Current Aspects of the Role of Autoantibodies Directed Against Appetite-Regulating Hormones and the Gut Microbiome in Eating Disorders

Kvido Smitka, Petra Prochazkova, Radka Roubalova, Jiri Dvorak, Hana Papezova, Martin Hill, Jaroslav Pokorny, Otomar Kittnar, Martin Bilej, Helena Tlaskalova-Hogenova, Kvido Smitka, Petra Prochazkova, Radka Roubalova, Jiri Dvorak, Hana Papezova, Martin Hill, Jaroslav Pokorny, Otomar Kittnar, Martin Bilej, Helena Tlaskalova-Hogenova

Abstract

The equilibrium and reciprocal actions among appetite-stimulating (orexigenic) and appetite-suppressing (anorexigenic) signals synthesized in the gut, brain, microbiome and adipose tissue (AT), seems to play a pivotal role in the regulation of food intake and feeding behavior, anxiety, and depression. A dysregulation of mechanisms controlling the energy balance may result in eating disorders such as anorexia nervosa (AN) and bulimia nervosa (BN). AN is a psychiatric disease defined by chronic self-induced extreme dietary restriction leading to an extremely low body weight and adiposity. BN is defined as out-of-control binge eating, which is compensated by self-induced vomiting, fasting, or excessive exercise. Certain gut microbiota-related compounds, like bacterial chaperone protein Escherichia coli caseinolytic protease B (ClpB) and food-derived antigens were recently described to trigger the production of autoantibodies cross-reacting with appetite-regulating hormones and neurotransmitters. Gut microbiome may be a potential manipulator for AT and energy homeostasis. Thus, the regulation of appetite, emotion, mood, and nutritional status is also under the control of neuroimmunoendocrine mechanisms by secretion of autoantibodies directed against neuropeptides, neuroactive metabolites, and peptides. In AN and BN, altered cholinergic, dopaminergic, adrenergic, and serotonergic relays may lead to abnormal AT, gut, and brain hormone secretion. The present review summarizes updated knowledge regarding the gut dysbiosis, gut-barrier permeability, short-chain fatty acids (SCFA), fecal microbial transplantation (FMT), blood-brain barrier permeability, and autoantibodies within the ghrelin and melanocortin systems in eating disorders. We expect that the new knowledge may be used for the development of a novel preventive and therapeutic approach for treatment of AN and BN.

Keywords: alpha-MSH; anorexia nervosa and bulimia; autoantibody; caseinolytic peptidase B; fecal microbial transplantation; ghrelin; gut and blood-brain barrier permeability; microbiome.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer LP declared a shared affiliation with several of the authors to the handling editor at time of review.

Copyright © 2021 Smitka, Prochazkova, Roubalova, Dvorak, Papezova, Hill, Pokorny, Kittnar, Bilej and Tlaskalova-Hogenova.

Figures

Figure 1
Figure 1
Scheme demonstrating the bi-directional interactions along the adipose tissue, microbiome, gut and brain leading to the development of eating disorders. Microbial composition and consequently the amount of microbial metabolites and components are affected by various factors like diet, antibiotics, infection and so on. Gut microbial metabolites and components act as signals to influence enteric nervous system and adipose tissue responses through various receptors. P/D1 like ghrelin cells in humans (or termed X/A like ghrelin cells in rodents) are localized in the oxyntic mucosa of the gastric fundus and duodenum. Enteroendocrine L cells secrete PYY and GLP-1/-2 (and/or co-release GLP-1/-2 together with PYY) in the mucosa of the distal ileum and colon. F (or PP) cells, which secrete pancreatic polypeptide (PP) under cholinergic control, are localized in the periphery of pancreatic islets of Langerhans, and also expressed in the distal gut. Enteroendocrine I and K cells, which secrete CCK and glucose-dependent insulinotropic peptide (GIP), are located in the mucosa of the upper small intestine. Short-chain fatty (FFA2-3) and hydroxy-carboxylic (HCA1-2) acid receptors are expressed on gastric P/D1 like ghrelin cells, ileal L cells, pancreatic α cells, enterochromaffin (EC) serotonin cells, duodeno-jejuno-ileal I and K cells, pancreatic β cells, and adipocytes. The signalization leads to ghrelin secretion inhibition or produce PYY, GLP-1/-2, serotonin, CCK, insulin, and leptin production. Leptin, an adipocyte-secreted hormone, is an indicator of energy stores and acts to reduce food intake and increase energy expenditure. These appetite-regulating hormones signal to NPY/AGRP and POMC/CART neurons, the mesolimbic reward system, and higher cortical areas, which all play a pivotal role in the regulation of metabolism. GABA has an inhibitory input from NPY/AGRP neurons to POMC/CART neurons in the hypothalamic arcuate nucleus. Activation of hypothalamic NPY/AGRP neurons stimulates hunger and inhibits energy expenditure and lipolysis in AT; however, stimulation of hypothalamic POMC/CART neurons together with MC4R leads to inhibition of food intake and enhancing of energy expenditure and lipolysis in AT. IgG immune complexes with orexigenic and anorexigenic peptides chronically activate MC4R leading to increased satiety in both AN and BN. Dysregulation of appetite-regulating circuits may affect altered feeding behavior leading to the onset, development, and maintenance of AN and BN. α2R, alpha-2 adrenoceptors; AGRP, agouti-related protein; AT, adipose tissue; β 1, 2, 3R, beta-1, 2, 3 adrenoceptors; BCFA, branched-chain fatty acids (isobutyrate, 2-methyl-butyrate, and isovalerate); ATB, antibiotics; CART, cocaine- and amphetamine-regulated transcript; CCK, cholecystokinin, CCK1, 2 R; cholecystokinin 1, 2 receptors; CLA, conjugated linoleic acid; ClpB, enterobacterial caseinolytic protease B; EC, enterochromaffin serotonin cells; FFAR, free fatty acid receptor; GABA, gamma-aminobutyric acid; GIP, glucose-dependent insulinotropic peptide; GIPR, glucose-dependent insulinotropic peptide receptor; GLP-1/-2, glucagon-like peptide-1 and 2; GLP1-R, glucagon-like peptide-1 receptor; GPR142, G protein receptor 142 for tryptophan, HCAR, hydroxy-carboxylic acid receptor; L-DOPA, L-3,4-dihydroxyphenylalanine; LPS, lipopolysaccharide; MC4R, melanocortin 4 receptor; NPY, neuropeptide tyrosine; POMC, pro-opiomelanocortin; PP, pancreatic polypeptide; PYY, peptide tyrosine tyrosine; PYY-Y1R, peptide tyrosine tyrosine-1 receptor, SCFA, short-chain fatty acids (butyrate, acetate, and propionate); TMA, trimethylamine; (+) = the stimulatory effect of ligands on hormone or serotonin secretion; (-) = the inhibitory effect of ligands on hormone secretion.

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