Papers by Serguei Fetissov
Nutrition, Oct 1, 2020
Anorexia represents a common and debilitating clinical problem in patients with several forms of ... more Anorexia represents a common and debilitating clinical problem in patients with several forms of cancer, in particular lung cancer, but its mechanisms are not completely understood. Recently, the caseinolytic-protease-B (ClpB) homologue protein, produced by common gut bacteria, such as Escherichia coli, was identified as an antigen-mimetic of a-melanocyte-stimulating hormone (a-MSH), an anorexigenic neuropeptide. ClpB was previously detected in human plasma and displayed satietogenic properties; however, its possible relevance to cancer anorexia has not yet been investigated. Methods: To address this question, we analyzed plasma ClpB concentrations as well as levels and affinities of anti-ClpB and a-MSHÀreactive antibodies in patients with lung cancer with and without anorexia as compared with body mass indexÀmatched healthy controls with normal appetite. Results: We found that plasma ClpB concentrations were significantly lower in non-anorexic patients with cancer than those of the control group (P = 0.028). In contrast, patients with cancer and anorexia had lower levels of anti-ClpB immunoglobulins (Ig)M (P < 0.0001) and of both a-MSH IgM and IgG (P < 0.05) with respect to controls. Moreover, in patients with cancer and anorexia, anti-ClpB IgG showed a trend of lower affinities compared with non-anorexic patients (P = 0.05). Conclusions: Taken together, the results revealed a reduced humoral immune response to ClpB in patients with cancer and anorexia, which may lead to an enhanced satietogenic effect of this enterobacterial protein contributing to the mechanisms of reduced appetite.
Brain Behavior and Immunity, Nov 1, 2021
International Journal of Molecular Sciences
A commercial strain of Hafnia alvei (H. alvei) 4597 bacteria was shown to reduce food intake and ... more A commercial strain of Hafnia alvei (H. alvei) 4597 bacteria was shown to reduce food intake and promote weight loss, effects possibly induced by the bacterial protein ClpB, an antigen-mimetic of the anorexigenic α-melanocyte-stimulating hormone. A decrease in the basal plasma glucose levels was also observed in overweight fasted humans and mice receiving H. alvei. However, it is not known whether H. alvei influences sweet taste preference and whether its protein extract or ClpB are sufficient to increase glucose tolerance; these are the objectives tested in the present study. C57BL/6J male mice were kept under standard diet and were gavaged daily for 17 days with a suspension of H. alvei (4.5 × 107 CFU/animal) or with H. alvei total protein extract (5 μg/animal) or saline as a control. Sweet taste preference was analyzed via a brief-access licking test with sucrose solution. Glucose tolerance tests (GTT) were performed after the intraperitoneal (IP) or intragastric (IG) glucose adm...
Discover Mental Health
Oxytocin is a neuropeptide produced mainly in the hypothalamus and secreted in the CNS and blood.... more Oxytocin is a neuropeptide produced mainly in the hypothalamus and secreted in the CNS and blood. In the brain, it plays a major role in promoting social interactions. Here we show that in human plasma about 60% of oxytocin is naturally bound to IgG which modulates oxytocin receptor signaling. Further, we found that IgG of violent aggressive inmates were characterized by lower affinity for oxytocin, causing decreased oxytocin carrier capacity and reduced receptor activation as compared to men from the general population. Moreover, peripheral administration of oxytocin together with human oxytocin-reactive IgG to resident mice in a resident-intruder test, reduced c-fos activation in several brain regions involved in the regulation of aggressive/defensive behavior correlating with the attack number and duration. We conclude that IgG is a natural oxytocin carrier protein modulating oxytocin receptor signaling which can be relevant to the biological mechanisms of aggressive behavior.
The World Journal of Biological Psychiatry
Behavioral and Brain Sciences, 2019
For gut microbiota to influence behavior, microorganisms should be able to interfere with specifi... more For gut microbiota to influence behavior, microorganisms should be able to interfere with specific brain neurochemical circuitries. Understanding these molecular mechanisms is a key task in the new microbiota-gut-brain field. Recent studies have revealed that one major mechanistic link is the modulation of neuropeptide signaling by homologous bacterial proteins acting both directly and indirectly via production of neuropeptide-reactive immunoglobulins.
Biologie Aujourd'hui, 2017
-Les animaux perçoivent des sensations alternatives de faim et de satiété, qui constituent le ryt... more -Les animaux perçoivent des sensations alternatives de faim et de satiété, qui constituent le rythme journalier de l'appétit et déterminent leur comportement alimentaire. Chez l'Homme, ce rythme inclut, environ 20 minutes après l'ingestion d'un repas, la survenue de la satiété d'une durée d'environ 5 heures suivie de la faim qui déclenche la recherche et la prise de nourriture. Les mécanismes moléculaires sous-jacentsà ces cycles d'appétit comprennent la sécrétion d'hormones intestinales de satiété et l'activation correspondante des voies cérébrales anorexigènes et de récompenseà l'alimentation. Desétudes récentes ont montré que les bactéries intestinales peuvent interférer avec les mécanismes moléculaires de l'hôte qui régulent l'appétit aussi bien au niveau intestinal qu'au niveau cérébral. En particulier, la dynamique de croissance stable des bactéries intestinales, déterminée par des facteurs indépendants de l'hôte tels que le temps nécessaireà la réplication de l'ADN bactérien et le quorum sensing, coïncide avec les cycles d'appétit de l'hôte. Intégrer la biologie bactérienne dans la régulation par l'hôte du métabolismeénergétique apparaît donc comme une stratégie nouvelle prometteuse pour comprendre le contrôle de l'appétit dans les conditions normales et pathologiques.
Biologie Aujourd'hui, 2016
Reçu le 2 novembre 2016 Résumé-Se nourrir est un comportement instinctif récompensé par une sensa... more Reçu le 2 novembre 2016 Résumé-Se nourrir est un comportement instinctif récompensé par une sensation de plaisir pendant l'obtention et l'ingestion d'aliments, correspondant respectivement aux phases de préparation et de consommation au cours d'un comportement motivé. La perception de cetétatémotionnel, avec des sensations alternatives de faim et de satiété, entraîne le comportement alimentaire.Étant donné que les altérations de ce comportement, incluant l'hyperphagie ou l'anorexie, peuvent conduire respectivement a l'obésité età la cachexie, comprendre les mécanismes neurochimiques de la régulation du plaisir de manger peut aiderà développer de nouvelles thérapies pour ces maladies. Le système dopaminergique (DA) des projections mésolimbiques joue un rôle clé dans la récompense comportementale en général et estégalement impliqué dans la régulation du plaisir associéà la nourriture dans le cerveau, au niveau du noyau accumbens (NAc) et de l'aire hypothalamique latérale (LHA). Cela suggère que ce système DA peutêtre sélectivement activé par des facteurs spécifiquesà différents types de comportements motivés, dont les hormones liéesà la faim età la satiété. Et, en effet, l'administration centrale soit de ghréline orexigène, soit d'α-MSH, anorexigène, augmente la libération de DA dans le NAc. Toutefois, on saitégalement que la DA, injectée dans la LHA historiquement connue comme un ((centre de la faim)), inhibe la prise de nourriture, ce qui indique l'implication fonctionnelle de la DA dans la régulationà la fois de l'appétit et du plaisir de manger. Bien que le NAc et la LHA contiennent tous deux des neurones qui expriment les récepteurs de la mélanocortine, seule la LHA reçoit les terminaisons des neurones producteurs d'α-MSH, issues du noyau arqué de l'hypothalamus, principal relais vers le cerveau des signaux périphériques de la faim et de la satiété. Uneétude récente a montré que l'α-MSH de la LHA promeut la satiété et inhibe le plaisir tout en stimulant la libération de DA dans cette aire pendant les phases de préparation et de consommation lors de la prise de nourriture. Cela suggère que la signalisation par l'α-MSH au système DA, modifiée dans la LHA, pourrait etre impliquée dans la physiopathologie de l'obésité et de l'anorexie. Les mécanismes sous-jacentséventuels sont discutés.
Brain Sciences
26RFa, also referred to as QRFP, is a hypothalamic neuropeptide mainly known for its role in the ... more 26RFa, also referred to as QRFP, is a hypothalamic neuropeptide mainly known for its role in the regulation of appetite and glucose metabolism. Its possible relevance to emotional regulation is largely unexplored. To address this, in the present exploratory study, we analyzed the plasma concentrations of 26RFa in humans characterized by different levels of anxiety and aggressive behavior. For this purpose, the study included 13 prison inmates who have committed violent crimes and 19 age-matched healthy men from the general population as controls. Anxiety, depression and aggressive behavior were evaluated in both groups using standard questionnaires. The inmate group was characterized by increased aggression and anxiety compared to the controls. We found that the mean plasma levels of 26RFa did not significantly differ between the inmates and the controls. However, several high outliers were present only in the inmate group. The plasma levels of 26RFa correlated positively with the a...
Journal of International Society of Microbiota, 2015
Appetite is precisely regulated by hormonal and neuronal circuitries generating alternating sensa... more Appetite is precisely regulated by hormonal and neuronal circuitries generating alternating sensations of hunger and satiety. When animals eat they also feed the numerous bacteria inhabiting their gastro-intestinal tract. Nutrient-induced bacterial growth produces biomass that contains molecules which may interfere with the host hormonal circuitries controlling appetite. In particular, some bacterial proteins may display molecular mimicry with the host peptide hormones and may act as their conformational mimetics in the gut and in the circulation. Such effects of bacterial proteins on appetite pathways can be direct, via peptide hormone receptors as well as indirect via production of autoantibodies cross-reactive with peptide hormones. Recent data suggest that such bacterial proteins may be involved in regulation of appetite in normal and pathological conditions including eating disorders.
The current "homeostatic theory" of appetite regulation assumes that alternation of hunger and sa... more The current "homeostatic theory" of appetite regulation assumes that alternation of hunger and satiety depends on energy balance in the host tissues encoded and transmitted to the brain by neuronal and hormonal signals. However, relatively low metabolic activity of fat tissue cannot explain short-term regulation of appetite. In this paper, I am presenting the evidence supporting bacterial contribution to the appetite regulation by showing that energy metabolism of gut bacteria can be linked to the host appetite cycles. Indeed, the daily metabolic activity of gut bacteria (~2 kcal/g) is about 100 times higher than that of the human body. Importantly, the reproduction cycle of gut bacteria, which is independently regulated from the host, is temporally identical to the short-term changes of appetite; 20 min of the bacterial exponential growth duration corresponds to 20 min necessary for physiological satiation. In further support of the "microbial theory", molecular pathways linking gut bacteria with the host regulation of appetite have been identified. For instance, bacterial caseinolytic protease B (ClpB), whose production increases during the bacterial stationary growth phase, i. e., when the host is satiated, acts as a conformational mimetic of anorexigenic α-melanocyte-stimulating hormone and activates the intestinal satiety pathway. The practical utility to stimulate this pathway and to control body weight gain in obesity was recently validated using ClpB-expressing probiotics. Thus, an important functional contribution of gut bacteria to the host energy metabolism should be considered as a new integral part of the "homeostatic theory" of appetite regulation.
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2001
Our past microdialysis studies in ventromedial hypothalamic nucleus (VMN) and lateral hypothalami... more Our past microdialysis studies in ventromedial hypothalamic nucleus (VMN) and lateral hypothalamic area (LHA) of changes in dopamine concentrations in response to changes in food intake [characterized as feeding pattern (changes in meal number and size)] in anorexia of cancer show abnormal presynaptic dopaminergic neurotransmission. To determine postsynaptic receptor status, studies were done in tumor-bearing (TB) and non-tumor-bearing (NTB) free-feeding control rats while continuously measuring their food intake via a rat eater meter. When TB rats developed anorexia, TB and control rats were killed, and postsynaptic D1- and D2-receptor mRNA expression in LHA and VMN were measured via RT-PCR. At anorexia, food intake decreased initially by a decrease in meal number, whereas a concurrent increase in meal size occurred for 24 h in an attempt to maintain food intake constant. Then meal size also decreased. At this time, D1- and D2-receptor mRNA expressions in LHA and VMN of TB vs. cont...
Nature Reviews Endocrinology, 2016
The life of all animals is dominated by alternating feelings of hunger and satiety-the main invol... more The life of all animals is dominated by alternating feelings of hunger and satiety-the main involuntary motivations for feeding-related behaviour. Gut bacteria depend fully on their host for providing the nutrients necessary for their growth. The intrinsic ability of bacteria to regulate their growth and to maintain their population within the gut suggests that gut bacteria can interfere with molecular pathways controlling energy balance in the host. The current model of appetite control is based mainly on gut-brain signalling and the animal's own needs to maintain energy homeostasis; an alternative model might also involve bacteria-host communications. Several bacterial components and metabolites have been shown to stimulate intestinal satiety pathways; at the same time, their production depends on bacterial growth cycles. This short-term bacterial growth-linked modulation of intestinal satiety can be coupled with long-term regulation of appetite, controlled by the neuropeptidergic circuitry in the hypothalamus. Indeed, several bacterial products are detected in the systemic circulation, which might act directly on hypothalamic neurons. This Review analyses the data relevant to possible involvement of the gut bacteria in the regulation of host appetite and proposes an integrative homeostatic model of appetite control that includes energy needs of both the host and its gut bacteria.
Frontiers in Neuroscience, 2016
Anorexia nervosa (AN) is classically defined as a condition in which an abnormally low body weigh... more Anorexia nervosa (AN) is classically defined as a condition in which an abnormally low body weight is associated with an intense fear of gaining weight and distorted cognitions regarding weight, shape, and drive for thinness. This article reviews recent evidences from physiology, genetics, epigenetics, and brain imaging which allow to consider AN as an abnormality of reward pathways or an attempt to preserve mental homeostasis. Special emphasis is put on ghrelino-resistance and the importance of orexigenic peptides of the lateral hypothalamus, the gut microbiota and a dysimmune disorder of neuropeptide signaling. Physiological processes, secondary to underlying, and premorbid vulnerability factors-the "pondero-nutritional-feeding basements"-are also discussed.
International Journal of Peptides, 2010
American journal of physiology. Regulatory, integrative and comparative physiology, 2002
As revealed by previous microdialysis studies, basal and food intake-accompanied dopamine release... more As revealed by previous microdialysis studies, basal and food intake-accompanied dopamine release significantly differs in the hypothalamus of obese vs. lean Zucker rats. In the present study, we determined whether dopaminergic receptors are also compromised in obesity. Dopaminergic D(1) and D(2) receptor mRNA expression was studied in the ventromedial hypothalamus (VMH), lateral hypothalamic area (LHA), and the adenohypophysis (AH) of obese and lean Zucker rats using RT-PCR technique. In obese Zucker rats, we found an upregulation of D(1) receptor mRNA in the VMH and AH and a downregulation in the LHA, whereas D(2) receptor mRNA was downregulated in both the VMH and LHA, but not changed in the AH, compared with lean rats. Also, an increase of D(1) receptor staining was seen in the paraventricular nucleus of obese rats by immunohistochemistry. We selected the VMH to test if the observed changes in the dopamine receptor expression of obese rats induce behavioral sensitization to dopa...
International Journal of Obesity, 2020
Background/objectives Based on the recent identification of E.coli heat shock protein ClpB as a m... more Background/objectives Based on the recent identification of E.coli heat shock protein ClpB as a mimetic of the anorexigenic α-melanocyte stimulating hormone (α-MSH), the objective of this study was to preclinically validate Hafnia alvei, a ClpB-producing commensal bacterium as a potential probiotic for appetite and body weight management in overweight and obesity. Methods The involvement of enterobacterial ClpB in the putative anti-obesity effects was studied using ClpB-deficient E.coli. A food-grade H. alvei HA4597 strain synthetizing the ClpB protein with an α-MSH-like motif was selected as a candidate probiotic to be tested in ob/ob and high-fat diet (HFD)-fed obese and overweight mice. The relevance of the enterobacterial ClpB gene to human obesity was studied by in silico analysis of fecal metagenomes of 569 healthy individuals from the “MetaHIT” database. Results Chronic per os administration of native but not ClpB-deficient E.coli strain reduced body weight gain (p < 0.05)...
Cell Metabolism, 2016
Highlights d Regular nutrition stabilizes the E. coli exponential (Exp) growth for 20 min d E. co... more Highlights d Regular nutrition stabilizes the E. coli exponential (Exp) growth for 20 min d E. coli proteome changes in the stationary (Stat) phase d Exp and Stat E. coli proteins intra-GI tract stimulate GLP-1 and PYY, respectively d Stat E. coli proteins i.p. activate anorexigenic neurons in the brain
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Papers by Serguei Fetissov