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Role of Gut Microbiota in etiology, in the progress of diseases and in the treatment of eating disorders. The study.


Eating disorders are regarded as severe mental pathologies occurring continually by means of shared behaviors, amongst syndromes negatively influencing cognitive, physiological and social aspects of function. Predominance of behaviors linked to eating disorders, within the community, is believed to be increasing; a general, cross-population survey in Southern Australia reported doubling of predominance in adults of 8.4% through the last decade, whereas the demographic profile deviated from a predominance of young whites and high-class women to an increase of aging men and lower-class men [1,2]. Although onset may take place anytime throughout lifetime, the majority of eating disorders show up during youth and adult age. A study performed in a large US city brought to evidence that 13% of young women experienced an eating disorder at least once through a 20-year span [3]. While the majority brings to evidence the influence of a negative image of body-shape, alongside concern about body weight intended as primary etiology of eating disorders (thus regarded as mental illness), evidence suggests how disturbed nutrition or eating tastes may also be biologically controlled. Whatever the reason (i), this generally leads to controlled consumption, and whenever such pursuit becomes an obsession through lifetime, patients pursue extreme diet restrictions, binge eating and balancing behavior. Hence, mood disorders and metabolism disorders further contribute to physical and psycho-social morbility. Income and employment reduction, heavy load and high healthcare costs: eating disorders not only play a negative role on individuals, but on social level too [4,5,6,7] .


By now, it is quite clear how necessary a correct function of gut microbiota is, in terms of regular physiology, as much as a general state of dysbiosys (a microbic profile that differs significantly from that observed in healthy individuals) may increase risk of diseases. The ever-increasing amount of literature concerning the effects that gut microbiota plays on host’s health, ranging from nutrient/energy metabolism to brain’s performance, has led us to consider a role of this “forgotten organ” in etiology as well as physio-pathology of eating disorders. Given the interaction between intestinal and brain, gut microbiota may well be regarded as a crucial mechanical bond between psychological and biological factors of such pathologies. Even more important, balancing behaviors (i.e., laxative abuse), and conventional treatments (nutritional rehab) should play an impact on the gut microbiota, whereby this change may help further modify progress of disease. We hereby evaluate proofs of how gut microbiota is integral part of eating disorders, from beginning to progress and treatment. We then suggest additional research to improve our understanding and possibly take advantage of therapeutic potential by gut bacteria, aimed at improving outcomes of eating disorders.




Classification of “eating disorders” describes a cluster of mental diseases showing up by means of disorders of nutritional behavior and adjustment of body-weight, with subsequent compromise within dominating physiological systems, such as gastro-intestinal and cardio-vascular functions. The fifth edition of diagnostic and statistic manual of the American Psychiatrists’ Association [8] recognizes three primary diagnoses within the nutritional disorder category:


- Nervous anorexia (NA)


- Nervous bulimia (NB)


- Binge eating disorder (BED)


Presentations of eating disorders not included in this disgnostic bracket (about 20-40% of cases) are classified among residual categories (other specific or non specified eating disorders OSFED). Despite diagnostic differentiation exist amongst categories, a range of symptoms (i.e., restriction of calories, clearance, binging, over-appreciation of body weight) appears to be common amongst diagnoses of eating disorders.


Diagnostic criteria and crucial behaviors in eating disorders.


Accuracy is unknown in etiology of eating disorders, even though genetic and neurobiologic attitudes are believed critical, alongside belief in interference from environmental and social-cultural factors, in addition to psychological traits, in the development of diseases. Relatives of a subject with an eating disorder are thought to be 7-12 times more likely to develop the same disease [9,10,11]. Role of genetics is further supported by data from two studies evaluating inheritance factor in 30-80% of NA and NB [10,12]. Importantly, maturation of age as well as puberty seems to contribute an emerging genetical risk facto ras for the symptoms of eating disorders during youth and median-belated puberty, probably due to sexual maturity (physical shape and hormonal changes) as well as a growing cultural pressure in favor of being “Lean” intended as the ideal model to pursue [13,14,15].


There seem to be supporters of eating disorders based on neurologic factors, particularly with regard to the role played by hypotalamus in appetite and control of body-weight. Neuropeptiteds and neuro-endocrinous alterations are quite typical of eating disorders [16], and studies on functions by functional MRI (fMRI) evidenced altered set-point and/or sensitivity to sensorial-interceptive reward processes toward consumption of food expected to exceed Omeostatic needs [17]. What is still unclear is whether patients with eating disorders are dealing with a primary neurobiologic disorder or it may be regarded as a consequence of physiologic alterations caused by the progressing disease. Ultimately, psychological and psycho-social traits are generally acknowledged as key components in the etiology of eating disorders. Psycho-social performance, quest for perfection, the process of acquisition of the lean model as ideal, the negative urgency, sensitivity to reward and reproach are amongst the key risk-factors potentially leading subjects to the onset of such diseases [18,19]. Beside etiology, eating disorders are further complicatedby their instability and chronicity: diseases may swiftly shift from activity to recovery and recurrency, whereby patients generally undergo reiterated courses of recovery-acquittance and even transition from symptoms of anorexia to bulimia and viceversa, throughout their lifetime [20]. Whereas some complications are clearly a direct consequence of chaotic eating behaviors, i.e. vomit and laxative abuse leading to electrolytic disorders, others are mainly caused by a meager nutrient intake, particularly gastric motility, constipation and subsequent reduction of bone mass. Such complications are not only liable of undermining physiological functions, they even triggerpsychological stress.


"Subsequent suffering depression and anxiety further contribute to the negative cycle of long-term morbility."


To date, treatment of eating disorders is typically composed of combined management of clinical complications, as well as psycho-social and psychiatric therapy, nutritional rehab. The measures best suited to clinical and psycho-pathologic profile of each patient, as well as to the response to previous treatments, are generally regarded as the most likely to optimize the outcome in treatment of eating disorders [23,24].




The Dysbiosis in eating disorders


Each subject is endowed with a unique, though remarkably dynamic, eco-system of the intestine, due to a series of complex interactions between genetic and environmental factors. Resemblance in microbial composition and functions among healthy individuals suggest quite an importance of microbioma’s nucleus, with regard to host’s health [25]. Many a disorder, ranging from metabolism (i.e., Obesity and T2D) to self-immune (i.e., multiple sclerosis) and neuro-degenerative (i.e., Alzheimer’s disease), have been associated with dysbiosis [26,27,28], and massive efforts have been applied to the development of treatment aimed at achieving a healthy microbioma. Because host’s diet is a crucial factor for the intestinal microbial configuration, and some eating disorders are generally associated to an irregular food intake, assuming a correlation between eating disorders and an altered gut microbiota is therefore logical. Surprisingly though, literature in this specific field is limited, reporting a mere handful of studies measuring the gut microbial profile in patients affected with NA [29,30,31,32], and no data available concerning other forms of eating disorders.


The Microbiota-Intestine-Brain Axis


The Intestine-Brain axis, connected by neuronal, hormonal and immunologic pathways, is a bi-directional communication system initially acknowledged for its role in regulating the digestive function as well as food intake [33,34]. A high prevalence of co-morbidity between psychiatric and gastro-intestinalsymptoms also does exist, for instance 40-60% of patients with gastro-intestinal functional symptoms report psychiatric symptoms [35], moreover up to 50% psychiatric patients are diagnosed with irritable bowel syndrome [36], clearly suggesting wider implications by this axis, concerning gastrointestinal and cerebral functions. Recent progress in our knowledge of gut microbiota shed new light on the interaction between the brain and gastro-intestinal tract, whereas microbiota is regarded as an integral part of intestinal communication, itself an independent component of the Microbiota-Intestine-Brain axis [37,38].


Effects of Gut-Mcrobiota on appetite


Altered brain communication is evident in eating disorders with an irregular control of appetite and distorted perception of repletion, amongst the predominant biological factors of extreme nutrition behaviors. From evolution standpoint, a role played by gut microbiota in modifying host’s nutrition behavior is utterly likely, for different bacteria have distinct nutritional requisites; for instance, Prevotella thrives on carbohydrates, whereas Bacteroides seem to prefer proteins and animal fats [39]. Alcock & Associates [40] furthermore hypothized that diversity of microbial population is the basis for the process of regulating host’s food intake, for the predomination of any particular microbial group might apply a greater selective process, therefore a positive-feedback cycle involving the host, ultimately leading to select diet and/or model preferences.


There are no definitive studies regarding such a microbiotic-host food intake relationship in human beings, however animal-based data show some likely mechanisms. The first one is likely the impact played by intestinal bacteria on appetie-regulating hormones.


Entero-endocrinous cells express receptors similar to Toll-type ones, which, once activated by means of a link with bacterial products (i.e., lipo-poly-saccharides LPS and flagelline), modify secretion of hormones (such as cholecystokinin) involved in regulating repletion and hunger [38]. Evidence also there exists regarding intestinal bacteria, through production of LPS, modulating effects of central nervous system on gastro-intestinal function,. as well as food intake and energy homeostasis. LPS interfere with hemo-hematic barrier (i.e., increasing permeability rate) [41] to increase impact of circulating cytokines on central appetite regulation; some animal data suggest LPS triggers directly an anorexial-type response (i.e., inflammation-inducted anorexia) by activating the signaling system of Toll-like 4/MyD88 signal within the central nervous system [42,43], even though it has been demonstrated otherwise [44].


Another key-mechanism through which intestinal bacteria influence food intake is by producing peptides whose sequence is analogous to appetite-regulating hormones in mammals. These peptides then mimic the effects of host’s hormones and/or trigger an auto-immune response interfering with normal regulation of appetite; in other words, the host produces antibodies against microbial peptides, behaving as auto-antibodies counteracting the effects of host’s own hormones [40]. The latter may turn out particularly relevant in the pathogenesis and progression of eating disorders, as much as Fetissov and Associates [45,46] have disclosed that a patient sub-group diagnosed with NA and NB presented with auto-antibodies bonded with a-melanocyte-stimulating (MSH) hormone, and the circulating rate of these auto-antibodies is correlated to psychological characters of eating disorders. Ultimately, data concerning C1pB bacterial protein (manufactured by “companion” pathogenic micro-organisms) intended as an a-MSH mimetic and related effects on activation of host-repletion pathways in rodents [47], alongside high plasma concentration of IgG anti-C1pB (cross-reactive with a-MSH in patients with eating disorders [48], altogether in accordance with the notion that interference inducted by auto-sympathetic with melanocortin central system is one of the key-mechanismsof gut microbiota contributing to altered appetite control, in pathologies caused by nutrition disorders.


Effects of gut Microbiota on brain’s funtion and behavior


Let’s carry out a further exploration of effects played by microbiota on the bowel-brain axis, in association with psycho-abusive incidents linked to eating disorders. Psychiatric and neuro-degenerative mental disorders, including major depression [49,50], autism disorder [51] and multiple sclerosis [26], are constantly associated with some kind of dysbiosis. Gut microbiota is necessary for brain’s regular functionality. Behavior in rodents with depleted gut microbiota (i.e., born and raised without germs, or chronically treated with antibiotics) reported a compromised cognitive function along with increase of behavior similar to depression [52,53]. Moreover, germ-deprived mice that received a transplant of cecal content would perform behavioral phenotypes mimicing donors [54], and those treated wit fecal transplant from patients with major depression condition even more so demonstrated behavior similar to depression, as compared to those colonized with microbiota from healthy subjects [50]. These data suggest how behavioral traits are transmissible through microbes of the bowel, thus yielding relevant evidence about relationship between gut microbiota and psycho-behavioral profile.


The effects of intestinal bacteria on behavior are mainly mediated by their action on the hypotalamus-hypofisys-adrenalin (HPA) axis, an important neuro-endocrinous system with the ability to regulate response to both psychological and physical conditions, and is believed to be fundamental to etiology and progression of eating disorders [55]. There appears to be a lapse in life’s initial phase, during which intestinal microbes are crucial for correct programming of the HPA axis. Colonization by menas of microbioma devoid of pathogenic agents in the neonatal phase is supposed having inverted enhanced HPA stress response in germless mice, but played no effect when microbes had been introduced in a later phase of lifetime, which implies a role in neonatal dysbiosys (or infection), thus predisposing stress-related pathologies [56] through life-cycle.


Evidence also does exist that gut microbiota should maintain its effect on the HPA axis throughout the adult life, modulating its activity by means of pathways mediated by neurons and cytokines. Bacteria are keen on producing a wide variety of neurotransmitters and neuromodulators, for example g-ammino butirric acid (GABA) by Bifidobacterium spp. controls anxiety and serotonin, by Enterococcus spp modulates mood, acts directly on afferent axons or interacts with intestinal epithelial cells, thus the intestinal nervous system, with the ability to modify neural signaling to the central nervous system [37]. LPS, a metabolite from Gram-negative bacteria, provides the gut microbiota with an alternate pathway to modulate behavioral and cognitive parameters. Peripheral administration of LPS demonstrated the ability to induct mediated peripheral and cerebral response, whether in animals or in humans that did mimic effects of bacterial infection [57,58]. By connecting its receptors to macrophages, lymphocytes and granulocytes, LPS triggers production of cytokines (particularly, interleukin-1, interleukin-6 and a-tumor necrosys factor) of immune cells, while activating an array of changes in the nervous-immunocompetent system which in turn activates the HPA axis (for details, refer to a comprehensive survey by Tilders and associates [59]). Vedder et al. [60] have also demonstrated that LPS was able to augment the activity of HPA axis in healthy men, in accordance with dosage. Finally, even though LPS circulation does not trespass the hemato-cerebral barrier to determine influence on neurons or glial cells [59], LPS modulates the funcyion of hemato-cerebral barrier thanks to a direct effect of proteins on narrow bond proteins, thus barrier permeability as much as interaction with brain’s endothelial cells for regulation of traffic of immune cells and cytokine transport are an indirect way by intestinal bacteria to influence the central nervous system [61].


Effects of brain on intestinal Microbiota


While research efforts have been extensively applied to figure out how intestinal microbes can alter cerebral function, the opposite direction microbiota-asthma-brain received very little attention. One would expect that central and autonomous nervous systems should play a key role in intestinal bacterial colonization. For instance, by regulating gastrointestinal functions such as motility, nutrients’ absorption, acid production and mucous immunity, the brain shapes the habitat in the stomach, thus operating a selective process for distinct microbial profile [62]. There also exists evidence of direct interaction between intestinal microbes and guest signaling molecules, released in the intestinal lumen. By means of a process known as inter-reign signal, many micro-organisms express receptors of eukaryote hormonal signals acting mainly by adjusting genic expression [63], i.e. when exposed to noradrenalin, Campilobacter jejuni has shown a greater growth alongside properties associated with in-vitro virulence.


Within the frame of eating disorders, the effect of psychological stress is the main example of how the disease may alter the gut microbiota. Chronic social stress (for example, social disgregation of aggressive cohabitants) and premature stress (for example, maternal separation) have all demostrated to alter diversity and composition of intestinal microbiota in rodents [65,66,67]. A study on infant monkeys has also demonstrated an inverted relationship between stress-indicative behavior, abundance of Lactobacillus, alongside that of total aerobic bacteria and optionally anaerobic bacteria in fecal specimens, when separated from respective mothers [68]. Stress-inducted dysbiosys (with subsequent compromised intestinal barrier and bacterial relocation) has been suggested in terms of a key molecular mechanism stimulating innate immunogenic activity, thus contributing to association between chronic psychological stress-generating factors and systemic inflammation in human beings [69,70].


Effects on Gut-Microbiota of nutritional behaviors linked to eating disorder


Nutritional restrictions in patients with eating disorders alter availability of energy substrate (type, quantity, duration) for intestinal microbes, leading to distinct microbial profiles. Limited nutritional choice constitutes a direct selective pressure, for different microbial cliusters have their favorite substrates, for example Roseburia and Bacteroides are respectively sensitive to carbohydrates and proteins, and percentage of Bacteroides is related to the type of food fibers reaching the colon [71,72,73]. Data deriving from various classes of vertebrated hosts revealed that, during extended fasting, very much similar to NA case, microbes that utilize host’s intestinal mucins may thrive even in absence/scarcity of food nutrients [74,75]. Pursuant to this notion, availability of degradation taxa of Verrucomicrobia mucin has been observed to be augmented in NA patients compared to baseline, and returned to levels similar to healthy controls after weight increase [32]. Proliferation of Methanobrevibacter, a bacterial genus that generates methane from hydrogen and carbon dioxide, is another example of how intestinal eco-system of NA patients increases energetic harvest , in response to the poor nutrient availability [31]. The collective effect of chronic caloric deprivation in individuals affected with NA [30] or malnutrition [76] appears as a reduction in the diversity of intestinal microbial clusters, frequently associated with poor clinical results. Notedly, animal data also suggest that this “fasting microbioma” further contributes to host’s malnutrition, as much as a microbial transplant from donor individuals with Kwashiorkor (a severe form of protein-energy malnutrition) inducts weight loss and altered protein and carbohydrate metabolism in mice [77].


Discontinuous periods of nutrition and food retention are typical of the majority of eating disorders. Regardless of total calorie intake, such nutritional model is suppesed to reflect on the Gut Microbiota. Gut Microbiota present with specific changes, through time, in its composition and functions in accordance with host’s own circadian cycle, with up to 10% of all microbes in tested human beings showing daily oscillations associated with distinct functional entities through the day, for example energy-specific metabolism pathways are predominant during daylight time, whereas detox ways are indicated to be more active at night-time [78]. In complex, intestinal pH changes alongside availability of nutrients and metabolite secondary substances should play a role in host’s metabolism [79]. Limited feeding in mice [79] and repeatedly extended feeding and food retention cycles in dogs [80] are all demonstration of how intestinal microbiology’s variation is triggered, seemingly controlled by changes in specific abundance, themselves differentiating according to their preferred fermented substrates (i.e., host vs diet-dervived glycans). Microbial abundance cycle appears to be much in line with nutritional planning which in turn overwrites the effects of hosting circadian cycle, thus implying a role by irregular feeding patterns in contributing to dysbiosys, in cases of eating disorders.


Ultimately, purifying behaviors, including self-inducted vomit and abuse of laxatives/diuretics, are quite common amongst affected by eating disorders, aimed at weight-control purposes, although their effects on gut microbioma have rarely been explored. Two studies have described the structure of intestinal microbial population in restrictive and binge-purging types of NA patients. Morita et al. [29] found no significant difference between the two sub-types when each species’ abundance has been compared. By relying on bonded ordination techniques, Mack et al. [32] reported that the comprehensive microbial structure differs between the two NA sub-types, although no specific strain leading to such difference had been identified, furthermore demonstrating a reduction of microbial diversity in those who had reported use of laxatives. The exact mechanisms by which these behaviors tend to influence intestinal microbes remain fundamentally unclear, although it is likely that it may be a consequence of structural and functional modifications of colon, such as damage to mucous sheath, electrolyte imbalance, or perhaps changes in time of transit and abdominal intra-pressure, altogether altering intestinal environment for microbial colonization [81,82].


Effects of nutritional rehabilitation on Gut-Microbiota


Nutritional rehabilitation, aka refeeding, is a key component in the treatment of patients with eating disorders aiming at restoring physiological functions by inverting malnutrition. Demonstration has been provided of how achieving a healthy body-weight determines recovery leading sometimes to aggressive approach, including high-calorie meals and/or enteral feeding, particularli in hospitalized patients [83]. Low (or absent) fiber and resistant-fiber content in such feeding patterns restricts availability of energy substrates for intestinal microbes; abnormal fluid secretion in colon, activated by enteral infusion leads to harmful effects on intestinal microbiota [84,85]. An effect of enteral feeding on gut microbial colonization is evidenced by reduction of total fecal bacteria and by content of short-chain fatty acids in healthy men, following two weeks of fiberless enteral feeding [86]. Data on gut microbiota in NA patients subjected to institutional nutritional rehab programs suggest that cooling increases intestinal microbial diversity, altering composition, but remaining significantly different from that of healthy control patients [30,32].





Are the Gut Bacteria Telling Us to Eat or Not to Eat? Reviewing the Role of Gut Microbiota in the Etiology, Disease Progression and Treatment of Eating Disorders