Bacterial ClpB heat-shock protein, an antigen-mimetic of the anorexigenic peptide α-MSH, at the origin of eating disorders

Abstract

The molecular mechanisms at the origin of eating disorders (EDs), including anorexia nervosa (AN), bulimia and binge-eating disorder (BED), are currently unknown. Previous data indicated that immunoglobulins (Igs) or autoantibodies (auto-Abs) reactive with α-melanocyte-stimulating hormone (α-MSH) are involved in regulation of feeding and emotion; however, the origin of such auto-Abs is unknown. Here, using proteomics, we identified ClpB heat-shock disaggregation chaperone protein of commensal gut bacteria Escherichia coli as a conformational antigen mimetic of α-MSH. We show that ClpB-immunized mice produce anti-ClpB IgG crossreactive with α-MSH, influencing food intake, body weight, anxiety and melanocortin receptor 4 signaling. Furthermore, chronic intragastric delivery of E. coli in mice decreased food intake and stimulated formation of ClpB- and α-MSH-reactive antibodies, while ClpB-deficient E. coli did not affect food intake or antibody levels. Finally, we show that plasma levels of anti-ClpB IgG crossreactive with α-MSH are increased in patients with AN, bulimia and BED, and that the ED Inventory-2 scores in ED patients correlate with anti-ClpB IgG and IgM, which is similar to our previous findings for α-MSH auto-Abs. In conclusion, this work shows that the bacterial ClpB protein, which is present in several commensal and pathogenic microorganisms, can be responsible for the production of auto-Abs crossreactive with α-MSH, associated with altered feeding and emotion in humans with ED. Our data suggest that ClpB-expressing gut microorganisms might be involved in the etiology of EDs.

The Microbiota, the Gut and the Brain in Eating and Alcohol Use Disorders: A ‘Ménage à Trois’?

“…Specifically, a Caseinolytic protease B (ClpB) heat-shock disaggregation chaperone protein from E. coli K12 can mimic α-MSH. ClpB-immunized mice produced antiClpB auto-Abs that also demonstrated cross-reactivity with α-MSH, and demonstrated lower MC4R signaling, which is involved in energy balance regulation (Tennoune et al, 2014). ClpB-immunization of mice did not contribute to a significant change in locomotor behavior.…”

“…Male C57Bl/6 mice Anti-ClpB auto-Abs cross-reactive with α-MSH lead to reduced MC4R signaling and influenced food intake, body weight, and anxiety behavior Conclusion: Anti-ClpB auto-Abs influence ED-related behaviors via reduced sensitivity to anorexigenic effects of α-MSH n = 8/group Tennoune et al (2014) Female patients with AN, BN, or BED Anti-ClpB auto-Abs against α-MSH elevated in ED patients and correlated with ED-related behaviors Conclusion: ClpB protein can alter auto-Ab production and impact feeding and emotion in humans with EDs AN n = 27 BN n = 32 BED n = 14 Control n = 65 Adult Wistar rats Sex-related differences in male and female rat food and water intake in response to E. coli K12 gavage Conclusion: Sex-related differences in gut microbiota contribute to differences in satiety, feeding, and emotion and may represent a risk factor for ED development…”

“…constant number of meals, but increased meal size) rather than operating through hunger. Thus, anti-ClpB auto-Abs influence anxiety behavior and food intake by reduced sensitivity to the anorexigenic effects of α-MSH (Tennoune et al, 2014).…”

“…A proteomics mouse study was conducted to validate the role of the gut microbiota and molecular mimicry in the pathophysiology of EDs (Tennoune et al, 2014). E. coli K12 was selected for its sequence homology with α-MSH.…”

Oral delivery of Bifidobacterium longum expressing α-melanocyte-stimulating hormone to combat ulcerative colitis

“…The immunomodulating and anti-inflammatory effects of a-MSH can be elicited via downregulation of pro-inflammatory cytokines and mediators such as IL-1, IL-2, IL-4, IL-6, IL-8, IL-1b, TNF-a and nitric oxide (NO), as well as upregulation of the anti-inflammatory cytokine IL-10 production (Brzoska et al, 2010). Moreover, an animal model experiment using a-MSH has been demonstrated in various inflammatory diseases, such as irritant and allergic contact dermatitis, vasculitis, inflammatory bowel disease (IBD), allergic airway inflammation, arthritis, acute pancreatitis, and liver, ocular and brain inflammation (Brzoska et al, 2008;Carniglia et al, 2013;Moraes et al, 2014;Tennoune et al, 2014). These diverse physiological and biological capabilities suggest that a-MSH may be a promising therapeutic drug for various inflammatory diseases as mentioned above (Brzoska et al, 2008).…”