Gut microbiome and anorexia
| Educator
17th Aug, 2021Article

Microbiome and AN

Anorexia nervosa (AN) is a complex and debilitating psychiatric disorder defined by extremely low body weight, a fear of weight gain, and image disturbance (1). The lifetime prevalence of AN for females ranges from 0.3%-1.5% and 0.1%-0.5% for males (2). It has the highest mortality rate of any psychiatric illness, and only one-half of patients experience long-term recovery. In addition, patients with AN often experience psychological co-morbidities, including anxiety (72% lifetime prevalence) (3) and depression (more than 81% lifetime prevalence) (4), further complicating treatment.

The causes and subsequent development of AN are complex and poorly understood. Genetic, psychological, sociocultural, and biological factors contribute to the risk of AN onset and maintenance (5,6). Nutritional rehabilitation procedures and psychotherapy are the mainstay treatments for AN (7,8); however, considering the high mortality and high chronicity, there is an urgent need to explore potential adjunct therapies. 

New research is shedding light on the role of the gut microbiota in AN. Compared to healthy individuals, the AN microbiome demonstrates significant differences in composition (dysbiosis), represented by low microbial diversity and taxonomic differences (9,10,11,12,13). The gut microbiome could play an important role in the disorder by regulating key features of AN, including appetite control, energy metabolism, gastrointestinal physiology, and mood. The microbiota may regulate these aspects through various immune, neuroendocrine, and metabolic pathways, forming the microbiota-gut-brain axis (14). While the relationship between the microbiome, dietary patterns and AN disease onset and progression remains poorly defined, preliminary studies suggest targeted microbiome-based interventions, including pre and probiotics and faecal microbiota transplants (FMT), may be beneficial adjuncts to standard AN therapy (14,15).

 

The gut microbiome and dysbiosis in AN

Microbial diversity is essential for health and disease prevention. A diverse microbiome includes species from the phyla Actinobacteria, Verrucomicrobia, Proteobacteria, Firmicutes, and Bacteroidetes (16). The gut microbiota of healthy individuals is far more diverse than the microbiota of AN individuals. However, there are conflicting results regarding specific changes in the microbiome in patients with AN, which could be due to patient dietary habits, lifestyle (e.g. stress, medication use and exercise levels) and the severity and duration of disease (15,17). 

The majority of studies found lower alpha microbial diversity  in AN patients compared to healthy controls (9,10,11,12,13); however, three studies found no difference in alpha diversity (18,19,20). In addition, two clinical trials following gut microbiome composition before and after nutritional rehabilitation found that weight gain did not restore bacterial diversity to levels comparable to normal-weight controls (9,19). These results suggest that dysbiosis might persist beyond weight recovery and potentially contribute to relapse, but further research is required. 

In general, a reduction in microbial diversity is associated with impaired immune defence and reduced capacity for harvesting calories from the diet (21), which may be relevant for AN pathophysiology. Furthermore, clinical symptoms of AN, including eating disorder psychopathology, anxiety symptoms and depression were related to a change in the composition and reduction in the diversity of gut microbiota, especially butyrate-producing bacterial species (9,20).

Current research demonstrates that acutely ill AN patients show a relative depletion of several carbohydrate-fermenting taxa belonging to the Firmicutes phylum (e.g. Roseburia, Clostridium, Anaerostipes, and Faecalibacterium prausnitzii), while Bacteroidetes (9,11,12,19,20) and Proteobacteria (Escherichia coli) are enriched (20,22). In contrast, the gut microbiome of individuals who are obese has an increased level of Firmicutes, and a reduced level of Bacteroidetes (23).

Increased abundance in the methane-producing archaeon Methanobrevibacter smithii (9,20,22,24) is consistently reported in AN studies. M. Smithii produces methane by metabolising excess hydrogen and carbon dioxide in the gut. It also enhances nutrient transformation into calories and increases fermentation of fibre and resistant starch, generating short-chain fatty acids (24). Therefore, the increase in the methanogens such as M. Smithii may be an adaptive response to prolonged caloric restriction in AN. 

Studies suggest decreased levels of carbohydrate-fermenters in AN individuals are accompanied by a shift toward mucin-degrading microorganisms (e.g. Verrucomicrobia, Bifidobacteria). These microorganisms favour delayed colonic transit commonly occurring in AN (25), and especially in a nutrient-deficient environment, they survive by digesting the protective intestinal mucus layer. Specifically, the mucin-degrader Akkermansia muciniphila found in several AN studies may represent an adaptive response (19,26). A. municiphilia is a symbiotic bacterium residing in the intestinal mucus layer and utilises intestinal mucin as its sole carbon, nitrogen, and energy source, especially in the absence of other dietary sources (27,28). A. municiphilia levels are positively associated with weight loss and are inversely associated with inflammation, body weight, obesity, and metabolic disorders (29,30).

 

Microbial metabolites in AN

The gut microbiota interacts with intestinal cells, the enteric nervous system, and the central nervous system, forming the microbiota-gut-brain axis. The microbiota produces various metabolites, including short-chain fatty acids (SCFAs), tryptophan metabolites, bile acids, neurotransmitters, and hormones. These bacterial metabolites can act on the intestinal epithelial barrier, cross the blood-brain barrier, and act directly on brain neurons, thereby affecting neurogenesis, cognitive function, and mood (31). Furthermore, microbial metabolites have immunomodulatory effects and can influence host appetite and eating behaviour by directly affecting nutrient sensing, appetite, and satiety-regulating systems (32).

Increased levels of faecal SCFAs are observed in obese and overweight people (33,34). However, faecal metabolite levels in AN patients show reduced SCFAs, particularly butyrate (19,20,35,36), compared to healthy subjects. Additionally, several butyrate-producing taxa belonging to the Firmicutes phylum (Roseburia, Clostridium, Eubacterium) are consistently underrepresented in AN gut microbiota (9,11,19,20).

Associations have been found between bacterial species, stool SCFA levels and clinical presentation in AN patients. In particular, the relative abundance of Roseburia spp. was correlated with decreased faecal butyrate levels (19,20), which were associated with increased anxiety and depression scores in AN patients (20).

Bacterial species produce several neuroactive compounds that may affect the peripheral and central nervous systems and human behaviour. For example, serotonin is one of the primary neurotransmitters present in the brain; however, more than 90% is produced in the gut, and its production is influenced by diet. Significantly lower brainstem serotonin levels have been observed in anorectic mice, which may be associated with reduced tryptophan intake resulting from restricted food intake (37). Recently, lower levels of serotonin, dopamine and gamma-aminobutyric acid (GABA) were detected in faecal samples of women with AN when compared with healthy women (38). In this study, an increased abundance of of Alistipes was observed. Alistipes is a genus of bacteria that can hydrolyse tryptophan (serotonin precursor) to indole and thus decrease serotonin availability (39).

 

Intestinal permeability and inflammation in AN

The gut mucosal barrier acts as a buffer between the external environment and the host's physiology and is essential to proper immune system development and function. A compromised gut epithelium and the subsequent bacterial translocation may trigger immune and inflammatory responses which can promote neuroinflammation across the blood-brain-barrier, and impact numerous functions that are dysregulated in AN including mood and feeding behaviour (40,41).

Chronic food restriction in AN may induce gut barrier dysfunction due to an increase in mucin degrading microorganisms (19,26), and altered tight junction protein expression which reduces gastric wall thickness (42). Furthermore, decreased availability of colonic butyrate may also lead to an inflammation-mediated disruption of the intestinal barrier in AN patients (43).

In two recent meta-analyses, patients with AN showed a low-grade inflammatory state with increased TNF-α, IL- 6, and IL-1β (44,45). Whether this systemic inflammation results in neuroinflammatory responses is largely unexplored in AN patients, although animal AN models suggest a role of microglia and neuroinflammation in AN (46,47,48). 

 

Autoimmunity in AN

Emerging evidence suggests that autoantibodies due to increased gut permeability could play a role in AN pathophysiology. Specifically, an increased abundance of autoantibodies against appetite modulating neuropeptides, such as α-melanocyte-stimulating hormone (α-MSH), have been identified in AN (49,50). In addition to central feeding regulation, α‐MSH signalling is involved in anxiety and depression (51).

Subsequent studies found that Escherichia coli, which are overrepresented in the gut of AN patients (11), produce caseinolytic protease B (ClpB), a heat-shock protein that can act as a partial homologue to α- MSH and cross-react with receptors of appetite- and satiety-regulating hormones. ClpB protein concentrations correlate positively with α-MSH-reactive IgG for all patients with eating disorders, thus may play an important role in AN development (52).

The link between AN, autoimmune disease and the gut microbiota is an area that warrants further research. Studies to date have found a strong bidirectional relationship between autoimmune disease and eating disorders, including AN (53). Specifically, gastrointestinal-related autoimmune diseases such as coeliac disease and Crohn's disease show a bidirectional relationship with AN, and the previous occurrence of type 1 diabetes increases the risk for AN (53). 

 

Microbiota-gut-brain axis in AN

To date, research cannot identify if altered gut microbiota is a cause or consequence of the long term reduced food consumption that underpins AN. However, regardless of which comes first, alterations in the microbiota-gut-brain axis are likely to contribute to disease chronicity and relapse, with altered immune system function, poor SCFA and butyrate production, and increased intestinal permeability perpetuating the cycle (Figure 1).

 

Figure 1 Model for gut microbiome involvement in AN pathophysiology. Adapted from (15) CC BY 4.0

Figure 1

 

Implications for treatment

Weight restoration and renourishment in AN typically involves high calorie, high fat/protein diets, which can cause gastrointestinal discomfort and may cause further dysbiosis and inflammation (54). Few studies have investigated the microbiome after nutritional rehabilitation in AN patients; however, initial results suggest bacterial diversity is not restored, and elevated levels of mucin and protein-degrading taxa, and reduced levels of butyrate-producing bacteria may persist (19). Therefore, including fibre in nutritional rehabilitation programs is an important consideration for restoring healthy gut microbiota composition and improving health outcomes in AN patients.

Similarly, it is vital to consider the type of dietary fat incorporated into rehabilitation programs. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) can modulate the diversity and abundance of gut microbiota (55) and exert important anti-inflammatory and immunomodulatory effects, which are relevant to AN. For example, n-3 PUFAS can increase the abundance of butyrate-producing bacteria and decrease levels of pro-inflammatory bacteria; and improve gastrointestinal homeostasis (56). Furthermore, n-3 PUFA supplementation may increase appetite (57), help weight gain (58), maintain integrity and restore disturbed blood-brain-barrier function, and stabilise neuronal membrane fluidity index (59), thereby positively affecting cognition and mood. Several studies suggest that the clinical benefits of n-3 PUFA treatments in AN may include weight regulation and mood improvement, but further studies are required (60,61,62).

The administration of pre and probiotics provides potential adjunctive treatment options for neuropsychiatric conditions (63), cognitive impairment (64), and gastrointestinal dysfunction (65), all relevant to AN. Furthermore, several clinical trials indicate clinical symptoms of AN are related to levels of SCFAs and butyrate-producing bacteria; thus, clinical trials investigating the effects of pre and probiotics in AN are warranted. 

FMT from healthy donors is currently being explored as a potential strategy for re-establishing a diverse microbiota and improving the outcomes of nutritional rehabilitation. Recent case studies of FMT in AN patients show promising results with improvements in weight gain, microbiota composition and gut barrier function (66,67).

Takeaway on the Microbiome and AN

  • Compared to healthy individuals, the microbiome of AN patients demonstrates significant differences in diversity and composition, although further studies are required to determine if differences are a cause or consequence of AN.
  • Microbial dysbiosis alters the production of microbial metabolites which affect metabolism, appetite, satiety and mood.
  • Microbial dysbiosis in AN patients may enhance intestinal permeability leading to neuroinflammatory and autoimmune responses that perpetuate disease pathogenesis.
  • Current nutritional rehabilitation therapies do not restore the gut microbiome in AN patients and further studies are required to optimise rehabilitation strategies, potentially incorporating adjunct therapies that target the microbiome.
References
1American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA. 2013.
2Keski-Rahkonen A, Raevuori A, Hoek HW. Epidemiology of eating disorders: an update. Annual Review of Eating Disorders. 2018 Apr 19:66-76.
3Godart NT, Flament MF, Perdereau F, Jeammet P. Comorbidity between eating disorders and anxiety disorders: a review. International Journal of Eating Disorders. 2002 Nov;32(3):253-70.
4Fernandez-Aranda F, Poyastro Pinheiro A, Tozzi F, La Via M, Thornton LM, Plotnicov KH, Kaye WH, Fichter MM, Halmi KA, Kaplan AS, Woodside DB. Symptom profile of major depressive disorder in women with eating disorders. Australian & New Zealand Journal of Psychiatry. 2007 Jan;41(1):24-31.
5Zipfel S, Giel KE, Bulik CM, Hay P, Schmidt U. Anorexia nervosa: aetiology, assessment, and treatment. The lancet psychiatry. 2015 Dec 1;2(12):1099-111.
6Yao S, Larsson H, Norring C, Birgegård A, Lichtenstein P, DʼOnofrio BM, Almqvist C, Thornton LM, Bulik CM, Kuja-Halkola R. Genetic and environmental contributions to diagnostic fluctuation in anorexia nervosa and bulimia nervosa. Psychological medicine. 2021 Jan;51(1):62-9.
7McMaster CM, Wade T, Franklin J, Hart S. A review of treatment manuals for adults with an eating disorder: nutrition content and consistency with current dietetic evidence. Eating and Weight Disorders-Studies on Anorexia, Bulimia and Obesity. 2020 Jan 30:1-4.
8Herpertz-Dahlmann B. Intensive Treatments in Adolescent Anorexia Nervosa. Nutrients. 2021 Apr;13(4):1265.
9Kleiman SC, Watson HJ, Bulik-Sullivan EC, Huh EY, Tarantino LM, Bulik CM, Carroll IM. The intestinal microbiota in acute anorexia nervosa and during renourishment: relationship to depression, anxiety, and eating disorder psychopathology. Psychosomatic medicine. 2015 Nov;77(9):969.
10Mörkl S, Lackner S, Müller W, Gorkiewicz G, Kashofer K, Oberascher A, Painold A, Holl A, Holzer P, Meinitzer A, Mangge H. Gut microbiota and body composition in anorexia nervosa inpatients in comparison to athletes, overweight, obese, and normal weight controls. International Journal of Eating Disorders. 2017 Dec;50(12):1421-31.
11Hanachi M, Manichanh C, Schoenenberger A, Pascal V, Levenez F, Cournède N, Doré J, Melchior JC. Altered host-gut microbes symbiosis in severely malnourished anorexia nervosa (AN) patients undergoing enteral nutrition: an explicative factor of functional intestinal disorders?. Clinical nutrition. 2019 Oct 1;38(5):2304-10.
12Monteleone AM, Troisi J, Fasano A, Dalle Grave R, Marciello F, Serena G, Calugi S, Scala G, Corrivetti G, Cascino G, Monteleone P. Multi-omics data integration in anorexia nervosa patients before and after weight regain: A microbiome-metabolomics investigation. Clinical Nutrition. 2021 Mar 1;40(3):1137-46.
13Mörkl S, Lackner S, Meinitzer A, Gorkiewicz G, Kashofer K, Painold A, et al. [Pilot study: Gut microbiome and intestinal barrier in anorexia nervosa]. Fortschr Neurol Psychiatr. 2019; 87:39–45.
14Roubalová R, Procházková P, Papežová H, Smitka K, Bilej M, Tlaskalová-Hogenová H. Anorexia nervosa: Gut microbiota-immune-brain interactions. Clinical Nutrition. 2020 Mar 1;39(3):676-84.
15Ghenciulescu A, Park RJ, Burnet PW. The Gut microbiome in Anorexia nervosa: friend or foe?. Frontiers in Psychiatry. 2021 Jan 12;11:1463.
16Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T, Mende DR. A human gut microbial gene catalogue established by metagenomic sequencing. nature. 2010 Mar;464(7285):59-65.
17Ruusunen A, Rocks T, Jacka F, Loughman A. The gut microbiome in anorexia nervosa: relevance for nutritional rehabilitation. Psychopharmacology. 2019 May 1:1-4.
18Prochazkova P, Roubalova R, Dvorak J, Kreisinger J, Hill M, Tlaskalova-Hogenova H, Tomasova P, Pelantova H, Cermakova M, Kuzma M, Bulant J. The intestinal microbiota and metabolites in patients with anorexia nervosa. Gut Microbes. 2021 Jan 1;13(1):1-25.
19Mack I, Cuntz U, Grämer C, Niedermaier S, Pohl C, Schwiertz A, Zimmermann K, Zipfel S, Enck P, Penders J. Weight gain in anorexia nervosa does not ameliorate the faecal microbiota, branched chain fatty acid profiles and gastrointestinal complaints. Scientific reports. 2016 May 27;6(1):1-6.
20Borgo F, Riva A, Benetti A, Casiraghi MC, Bertelli S, Garbossa S, Anselmetti S, Scarone S, Pontiroli AE, Morace G, Borghi E. Microbiota in anorexia nervosa: the triangle between bacterial species, metabolites and psychological tests. PLoS One. 2017 Jun 21;12(6):e0179739.
21Lippert K, Kedenko L, Antonielli L, Kedenko I, Gemeier C, Leitner M, Kautzky-Willer A, Paulweber B, Hackl E. Gut microbiota dysbiosis associated with glucose metabolism disorders and the metabolic syndrome in older adults. Beneficial microbes. 2017 Aug 24;8(4):545-56.
22Million Á, Angelakis E, Maraninchi M, Henry M, Giorgi R, Valero R, Vialettes B, Raoult D. Correlation between body mass index and gut concentrations of Lactobacillus reuteri, Bifidobacterium animalis, Methanobrevibacter smithii and Escherichia coli. International journal of obesity. 2013 Nov;37(11):1460-6.
23Tseng CH, Wu CY. The gut microbiome in obesity. Journal of the Formosan Medical Association. 2019 Mar 1;118:S3-9.
24Armougom F, Henry M, Vialettes B, Raccah D, Raoult D. Monitoring bacterial community of human gut microbiota reveals an increase in Lactobacillus in obese patients and Methanogens in anorexic patients. PloS one. 2009 Sep 23;4(9):e7125.
25Vandeputte D, Falony G, Vieira-Silva S, Tito RY, Joossens M, Raes J. Stool consistency is strongly associated with gut microbiota richness and composition, enterotypes and bacterial growth rates. Gut. 2016 Jan 1;65(1):57-62.
26Di Lodovico L, Mondot S, Doré J, Mack I, Hanachi M, Gorwood P. Anorexia nervosa and gut microbiota: A systematic review and quantitative synthesis of pooled microbiological data. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2020 Sep 22:110114.
27Reunanen J, Kainulainen V, Huuskonen L, Ottman N, Belzer C, Huhtinen H, de Vos WM, Satokari R. Akkermansia muciniphila adheres to enterocytes and strengthens the integrity of the epithelial cell layer. Applied and Environmental microbiology. 2015 Jun 1;81(11):3655-62.
28Lukovac S, Belzer C, Pellis L, Keijser BJ, de Vos WM, Montijn RC, Roeselers G. Differential modulation by Akkermansia muciniphila and Faecalibacterium prausnitzii of host peripheral lipid metabolism and histone acetylation in mouse gut organoids. mBio. 2014 Aug 12;5(4):e01438-14.
29Isokpehi RD, Simmons SS, Johnson MO, Payton M. Genomic evidence for bacterial determinants influencing obesity development. International journal of environmental research and public health. 2017 Apr;14(4):345.
30Zhou K. Strategies to promote abundance of Akkermansia muciniphila, an emerging probiotics in the gut, evidence from dietary intervention studies. J Funct Foods. 2017 Jun;33:194-201.
31Dinan TG, Cryan JF. The microbiome-gut-brain axis in health and disease. Gastroenterology Clinics. 2017 Mar 1;46(1):77-89.
32Van de Wouw M, Schellekens H, Dinan TG, Cryan JF. Microbiota-gut-brain axis: modulator of host metabolism and appetite. The Journal of nutrition. 2017 May 1;147(5):727-45.
33la Cuesta-Zuluaga D, Mueller NT, Álvarez-Quintero R, Velásquez-Mejía EP, Sierra JA, Corrales-Agudelo V, Carmona JA, Abad JM, Escobar JS. Higher fecal short-chain fatty acid levels are associated with gut microbiome dysbiosis, obesity, hypertension and cardiometabolic disease risk factors. Nutrients. 2019 Jan;11(1):51.
34Kim KN, Yao Y, Ju SY. Short chain fatty acids and fecal microbiota abundance in humans with obesity: A systematic review and meta-analysis. Nutrients. 2019 Oct;11(10):2512.
35Morita C, Tsuji H, Hata T, Gondo M, Takakura S, Kawai K, Yoshihara K, Ogata K, Nomoto K, Miyazaki K, Sudo N. Gut dysbiosis in patients with anorexia nervosa. PloS one. 2015 Dec 18;10(12):e0145274.
36Speranza E, Cioffi I, Santarpia L, Del Piano C, De Caprio C, Naccarato M, Marra M, De Filippo E, Contaldo F, Pasanisi F. Fecal short chain fatty acids and dietary intake in Italian women with restrictive anorexia nervosa: a pilot study. Frontiers in nutrition. 2018 Nov 29;5:119.
37Hata T, Miyata N, Takakura S, Yoshihara K, Asano Y, Kimura-Todani T, Yamashita M, Zhang XT, Watanabe N, Mikami K, Koga Y. The gut microbiome derived from anorexia nervosa patients impairs weight gain and behavioral performance in female mice. Endocrinology. 2019 Oct;160(10):2441-52.
38Prochazkova P, Roubalova R, Dvorak J, Kreisinger J, Hill M, Tlaskalova-Hogenova H, Tomasova P, Pelantova H, Cermakova M, Kuzma M, Bulant J. The intestinal microbiota and metabolites in patients with anorexia nervosa. Gut Microbes. 2021 Jan 1;13(1):1-25.
39Parker BJ, Wearsch PA, Veloo ACM, Rodriguez-Palacios A. The Genus Alistipes: Gut Bacteria With Emerging Implications to Inflammation, Cancer, and Mental Health. Front Immunol. 2020 Jun 9;11:906.
40Reis WL, Yi CX, Gao Y, Tschöp MH, Stern JE. Brain innate immunity regulates hypothalamic arcuate neuronal activity and feeding behavior. Endocrinology. 2015 Apr 1;156(4):1303-15.
41Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biological psychiatry. 2009 May 1;65(9):732-41.
42Jésus P, Ouelaa W, François M, Riachy L, Guérin C, Aziz M, Do Rego JC, Déchelotte P, Fetissov SO, Coëffier M. Alteration of intestinal barrier function during activity-based anorexia in mice. Clinical nutrition. 2014 Dec 1;33(6):1046-53.
43Knudsen KEB, Lærke HN, Hedemann MS, Nielsen TS, Ingerslev AK, et al. Impact of diet-modulated butyrate production on intestinal barrier function and inflammation. Nutrients. 2018 Oct;10(10):1499.
44Solmi M, Veronese N, Favaro A, Santonastaso P, Manzato E, Sergi G. Inflammatory cytokines and anorexia nervosa: a meta-analysis of cross- sectional and longitudinal studies. Psychoneuroendocrinology. 2015 Jan 1;51:237– 52.
45Dalton B, Bartholdy S, Robinson L, Solmi M, IbrahimMA, Breen G. A meta- analysis of cytokine concentrations in eating disorders. J Psychiatr Res. 2018 Aug 1;103:252–64.
46Reyes-Ortega, P.; Ragu Varman, D.; Rodríguez, V.M.; Reyes-Haro, D. Anorexia induces a microglial associated pro-inflammatory environment and correlates with neurodegeneration in the prefrontal cortex of young female rats. Behav. Brain Res. 2020, 392, 112606.
47Nilsson, I.; Lindfors, C.; Fetissov, S.O.; Hökfelt, T.; Johansen, J.E. Aberrant agouti-related protein system in the hypothalamus of theanx/anx mouse is associated with activation of microglia. J. Comp. Neurol. 2008, 507, 1128–1140.
48Nilsson, I.A.K.; Thams, S.; Lindfors, C.; Bergstrand, A.; Cullheim, S.; Hökfelt, T.; Johansen, J.E. Evidence of hypothalamic degeneration in the anorectic anx/anx mouse. Glia 2011, 59, 45–57.
49Fetissov SO, Hallman J, Oreland L, af Klinteberg B, Grenbäck E, Hulting AL, Hökfelt T. Autoantibodies against α-MSH, ACTH, and LHRH in anorexia and bulimia nervosa patients. Proceedings of the National Academy of Sciences. 2002 Dec 24;99(26):17155-60.
50Fetissov SO, Sinno MH, Coëffier M, Bole-Feysot C, Ducrotté P, Hökfelt T, Déchelotte P. Autoantibodies against appetite-regulating peptide hormones and neuropeptides: putative modulation by gut microflora. Nutrition. 2008 Apr 1;24(4):348-59.
51Kokare DM, Dandekar MP, Singru PS, Gupta GL, Subhedar NK. Involvement of alpha-MSH in the social isolation induced anxiety- and depression-like behaviors in rat. Neuropharmacology. 2010 Jun;58(7):1009-18.
52Breton J, Déchelotte P, Ribet D. Intestinal microbiota and anorexia nervosa. Clinical Nutrition Experimental. 2019 Dec 1;28:11-21.
53Hedman A, Breithaupt L, Hübel C, Thornton LM, Tillander A, Norring C, Birgegård A, Larsson H, Ludvigsson JF, Sävendahl L, Almqvist C. Bidirectional relationship between eating disorders and autoimmune diseases. Journal of Child Psychology and Psychiatry. 2019 Jul;60(7):803-12.
54Murphy EA, Velazquez KT, Herbert KM. Influence of high-fat diet on gut microbiota: a driving force for chronic disease risk. Curr Opin Clin Nutr Metab Care. 2015 Sep;18(5):515-20.
55Shih PB, Morisseau C, Le T, Woodside B, German JB. Personalized polyunsaturated fatty acids as a potential adjunctive treatment for anorexia nervosa. Prostaglandins Other Lipid Mediat. 2017 Nov;133:11-19.
56Fu Y, Wang Y, Gao H, Li D, Jiang R, Ge L, Tong C, Xu K. Associations among Dietary Omega-3 Polyunsaturated Fatty Acids, the Gut Microbiota, and Intestinal Immunity. Mediators Inflamm. 2021 Jan 2;2021:8879227.
57Damsbo-Svendsen S, Rønsholdt MD, Lauritzen L. Fish oil-supplementation increases appetite in healthy adults. A randomized controlled cross-over trial. Appetite. 2013 Jul 1;66:62-6.
58Barber MD, Ross JA, Voss AC, Tisdale MJ, Fearon KC. The effect of an oral nutritional supplement enriched with fish oil on weight-loss in patients with pancreatic cancer. British journal of cancer. 1999 Sep;81(1):80-6.
59Zhang W, Zhang H, Mu H, Zhu W, Jiang X, Hu X, Shi Y, Leak RK, Dong Q, Chen J, Gao Y. Omega-3 polyunsaturated fatty acids mitigate blood–brain barrier disruption after hypoxic–ischemic brain injury. Neurobiology of disease. 2016 Jul 1;91:37-46.
60Ayton AK, Azaz A, Horrobin DF. Rapid improvement of severe anorexia nervosa during treatment with ethyl-eicosapentaenoate and micronutrients. European psychiatry. 2004 Aug;19(5):317-9.
61Ayton AK, Azaz A, Horrobin DF. A pilot open case series of ethyl-EPA supplementation in the treatment of anorexia nervosa. Prostaglandins, leukotrienes and essential fatty acids. 2004 Oct 1;71(4):205-9.
62Mauler B, Dubben S, Pawelzik M, Pawelzik D, Weigle DS, Kratz M. Hypercaloric diets differing in fat composition have similar effects on serum leptin and weight gain in female subjects with anorexia nervosa. Nutrition research. 2009 Jan 1;29(1):1-7.
63Zagórska A, Marcinkowska M, Jamrozik M, Wiśniowska B, Paśko P. From probiotics to psychobiotics - the gut-brain axis in psychiatric disorders. Benef Microbes. 2020 Dec 2;11(8):717-732.
64Zhu G, Zhao J, Zhang H, Chen W, Wang G. Probiotics for Mild Cognitive Impairment and Alzheimer's Disease: A Systematic Review and Meta-Analysis. Foods. 2021 Jul 20;10(7):1672.
65Zhang XF, Guan XX, Tang YJ, Sun JF, Wang XK, Wang WD, Fan JM. Clinical effects and gut microbiota changes of using probiotics, prebiotics or synbiotics in inflammatory bowel disease: a systematic review and meta-analysis. Eur J Nutr. 2021 Aug;60(5):2855-2875.
66Prochazkova P, Roubalova R, Dvorak J, Tlaskalova-Hogenova H, Cermakova M, Tomasova P, Sediva B, Kuzma M, Bulant J, Bilej M, Hrabak P. Microbiota, microbial metabolites, and barrier function in a patient with anorexia nervosa after fecal microbiota transplantation. Microorganisms. 2019 Sep;7(9):338.
67de Clercq NC, Frissen MN, Davids M, Groen AK, Nieuwdorp M. Weight gain after fecal microbiota transplantation in a patient with recurrent underweight following clinical recovery from anorexia nervosa. Psychotherapy and psychosomatics. 2019;88(1):58-60.