THE ROLE OF MICROBIOTA IN FEEDING and EATING DISORDERS: a biological and psycodinamic vision for treatment with Brief Dynamic Therapy
By Zebi L. [1], Barbi M. [1], Lupattelli I. [1], Moretti P. [1]

1. Section of Psychiatry, Department of Medicine and Surgery, University of Perugia, Perugia, (PG), Italy

Key Words: microbiota,Feeding and Eating Disordergut-brain axis , dysbiosis”,myth, personal unconscious ,collective unconscious.

Abstract: Interest in the identification of new factors that contribute to the genesis of Eating Disorder (ED or Feeding and Eating Disorder FED) has recently focused on the study of microbiota. The term gut-brain axis refers to the bidirectional interaction between the intestinal microbiota and the CNS. The topic of the microbiota shows the overcoming of the ontological split between mind and body. The development of thought, and consequently of behavior, are closely connected to somatic structures capable of influencing and determining mental functions. The intestine-brain axis and the two-way communication between the two organs show as reductionist medical vision of the brain as the place of mental illness. In this sense, the microbiota is placed as an intermediate biological structure between the ego and the environment. From this point of view, the microbiota symbolizes the factor of the dual bidirectional communication between the Ego and the food environment understood as the “world”, but it is also an expression of the collective unconscious in the body of the single person for its function of intermediation and integration between the singularity of the individual and the universality of his relational environment.The “conviviality” of eating together becomes a symbolic vehicle of being together with others not only on an emotional-relational level, but also on a biological level. The intestinal population, common to all the guests also in its composition, acts as a mediator between the personal unconscious and the collective unconscious.

INTRODUCTION

The etiology of Eating Disorder (ED or Feeding and Eating Disorders FED) is referredto as “multifactorial”. So far, the main focus has been on psychological factors, which is why psychotherapy is the primary treatment method (Herman A et al., 2021). Interest in the identification of new factors that contribute to the genesis of these disorders has grown around the etiology of ED: research has recently focused on the study of microbiota (Carbone EA et al., 2020). The term microbiota indicates the set of microorganisms that populate the digestive tract, mostly in intestine. It’s about over one thousand billion bacteria, viruses, fungi and protozoa with a total weight of about one and half kilograms which, communicating each other, act as if they were a single organism and perform important functions for human health. Sometimes, improperly, the term microbiome is used instead of microbiota, which exclusively indicates the genetic heritage (set of its genes) of the microbiota.Studying the microbiome is important, first of all, because it represents about 90% of the total number of genes, represented by the genes of the microbiota and the human genome; secondly, because it allows to know the structure of the microbiota, that is the microbes that make it up, in order to then evaluate the functions and study their metabolism. The part made up of bacteria is called bacteriota, that made up of viruses is called virota, that represented by fungi is called micota. However, when we talk about microbiota we generally mean the bacterial part of it, due to the greater ability of bacteria to metabolize (process and convert into other substances valuable for health) the product of digestion. Basically these deal with the final processing (fermentation) of carbohydrates and proteins from which short-chain fatty acids (SCFA), hydrogen, carbon dioxide, ammonia, amines, phenols and energy are produced. The diversity of microbes and the prevalence of some species over others depend on multiple host factors:

• population to which it belongs;
• place where it lives;
• genetic heritage
• personal history, including mother’s pregnancy;
• type of delivery and breastfeeding;
• diet;
• lifestyle.

For a long time it was thought that, before, birth, the fetus was not colonized by microorganisms. Some studies, on the other hand, would seem to indicate that bacteria contained within the placenta can contribute to the formation of the microbiota and the body’s defense system (immune system) of the unborn child. However, some compounds produced by maternal microbiota are thought to be more likely to influence the immune system of the fetus and newborn. In any case, it is now increasingly evident that the neonatal period and the first years of life, when the microbiota develops, represent a critical moment for the potential long-term implications of health and the emergence of some types of disease.

The microbiota changes with age and with the variation of the elements that influence it such as the environment and diet which, in the space of a single day, is able to temporarily change about 60% of its composition. The remaining 40% tend to remain stable, at least in the middle part of life. Instead, it tends to be unstable in the initial phase, when the maturation process underway, and in the final phase, typical of advanced age, Also for this reason, these age groups are considered “fragile” and more exposed to risks. Man and the microorganisms that inhabit his intestine coexist establishing a relationship based on the exchange of mutual benefits. The former supplies the nutrients, while the latter perform physiological, metabolic and immunological functions essential for maintaining a state of physical and mental well-being. This well-being would seem to depend on the state of health of the microbiota measured by taking into account three factors:

• rich diversity of microbe species present;
• relative numerical abundance of each species;
• ratiobetween beneficial and potentially harmful species(if they are more numerous than each other).

In other words, a microbiota made up of different species of microbes is considered healthy when it is composed of a good number of units with a prevalence of those beneficial to humans and in balance with each other and with the intestine that host them.

Even vaginal birth is a fundamental occasion for the exchange of microbes between mother and newborn and favors the development of a microbiota rich in many different species. It is considered so much important that the possibility of contaminating the newborn by cesarean delivery with the mother’s microbes by means of a swab is being considered. Caesarean delivery, on the other hand, would seem to impoverish this diversity and favor the prevalence of some bacteria such as Escherichia coli and Clostridium difficilis(potentially harmful) and the development (onset) of intestinal disease and others not strictly related to it such as, for example, allergies.

Even breastfeeding, by virtue of the mother-child exchange, represents an important stage in the formation of microbiota, due to the richness of the species (diversity) and the development of a good immune system in the newborn. A lack of contamination of the child by the mother with some bacterial species (for exampleBifidobacteria), or their reduction due to early antibiotic therapies, can determine an unbalanced maturation of the immune system.

This state of equilibrium is defined in scientific language as “eubiosis”. In particular conditions it can break causing a process of alteration of the microbiota which leads to a state defined “dysbiosis”, a condition found in many disease: EDs, obesity, some inflammatory bowel diseases, some immunological and metabolic diseases. Currently, numerous researches are aimed at trying to establish whether dysbiosis can be considered the cause or the consequence of numerous pathologies. The EDs produce a physiological imbalance that triggers “intestinal dysbiosis”, i.e. alterations in the abundance and composition of the intestinal microbiota, which can cause negative effects on the health of the host. Through the gut-brain axis, psychological stress can cause disturbances to the normal state of the gut microbiota, which in turn can affect the central nervous system (CNS) and, consequently, cause changes in the host’s mood and behavior (Herman A et al., 2021). Exposure to viral or bacterial infections has been linked to an increased risk of EDs development and several cases are reported in which the onset of Anorexia Nervosa (AN) occurred after an infection. It has been hypothesized that secondary Anorexia that occurs during infection is a result of a release of proinflammatory cytokines with activation of the immune system. The persistence of secondary Anorexia after infection could constitute a risk factor for the development of AN (Galmiche M et al., 2022).

The gut-brain axis can be altered by various factors such as diet, lifestyle, infections and antibiotic treatments. Diet alterations generate intestinal dysbiosis which influences immune system responses, inflammatory mechanisms, intestinal permeability, as well as the production of short chain fatty acids (SCFA) and neurotransmitters by the intestinal microbiota (Navarro-Tapia E et al., 2021). Diet seems to have an impact not only on the modification of the intestinal microbiota, facilitating dysbiosis, but also on its recovery in patients with EDs (Carbone EA et al., 2020). Recent studies indicated that patients with eating disorders, in particular Anorexia Nervosa (AN), Bulimia Nervosa (BN) and Binge Eating disorder (BED), show a specific profile of the intestinal microbiota and this imbalance can be partially restored after a single or multi-strain probiotic supplementation. One of the factors influencing EDs’ pathophysiology is the gut microbiota composition due to the strong association between microbiota and brain function. The gut microbiota includes the phyla Firmicutes (including the genera Lactobacillus, Enterococcus and Clostridium) and Bacteroidetes (including the genus Bacteroides) as well as QActinobacteriaandProteobacteria(Navarro-Tapia E et al, 2021). The two phyla Bacteroidetes and Firmicutes represent about 90% of the identified bacterial populations while the remaining 10% is mainly composed of Actinobacteria and Proteobacteria(Carbone EA et al., 2020).Bifidobacterium spp. and Lactobacillus spp. produce GABA, related to anxiety control; Enterococcus spp. Escherichia spp. Streptococcus spp. and Candida spp. produce serotonin, a neurotransmitter involved in mood regulation, as well as dopamine produced by Bacillus spp.. In generalm gram-negative bacteria produce bacterial lipopolysaccharides, involved in the regulation of food intake through the activation of enteroendocrine cells which express toll-like receptors (TLRs). An imbalance of these molecules can compromise eating behaviors and weight loss. Furthermore, disturbances in microbiota composition have been linked to the anxiety and depression typical of patients with AN, and psychological stress can lead to microbial translocations that increase intestinal inflammation(Terry SM et al., 2022).

The neural mechanisms altered in the EDs are mainly related to the reward circuitry, behavioral control and decision-making pathways. In AN and BN there is greater connectivity between the insula, orbitofrontal cortex, and ventral striatum, but less connectivity from the orbitofrontal cortex and amygdala to the hypothalamus. In BED, there is decreased activity in the ventromedial prefrontal cortex, inferior frontal gyrus, and insula, areas involved in self-regulation and impulse control. Furthermore, the alteration of the dopamine pathway gives an important contribution to the development of any EDs. Harm avoidance mechanisms related to serotonin receptor availability and dopamine receptor binding are also impaired in AN and BN (Navarro-Tapia E et al., 2021).

GUT-BRAIN AXIS IN EATING DISORDERS

The term gut-brain axis refers to the bidirectional interaction between the intestinal microbiota and the CNS.Intestinal bacteria affectCNS by secreting neurotransmitters such as noradrenaline, serotonin, melatonin, GABA, histamine, acetylcholine (Herman A et al., 2021).Furthermore, the gut microbial diversity is associated with the dysregulation of appetite due to ability to influence the intestinal satiety pathways(Navarro-Tapia E et al., 2021). The fermentation of indigestible carbohydrates (fibers and resistant starch) by the colon microbiota produces short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, implicated on the maintenance of homeostasis, the regulation of appetite, and anti-inflammatory processes(Navarro-Tapia E et al., 2021).The levels of SCFAs represent the indirect measurement of the microbial composition and are influenced by dysbiosis. It was observed that SCFAs were lower in stool samples of AN patients, especially in the AN-restricter subgroup, compared to the control group.The reduction of SCFAs in patients with AN is a consequence of the low abundance of Roseburia. A significant increase in both fecal acetate and butyrate levels during renourishment of AN patients and changed microbiota composition, especially increased Firmicutes, after weight regain were demonstrated. A beneficial role in appetite regulation as well as the involvement of SCFAs in energy homeostasis regulation has been suggested. The importance of SCFAs on appetite and energy metabolism suggests SCFA modulation as new nutritional target to prevent or counteract EDs(Carbone EA et al., 2020).

Modification in food intake may generate imbalance in microbial diversity (alpha diversity) with reduction of Firmicutes and increase of Bacteroides in the intestine (Seitz J et al., 2018). Recent studies observed that alpha diversity and fatty acid levels were lower in patients with AN(Carbone EA et al., 2020).Alpha diversity was lower during the phase of weight loss, resulting in a reduction of Firmicutes and SCFAs and increase of Bacteroides, Actinobacteria, Enterobacteriaceae, and Methanobrevibactersmithii. A re-established Firmicutes/Bacteroides (F/B) ratio and an increase of SCFAs levels were reported during renourishment and weight gain(Carbone EA et al., 2020). Moreover, alterations of gut microbiota decrease the intake of calories from the diet, altering the immunological response(Navarro-Tapia E et al., 2021).

The increase oflipopolysaccharides (LPS), endotoxin produced by gut bacteria activates innate immune system under dysbiosis. LPS also increase the permeability od blood-brain barrier, making cytokines have a larger impact on appetite regulation.(Herman et al., 2021).Endotoxins trigger the release of proinflammatory cytokine such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) (Seitz J et al., 2019).It is now largely accepted that peripheral inflammatory events may directly cause CNS inflammation.Circulating proinflammatory cytokines pass through blood-brain barrier activating microglia to release other proinflammatory cytokines (Na KS et al., 2014).Central changes in immune signaling can have significant impacts on a variety of brain functions, including feeding behavior and mood regulation (Butler MJ et al., 2021).

Lastly, recent studies demonstrate gut microbiota modulates the hypothalamic-pituitary-adrenal axis activity, therefore its imbalance may produce abnormal levels of corticoid hormones promoting behavioral changes (Seitz J et al., 2019).Considering the role of gut microbiota in the modulation of neuronal circuits through gut-brain axis, analyzing microbial profiles in patients with EDs is vital.Knowing the changes in these patient’s microbial population may help to develop new therapies based on microbiota modulation (Terry SM et al., 2022).

Furthermore, neuroendocrine and metabolic pathways mediate interactions between gut microbiota and CNS, regulating satiety hormones such as alpha-melanocite stimulating hormone (αMSH) and hunger stimulating peptides originating from gastrointestinal tract (ghrelin, leptin e orexin) (Terry SM et al., 2022).Appetite-regulating neuropeptides play a role in the aetiology and course of EDs; appetite inhibiting peptides other than α-MSH such as cholecystokinin (CCK), peptide tyrosine tyrosine (PYY), and appetite stimulants such as ghrelin and neuropeptide Y (NPY). These peptides are synthesized in the digestive tract and affect the hypothalamic centers responsible for maintaining the body’s energy homeostasis. Fasting and binge cycles in BN may be the result of differences in the secretion of these proteins(Herman et al., 2021).

COMPOSITION OF MICROBIOTA IN EATING DISORDERS

The first studies in people with AN showed 11 new bacterial species classified in Firmicutes (Soleaferreamassiliensis, Stoquefichusmassiliensis, Doreamassiliensis, Holdemaniamassiliensis, Clostridium anorexicus, Clostridium anorexicamassiliense, Bacillus marseilloanorexicus), Bacteroidetes (Bacteroidestimonensis, Alistipesmarseilloanorexicus), and Actinobacteria (Streptomyces massiliensis, Blastococcusmassiliensis)and four new micro-eukaryote species (Tetratrichomonas sp., Aspergillus ruber, Penicilliumsolitum, and Cladosporiumbruhnei), respectively, in a single fecal sample, demonstrating an abnormal state in the intestinal tract of people with AN (Navarro-Tapia E et al., 2021).

Recent studies conducted on populations affected with AN demonstrated a reduction of the total amount of bacteria in patients with AN. Moreover, Streptococcus, Lactobacillus plantarum and Roseburia, butyrate producers, Ruminococcus, carbohydrate fermenter, Ruminococcusand Clostridium, belonging to Firmicutes, were reduced with decreased acetate, propionate, and butyrate concentration in the feces (Terry SM et al., 2022). Propionate exhibited a positive correlation with insulin concentrations and with the relative depletion of the propionate producer Roseburiainulinivorans, whereas butyrate levels were negatively correlated with anxiety and depression. This may explain the reduced insulin levels and the increased anxiety in AN individuals (Navarro-Tapia E et al., 2021).Methan-producing Methanobrevibacterwas increased in AN compared with healthy controls. Methanobrevibactersmithii improves the efficiency of microbial fermentation, and its richness optimizes calorie extraction from a diet with very low calories content. The development of Methanobrevibacter in AN patients might be associated with an adaptive mechanism to optimize the absorption of a hypocaloric diet.The nutrient-deficient environment, together with a delayed colonic transit in AN patients, favors the increase of mucin-degrading microorganisms. This will contribute to a disrupted gut barrier and a chronic state of low-grade inflammation, exacerbating the disease. Therefore, the microbiota profile has been linked to gut inflammation and impaired structure of epithelial layer, as demonstrated by the increased levels of IL-6 found in AN patients and IL-6 and IL-1 α in obese individuals. LPS also produces an increase in blood–brain barrier permeability with the elevation of plasma circulating cytokines responsible for the anorexigenic response(Terry SM et al., 2022).

Although there is an association between cytokine production and specific gut microbiota in a healthy population, more studies are needed in ED patients(Navarro-Tapia E et al., 2021). Changes in microbiota seem to be involved in appetite regulation mechanisms in BN too. Caseinolytic protease B (ClpB) produced by Enterobacteriaceae is, in fact, an antigen-mimetic of α-MSH capable of triggering immune response. IgG autoantibodies against α-MSH allow internalization of the IgG/α-MSH immunocomplex (Carbone EA et al., 2020), capable of activating the melanocortin system, particularly the MC4R receptor, involved in appetite regulation and eating behavior(Lucas N et al., 2019; Smitka K et al., 2021).

There is a lack of studies concerning BED. A similar mechanism, although opposite to the one already described in AN, was hypothesized due to the IgG reactivity to α-MSH in overweight and obese patients. A recent study showed decreased levels of anti-α-MSH antibodies in obese patients, while increased in individuals with AN and BN (Lucas N et al., 2019).Plasma concentrations of ClpB in patients with AN, BN, and BED were found higher compared to healthy controls (Carbone EA et al., 2020).BED is very often associated with numerous comorbidities, especially obesity, and patients with BED and obesity exhibited an unfavorable metabolic and inflammatory profile related to their characteristic eating behaviors.A diet rich in lipids can raise levels of Firmicutes and Proteobacteria and decrease levels of Bacteroides, thus leading to an increased F/B ratio.A lower alpha diversity has been demonstrated in gut microbiota in both underweight and obese patients, with a significant correlation with BDI score indicating greater levels of depression (Carbone EA et al., 2020).

Gut microbiota in obese patients has a specific composition and differs from obese individuals without BED. A cross-sectional study (Leyrolle Q et al., 2021) of a cohort of 101 obese patients showed a decrease ofAkkermansia in obese patients with BED. Akkermansiamuniphila produces propionate, an important regulator of satiety and acetate and increased intestinal levels of several acylglycerols (2-OG, 2-arachidonylglycerol, and 2-palmitoyl glycerol) involved in the regulation of the inflammation and immunity reactions (Navarro-Tapia E et al., 2021).

A PSYCHODYNAMIC VIEW OF THE MICROBIOTA

The topic of the microbiota shows the overcoming of the Platonic and Cartesian ontological split between mind and body. The development of thought, and consequently of behavior, are closely connected to somatic structures capable of influencing and determining mental functions. However, the microbiota shows the fragility of medical vision, which divides the body into organs with specific functions. The intestine-brain axis and the two-way communication between the two organs show as reductionist medical vision of the brain as the place of mental illness, which instead requires a holistic view of the soma. The biological alterations of mental illness are expressed in the whole body, of which being sick is an attribute. The famous Latin expression “Menssana in corporesano” (a healthy mind in a healthy body) taken from Juvenal’s Satires becomes “a healthy mind is a healthy body”. The body does not constitute the container but is a biological entity that finds ontic expression in the mind.

In this sense, the microbiota is placed as an intermediate biological structure between the ego and the environment. This concept enlarges the analytic notion of “Skin-Ego” introduced by Didier Anzieu. The skin constitutes the barrier that divides the internal and external environment, and symbolically constitutes the limit of the person, it delimits and contains individuality and the diffusion of identity. The microbiota, which covers the skin and mucous membranes, constitutes an entity that stands between the subject and the environment, between the skin and external reality. It composes a variegated structure that is not Ego, which is not made up of cells belonging strictly to the soma, but which lives symbiotically with the human body. It, therefore, makes the physical and theoretical limit between the Ego and the environment more nuanced.

Furthermore, the intestinal microbiota, as previously underlined, varies according to eating behavior and therefore constitutes an individual expression of “food environment”. Food is a very broad and complex topic, which concerns nutrition, the intake of macro- and micro-nutrients, but also the relationship with own body, self-image, hedonia, the relationship with food and with other people, sociability. Very often in Western society the relationship with food is reduced to the simple organic component and to the correct intake of adequate quantities of nutrients. Although the nutritional component is fundamental in developing a valid relationship with food, nutrition includes several other components. First of all, the relationship with food reflects the relationship with pleasure and the ability to value or limit the hedonic component, and therefore the drive component. Furthermore, food is sharing: the gesture of eating with others symbolizes the sharing of what feeds our body, and therefore of our essence. The etymology of the word “conviviality” is not “eating together”, but cum vivere, “living together”. In this sense, the refusal of food (both restrictive and elimination) becomes a refusal of the Other, which becomes the projection of an anorectic greed, which dries up the Identity of the Ego like the body. In Boris’ vision the conception of the nervous anorexia is thought as determined by an intense greed (and therefore orality) projected onto the parents (to be understood as the reference figures). According to Selvini-Palazzoli, in nervous anorexia the body assumes the role of a bad introject of the mother-environment, and it has to be annihilated.

Anorexia (like hyperorality) therefore constitutes one of the modalities of counter-response toward each person’s environment.

We can find the somato-psychic unity that the microbiota can represent in the exchange that takes place between mother and child during childbirth and breastfeeding. This exchange can be read in the Demeter-Persephone (Kore) myth, in which Gea (the jealous mother-earth of Demeter) allows Hades to capture Kore and take her away from her mother. Hades represents in this story the male principle in the underworld. Hearing her daughter’s cries, Demeter rushes to look for her, but she cannot find her anywhere and “she suffers anguish and horror… that mother who surrounds with love her daughter, crushes her daughter in a deadly embrace, in a tremendous and continuous contradiction, and in the horror feeling that a young woman always feels, in a certain phase of her life, in the complex and varied relationship with her mother” (F. La Rosa, 2006). Demeter’s laments reach Olympus. The gods decree that the raped virgin can be returned to her mother on the condition that she has not eaten anything underground. Hades, having heard the verdict of the gods, forces a pomegranate seed into Persephone’s mouth. Persephone is condemned to spend a third of the year underground while the rest of the time remains with her mother. Kore’s abduction unleashes her negative aspect in Demeter. From the divinity of the harvest, she transforms into the divinity of vengeance and sterility, the Shadow of the feminine principle. Persephone offers herself to sacrifice, descending into the darkness of her father’s masculinity. The archetypal model tells us that the woman has to separate from her mother and surrender to the masculine principle, through union with her own inner masculine. The risk she runs in both cases is that of being possessed by the Animus. The natural way of the feminine principle, through the body and the sense of transformation rites, is to recognize the girl as part of the cosmos. In the absence of rites, in the modern era, most women (but also men) are identified with the masculine principle and there is no room for feminine instincts. In this case, the masculine and the feminine are not authentic and therefore there cannot be a not-Self to which the feminine can surrender. (Jung 1934) Without this, the purpose of the action of Hades who kidnaps Kore and transforms her into Persephone is meaningless. “The woman is possessed by the Animus, a prisoner of an undifferentiated masculine, fierce against her own feminine nature” Jung, commenting on this myth in “The psychological aspects of Kore”, writes: “Each mother contains her daughter and each daughter contains the mother… each woman extends back into the mother and forward into the daughter. This kind of experience gives to the individual a place and a meaning in the life of generations… at the same time the individual is freed from isolation and restored to wholeness.” This is the cycle of nature. The feminine principle Gea imposes on Demetra the kidnapping of her daughter so that the renewal and the reunion between old and new can take place.

From this point of view, the microbiota symbolizes the factor of the dual bidirectional communication between the Ego and the food environment understood as the “world”, but it is also an expression of the collective unconscious in the body of the single person for its function of intermediation and integration between the singularity of the individual and the universality of his relational environment.

The “conviviality” of eating together becomes a symbolic vehicle of being together with others not only on an emotional-relational level, but also on a biological level. The intestinal population, common to all the guests also in its composition, acts as a mediator between the personal unconscious and the collective unconscious.

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