief that good diet quality is important for mental and brain health. AR is a recipient of Postdoctoral Research Fellowship from Faculty of Health, Deakin University, Australia, and has received research funding from Kuopio University Hospital, Finland. She holds a university lecturer’s position at the University of Eastern Finland. AR has received travel or speakers’ honoraria funds from Nutrition Society of Australia, Eastern Finland Medicine Association, University of Turku and The Association of Clinical and Public Health Nutritionists in Finland.
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