Anorexia nervosa (AN) is defined by Diagnostic and Statistical Manual of Mental Disorders (DSM 5) as a mental illness characterised by a high restriction in energy intake, with a very low weight and terrible fear of weight increase. The AN classification is: restrictive and compulsive. In the restrictive mode, patients will describe during past three months laxatives abuse, vomiting, and diuretics use. The compulsive type is an alternation of binge eating and purging(1). The main target in AN is weight recovery. This will be mandatory for the prevention of psychological or somatic sequelae(2).
Gut microbiota plays more and more a recognised role for the host and is constituted of different microorganisms, living in symbiosis with the host. The microbiota is specific and unique for each person, the composition being like a fingerprint(3). Along the intestine, microbiota’s changes in density and composition are affected by nutritional, immunological and chemical factors. In fact, these bacterial communities will be found in the colon(4). A disruption of the normal gut microbiota, defined as dysbiosis, is described in AN.
The brain-gut axis: implications in anorexia nervosa
The bidirectional communication system between the host brain and the gut is defined as the brain-gut axis. The regulatory mechanisms are immunological, endocrine and neural systems, microbiota playing a key role(5,6). The communication to the nervous system is through ENS- enteric nervous system. The role of these connections is to control and coordinate motility, mucosal transport, blood flow and secretions in the gastrointestinal tract, with direct influence on the composition of gut microbiota. Motor neurons act as effector cells in the gastrointestinal tract(7). The connection between CNS and ENS is realised by the vagus nerve, creating neurochemical signals via gut microbiota to the brain(8) and back from nervous system to gut microbiota(9).
The observation from animal studies reveals that, in the absence of microbiota, an abnormal hypothalamic pituitary adrenal axis will be developed, with effect on releasing cortisol, the stress-induced hormone(10).
An important effect of gut microbiota can be seen on thyroid and sexual hormones, coordinating hormones and peptides release that are involved in feeding behaviour and in energy balance(11). It can be assumed that microbiota organisms will be able to influence host food habits and also emotional behaviour, influencing molecule secretion(12). It is interesting that bacteria can communicate on the other side with host’s brain, because they have receptors for hormones(13). Gamma aminobutyric acid (GABA) is the neurotransmitter that reduces stress and anxiety, and Bifidobacteria and Lactobacillus are able to synthetize this neurotransmitter(14). Norepinephrine is produced by Bacillus, Saccharomyces and Escherichia(14). Moreover, Streptococcus, Candida, Enterococcus and Escherichia produce serotonin, while Serratia and Bacillus are producing dopamine, which could be considered the major CNS disruptor(15).
Butyrate acid is produced by gut microbiota, and its beneficial effects in the brain are well known(16). Butyrate acid is a short chain fatty acid resulted after fibres bacterial fermentation in colon and can improve brain health.
Practically, microbiota could be seen as a recruiter for bidirectional communication between the gut and the brain and is a modulator for brain development, behaviour and function(17).
Alcock and Maley(18) suggest that gut microbiota can control the preference for food and our appetite. In anorexia nervosa, the main features are:
Eating disorders are associated with an neuroendocrine and neuropeptide dysregulation(20), but still some mechanisms behind AN need to be elucidated. In AN, it has been described the dysregulation of the entire endocrine system, including appetite regulation hormones and adipokines(21). New data are associating the dysregulation of serotonin pathways with behavioural inhibition, anxiety and distorsions of the body image, described in AN(22). It is well known that psychological stress can induce microbiota changes(23). Stress is positively correlated with Camphylobacter(24) and negatively with Lactobacillus(25).
Dysbiosis in anorexia nervosa patients
Dysbiosis is defined as a disruption of the normal gut microbiota composition and is associated with different diseases. Dysbiosis can be described by the lack of beneficial bacteria, pathobionts presence and low microbial diversity. A growing number of diseases are associated with dysbiosis: obesity(26), asthma(27) and neuropsychiatric disorders (schizophrenia, psychotic disorders, autism spectrum disorder, Alzheimer disease, Parkinson disease, major depressive disorders and anorexia nervosa)(28-37).
The gut microbial dysbiosis is associated with anorexia nervosa and is marked by taxonomic differences and lower microbial diversity versus healthy controls. Dysbiosis is accompanied by eating disorders and depression psychopathology(38). There was an interesting result found in another study, where microbial composition was evaluated before and after weight regain in AN, showing profound differences in microbiota which didn’t recover after weight gain(39). Reduced levels of butyrate, and also decreased Bacteroidetes/Firmicutes ratio were described in AN patients, before and after weight gain.
Recent evidence(40) are describing dysbiosis in AN: lower alpha diversity, increase in Turcibacter, Anacrotruncus, Salmonella and Klebsiella, and decrease in Eubacterium, Anacrostipes, Roseburia and Peptostreptococcaceae.
The neurodevelopment is related to genetic expression and environmental factors coordination. The development of social behaviour, emotions and cognitions requires precise regulation and molecular signalling pathways are involved together with the microbiome-gut-brain axis(41,42).
All evidence about gut microbiota in psychiatric disorders are suggesting that an intervention is needed on gut microbiota. How microbiome could be modulated? Antibiotics, probiotics, prebiotics or fecal microbiome transplantations (FMT) are possible interventions. The International Scientific Association for Probiotics and Prebiotics (ISAPP) defines probiotics as living organisms that, when administered in adequate quantities, confer benefits for host health(43). ISAPP scientific panel is confirming that probiotics help in having a healthy digestive tract, emphasizing general benefits of probiotics for gut microbiota.
Increasing interest, due to promising study results(44,45), is attributed to probiotics, live bacteria which could confer health benefits when the intake is adequate. Behavioural abnormalities could be improved by Lactobacillus strains(46) and evidence are showing that other probiotics are improving emotions(47). There are described probiotic bacteria with positive outcomes on mental health benefits, which associated with prebiotics will be named psychobiotics. Human gut has a unique bacterial colonization and will influence the clinical presentation of patients with stress-related or affective disorders. In the future, personalised psychobiotics could play an important role in modulating dysbiosis in AN.
All these suggested that treatments with probiotics in AN must be managed carefully, because is a high risk of bacterial infections and need to be in accordance with nutritional rehabilitation(48), having as target psychological functions restoration and reversing malnutrition. The existing data are revealing that in AN gut microbial diversity is increasing after refeeding.
Using functional foods, with the potential of modulation for gut-brain axis, influencing mental health, is a novel and interesting topic. Fermented foods, due to important health benefits, are considered functional foods.
Immune mechanisms in the regulation of metabolism and food intake
The chronic food restriction in AN may lead to gut barrier dysfunction, contributing to different diseases. Many changes in immune reactivity are described in anorexia nervosa: increased release of TNF-(49) and decrease of interferon gamma by mononuclear cells(49), decreased cell-mediated cytotoxicity, increased serum levels of IL-6, IL-2 and transforming growth factor beta (TGF-)(50), cross-reacting autoantibodies reacting specifically with several appetite regulating peptides(51), the association between eating disorders and several autoimmune diseases(52), the association of autoimmune and antiinflammatory diseases with increased risk of eating disorders(53). Starvation will lead to a “leaky gut”, and increased mucin-degrading bacteria will influence chronic low-grade inflammation expected in AN patients. Anorexia nervosa is an autoimmune disease – it is an hypothesis elaborated by Acres et al., named “hygiene hypothesis”, and is produced by a delayed exposure to microorganisms that are common and then autoantibodies are produced for appetite regulating neurotransmitters, neuropeptides and hypothalamic neurons that disturb completely the appetite and, as a result, it decreases the food intake(54).
Microbiota patterns – the role of lifestyle
AN etiology is complex. The healthy state depends on interactions between environmental factors and genetics. Culbert et al. are suggesting that psychological and environmental factors could potentiate the genetic risk and induce eating disorder(55).
Gut microbiota is influenced by lifestyle factors, both dietary and not dietary, but for AN patients there are not many data available. The disordered feeding behaviours such as vomiting and laxative abuse are part of an unhealthy lifestyle. Unhealthy feeding behaviour and lifestyle could lead to AN – this is a discussed subject. Practically, the obsession for a very low weight(56) is accompanied by inappropriate lifestyle practices, with direct influence on microbiota. It is well known that patients with anorexia nervosa avoid carbohydrates and increase protein intake, especially of animal origin. With smaller fibres intake, short chain fatty acids (SCFAs) formed are in smaller quantity and microbiota composition will be altered. Due to fatty acids imbalance, insulin resistance and metabolic dysfunctions will be relevant in eating disorders(57). A common comorbidity for patients with AN is the anxiety disorder(58).
A relation with this comorbidity and inflammation has been established in animal studies. Some stressors can induce microbial translocation, generating gut inflammation, maybe the link between microbiota changes in AN and its onset(59).
Despite the fact that inflammation biomarkers are not changed in severe AN cases(60), commensal microbiota typical in inflammation is changed in AN patients(57).
In addition, hyperproteic diets used for refeeding could develop a type of microbiota characterised by inflammatory profile(61). Probably, microbiota changes in AN from the onset to the first stages could give more details about different implications in eating disorder progression. The neurodevelopment can be influenced by early life perturbations and it could be responsible for different mental disorders that appear later in life. At this point, lifestyle-based therapeutic interventions could prevent future brain disorders(62).
Human microbiome detailed analysis was possible due to advanced techniques in molecular biology. It is generally accepted the role of microbiota in diseases and health. In recent years, studies on anorexia nervosa and microbiota emerged. Significant changes in gut composition are associated with behavioural disorders, mainly eating disorders.
In anorexia nervosa, the biomarker for disease onset and progression can be considered increased M. smithii.
The recommended intervention will be to restore microbiota, which is impaired in AN, considering the intake of pro-/prebiotics, or fecal microbiota transplantation.
In AN, psychiatric intervention should be initiated as early as possible and, after analyzing the available data, microbiota could be a starting point and should be included in nutritional intervention as part of a rehabilitation program. The whole protocol must include refeeding under specialised control, increase dietary fibres, and including in the diet pro-/prebiotics. New psychobiotics may improve mood, decrease anxiety and strengthen memory, as described in preliminary findings. In the near future, anxiety, depression or other mental disorders may be treated with probiotics/psychobiotics, using them in food or supplements to change gut microbiome(63).
The personalised psychobiotics approach will be the future perspective.