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Gut microbiota and neurotransmission




Gut microbiota influences the release of some of the major brain neurotransmitters which act in the gut-brain axis and modulate food intake and energy balance [72] i.e., short chain fatty acids (SCFAs), Peptide YY (PYY), tryptophan, serotonin, endocannabinoid ligands, cholecystokinin, and ghrelin. The gut hormones affect glucose metabolism by altering food intake, body weight, insulin sensitivity, gastric delay, gut motility, glucose levels and plasma glucose levels. It has been shown that low doses of PYY3-36 and GLP-1 can additively reduce food intake in rodents and man [73]. The interaction between SCFAs produced by the gut bacteria, and Gpr41 increases circulating levels of PYY, a potent orexigenic agent [48]. Conventionalized germ-free mice present with a 2.8-fold increase in plasma serotonin levels respect to control animals [74]. Administration of Bifidobacterium infantis 35624 to Sprague-Dawley rats, for example, has been shown to induce an elevation in plasma tryptophan levels, a precursor to serotonin [75].

Serotonergic neurotransmission modulates many brain functions including emotion, cognition, motor function, pain as well as neuroendocrine functions such as food intake, circadian rhythms and reproductive activity [76]. 5-HT is an important signaling molecule in the brain-gut axis and the 5-HT released from enterochromaffin cells modulates peristaltic, secretory, vasodilatory, vagal and nociceptive reflexes [77]. A high incidence of specific psychological features, including anxiety and obsessive compulsive behavior was observed in irritable bowel syndrome (IBS) patients. A positive correlation between neuropeptide Y and state anxiety and simulation/social ingenuity was found in these patients. In diarrhea-predominant IBS, plasma cortisol was linearly related to plasma serotonin [78].

Diet supplementation with prebiotic fiber has been associated with alterations in the expression or content of various gut hormones linked to the regulation of energy balance, notably increasing the satiety hormone PYY and reducing the expression of the orexigenic peptide ghrelin [79]. It has been demonstrated that prebiotic treatment was increasing plasma levels of GLP-1 and PYY [80]. Probiotics are capable of producing and delivering neuroactive substances such as gamma-aminobutyric acid and serotonin, which act on the brain-gut axis. Preclinical evaluation of probiotics in rodents suggests that certain probiotics possess antidepressant or anxiolytic activity and therefore, better called as psychobiotics [81].

A potential role for the microbiota in the development of autism, a developmental disorder that appears in the first 3 years of life and affects the brain’s normal development of social and communication skills [82]. Interestingly in a study of 58 autism patients >90% had gastrointestinal problems compared to none in the control group [83]. There is evidence to support alterations of the fecal microbiota in patients with autism, with an increase in several subtypes of Clostridium [84,85], pathogens from the family Alcaligenaceae and Sutterella, which may contribute to the pathogenesis of GI disturbances in children with autism [86]. Metagenomic analyses demonstrate a dysbiosis with reductions in Bacteroidetes and increase in the ratio of Firmicutes to Bacteroidetes, as well as in Betaproteobacteria [87]. In case of Clostridium, the majority of cases treatment with vancomycin, an antibiotic that targets gram positive anaerobes and is minimally absorbed by the GIT, can improve symptoms [88]. The possibility of microbiota involvement in development of Parkinson disease and cerebrum metabolic changes has been discussed [89]. It has been shown that increased peptidoglycan production by the gut metagenome may contribute to symptomatic atherosclerosis. Because atherosclerosis is associated with lipid accumulation and inflammation in the arterial wall, enriched presence of Collinsella bacteria in gut microbiota have been suggested as a causative agent of this disease [90,91]. Also, it has been found that decrease in Clostridium in gut microbiota content is associated with an increased inflammatory response and liver injury progress and induction of experimental cirrhosis in CCl4-treated mice [92,93], as well as fat deposition in the liver [94,95]. There is also a number of publications on the potential role of microbiota’s misbalance in case of perinatal programmed asthma [96], allergy [97], and Crohn’s disease [98].

Bercik et al. reported that alteration in the brain-derived neurotrophic factor (BDNF) mRNA and protein level in hippocampus and amygdala in mice of antibiotic-induced dysbiosis [99]. Oral administration of non-absorbable antimicrobials to SPF mice transiently altered the composition of the microbiota and increased exploratory behavior and hippocampal BDNF expression. BDNF levels in antimicrobial treated mice were greatly higher in the hippocampus and lower in the amygdala compared with control mice [99]. Alterations in the BDNF level were consistent with the behavioral changes observed in that study. On the other hand, changes in BDNF level have also been implicated in the pathogenesis and treatment of depression. There are ample evidences which suggest that BDNF and its mediated signaling may participate in the pathophysiology of depression [100]. Antidepressant-like property of BDNF has been reported in animal models of depression [101] and it is now established that BDNF contributes to the therapeutic action of antidepressant treatment [102]. Hence, BDNF might be the common substrate through which alteration in the gut microbiota mediate the behavioral effect.





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