Bifidobacterium pseudocatenulatum CECT 7765 Ameliorates Neuroendocrine Alterations Associated with an Exaggerated Stress Response and Anhedonia in Obese Mice
Obesity, besides being a problem of metabolic dysfunction, constitutes a risk factor for psychological disorders. Experimental models of diet-induced obesity have revealed that obese animals are prone to anxious and depressive-like behaviors. The present study aimed to evaluate whether Bifidobacterium pseudocatenulatum CECT 7765 could reverse the neurobehavioral consequences of obesity in a high-fat diet (HFD) fed mouse model via regulation of the gut–brain axis. Adult male wild-type C57BL-6 mice were fed a standard diet or HFD, supplemented with either placebo or the bifidobacterial strain for 13 weeks. Behavioral tests were performed, and immune and neuroendocrine parameters were analyzed including leptin and corticosterone and their receptors, Toll-like receptor 2 (TLR2) and neurotransmitters. We found that obese mice showed anhedonia (p < 0.050) indicative of a depressive-like behavior and an exaggerated hypothalamic-pituitary axis (HPA)-mediated stress response to acute physical (p < 0.001) and social stress (p < 0.050), but these alterations were ameliorated by B. pseudocatenulatum CECT 7765 (p < 0.050). These behavioral effects were parallel to reductions of the obesity-associated hyperleptinemia (p < 0.001) and restoration of leptin signaling (p < 0.050), along with fat mass loss (p < 0.010). B. pseudocatenulatum CECT 7765 administration also led to restoration of the obesity-induced reductions in adrenaline in the hypothalamus (p < 0.010), involved in the hypothalamic control of energy balance. Furthermore, the bifidobacterial strain reduced the obesity-induced upregulation of TLR2 protein or gene expression in the intestine (p < 0.010) and the hippocampus (p < 0.050) and restored the alterations of 5-HT levels in the hippocampus (p < 0.050), which could contribute to attenuating the obesity-associated depressive-like behavior (p < 0.050). In summary, the results indicate that B. pseudocatenulatum CECT 7765 could play a role in depressive behavior comorbid with obesity via regulation of endocrine and immune mediators of the gut–brain axis.
KeywordsObesity Bifidobacterium Microbiota Depression Stress Serotonin TLR2
Compliance with Ethical Standards
Experiments were carried out in strict compliance with the recommendations provided in the Guide for the Care and Use of Laboratory Animals of the University of Valencia (Central Service of Support to Research [SCSIE], University of Valencia, Spain), and the protocol was approved by its Ethics Committee (Approval number 2015/VSC/PEA/00041).
Conflict of Interest
The authors declare that they have no conflict of interest.
- 5.Morris G, Berk M, Carvalho A, Caso JR, Sanz Y, Walder K, Maes M (2016) The role of the microbial metabolites including tryptophan catabolites and short chain fatty acids in the pathophysiology of immune-inflammatory and neuroimmune disease. Mol Neurobiol 54(6):4432–4451Google Scholar
- 18.Sanz Y (2016) The encyclopedia of food and health. Academic Press, OxfordGoogle Scholar
- 28.Moratalla A, Gomez-Hurtado I, Santacruz A, Moya A, Peiro G, Zapater P, Gonzalez-Navajas JM, Gimenez P et al (2014) Protective effect of Bifidobacterium pseudocatenulatum Cect7765 against induced bacterial antigen translocation in experimental cirrhosis. Liver Int 34(6):850–858CrossRefPubMedGoogle Scholar
- 29.Moratalla A, Caparros E, Juanola O, Portune K, Puig-Kroger A, Estrada-Capetillo L, Bellot P, Gomez-Hurtado I et al (2016) Bifidobacterium pseudocatenulatum Cect7765 induces an M2 anti-inflammatory transition in macrophages from patients with cirrhosis. J Hepatol 64(1):135–145CrossRefPubMedGoogle Scholar
- 34.Liu J, Guo M, Lu XY (2015) Leptin/Leprb in the ventral tegmental area mediates anxiety-related behaviors. Int J Neuropsychopharmacol 19(2). https://doi.org/10.1093/ijnp/pyv115
- 42.Seibenhener ML, Wooten MC (2015) Use of the open field maze to measure locomotor and anxiety-like behavior in mice. J Vis Exp (96):e52434. https://doi.org/10.3791/52434
- 45.Castagne V, Moser P, Porsolt RD (2009) Behavioral assessment of antidepressant activity in rodents. In: Buccafusco JJ (ed) Methods of behavior analysis in neuroscience, 2nd edn. CRC Press, Boca RatonGoogle Scholar
- 48.Moya-Perez A, Perez-Villalba A, Benitez-Paez A, Campillo I, Sanz Y (2017) Bifidobacterium Cect 7765 modulates early stress-induced immune, neuroendocrine and behavioral alterations in mice. Brain Behav Immun 65:43–56Google Scholar
- 51.Slyepchenko AMM, Jacka FN, Köhler CA, Barichello T, RS MI, Berk M, Grande I, Foster JA et al (2017) Gut microbiota, bacterial translocation, and interactions with diet: pathophysiological links between major depressive disorder and non-communicable medical comorbidities. Psychother Psychosom 86(1):31–46CrossRefPubMedGoogle Scholar
- 54.Stepanichev MY, Tishkina AO, Novikova MR, Levshina IP, Freiman SV, Onufriev MV, Levchenko OA, Lazareva NA et al (2016) Anhedonia but not passive floating is an indicator of depressive-like behavior in two chronic stress paradigms. Acta Neurobiol Exp (Wars) 76(4):324–333Google Scholar
- 73.Reimann M, Qin N, Gruber M, Bornstein SR, Kirschbaum C, Ziemssen T, Eisenhofer G (2017) Adrenal medullary dysfunction as a feature of obesity. Int J Obes (Lond) 41(5):714–721Google Scholar
- 74.Gotthardt JD, Verpeut JL, Yeomans BL, Yang JA, Yasrebi A, Roepke TA, Bello NT (2016) Intermittent fasting promotes fat loss with lean mass retention, increased hypothalamic norepinephrine content, and increased neuropeptide Y gene expression in diet-induced obese male mice. Endocrinology 157(2):679–691CrossRefPubMedGoogle Scholar