Abstract EN:

Peripheral and central regulatory peptides play important roles in mechanisms of appetite and body weight control. Recently autoantibodies (autoAbs) directed against appetite-regulating neuropeptides have been identified in subjects with eating disorders, suggesting that they may be involved in the mechanisms of altered appetite, but the origin of these autoAbs is unknown. Insilico study showed sequence homologies between α-melanocyte-stimulating hormone (α-MSH), a neuropeptide critically involved in the regulation of energy metabolism and proteins of gut microbiota. It suggests that gut microbiota can stimulate production of autoAbs against α-MSH by molecular mimicry. The aim of this project was to validate the molecular mimicry concept between gut microbiota proteins and α-MSH. In the first part, we applied a proteomic approach to identify if proteins of Escherichia coli (E. Coli) K12, a commensal strain of gut bacteria, may have molecular mimicry with α-MSH. We determine that E. Coli ClpB protein has conformational mimicry with α-MSH and that immunization of mice with ClpB stimulates production of anti-α-MSH IgG accompanied by increased food intake and body weight and lower anxiety in mice. We also showed that providing E. Coli K12 by gavage in rats increases body weight and plasma levels of ClpB and α-MSH-reactive IgG. Finally, we showed that anti-ClpB IgG are present in humans and that their plasma levels correlate with psychopathological traits in patients with eating disorders. Thus, bacterial proteins-stimulated production of IgG cross-reacting with peptide hormones appears as a molecular mechanism underlying bacterial control of host feeding behavior and emotion. In second part, to study gender differences observed in ED, we compared effects of chronic gavage with E. Coli K12 on the production of autoAbs against these melanocortin peptides between female and male rats. We found that prior to gavage, E. Coli K12 cDNA was detected in feces of female but not male rats. During gavage phase, body weight was increased in E. Coli exposed female rats but decreased in male rats. Independently to E. Coli treatment, plasma levels of anti- α-MSH and ACTH- IgG were higher in female than male rats. After gavage, female rats responded to E. Coli by increasing α-MSH IgG but male rats α-MSH IgM. Furthermore, E. Coli-treated females showed increased affinities of IgG for α-MSH which was not observed in males, but affinity of IgG for ACTH was increased in both female and male rats, although with different affinity kinetics. IgG from both control and E. Coli treated female rats enhanced more efficiently than IgG from male rats α-MSH-induced cAMP production by melanocortin 4 receptor expressing cells. Thus, these data show that the response to E. Coli K12 to produce autoAbs against melanocortin peptides is gender-dependent suggesting that presence or absence of E. Coli K12 as gut commensals may represent a gender-related risk factor relevant to eating disorders. Finally we studied if gut microbiota proteins can directly influence eating behaviour. Dynamics of bacterial growth depend on nutrients availability suggesting that it may differentially affect host control of food intake. We showed that repetitive nutrients provision to commensal E. Coli K12 bacteria modifies their proteomes so that the relative amount of bacterial enzymes involved in catabolic vs. Anabolic processes were elevated in the stationary phase indicating increased bacteria-derived energy substrates to the host. Furthermore, intraperitoneal administration of E. Coli proteins from the exponential phase increased but from the stationary phase decreased food intake in overnight fasted rats. In free feeding rats, E. Coli proteins increased c-fos expression in the hypothalamic ventromedial nucleus. These data show that nutrients-triggered changes of E. Coli proteome may increase satiety signalling to the host supporting involvement of gut microbiota in host control of food intake.