BackgroundThe gastrointestinal motility is affected by gut microbiota and the relationship between them has become a hot topic. However, mechanisms of microbiota in regulating motility have not been well defined. We thus investigated the effect of microbiota depletion by antibiotics on gastrointestinal motility, colonic serotonin levels, and bile acids metabolism.MethodsAfter 4 weeks with antibiotics treatments, gastrointestinal and colon transit, defecation frequency, water content, and other fecal parameters were measured and analyzed in both wild-type and antibiotics-treated mice, respectively. Contractility of smooth muscle, serotonin levels, and bile acids levels in wild-type and antibiotics-treated mice were also analyzed.ResultsAfter antibiotics treatment, the richness and diversity of intestinal microbiota decreased significantly, and the fecal of mice had less output (P < 0.01), more water content (P < 0.01), and longer pellet length (P < 0.01). Antibiotics treatment in mice also resulted in delayed gastrointestinal and colonic motility (P < 0.05), and inhibition of phasic contractions of longitudinal muscle from isolated proximal colon (P < 0.01). In antibiotics-treated mice, serotonin, tryptophan hydroxylase 1, and secondary bile acids levels were decreased.ConclusionGut microbiota play an important role in the regulation of intestinal bile acids and serotonin metabolism, which could probably contribute to the association between gut microbiota and gastrointestinal motility as intermediates.

The gut microbiota is involved in various physiological functions, and disturbances in the host-microbiome have been proven to contribute to the dysfunction of gut; however, whether microbiota participates in the pathogenesis of constipation remains unclear. In this study, we extracted and analyzed microbiota in feces from constipated donors who had undergone effective therapy with fecal microbiota transplantation, transplanted microbiota into pseudo-germ-free mice, and measured gut motility. These mice presented with lower pellet frequency and water percentage, smaller pellet size, delayed gastrointestinal transit time, and weaker spontaneous contractions of colonic smooth muscle. To determine the mechanism underlying delayed gut motility, microbial metabolites were measured. Short chain fatty acids and secondary bile acids were decreased in mice receiving microbiota from constipated donors. Moreover, the compositional changes of gut microbiota in constipated patients were identified, including the operational taxonomic unit, and the species richness and α diversity were much greater than those in healthy volunteers. These findings suggest that alterations of the microbiome might affect gut motility via altered microbial-derived metabolites in the development of constipation, and the restoration of disturbed microbiota might improve the clinical phenotype. This study indicates that regulating the intestinal environment may be a novel therapy strategy for constipation.

Rationale In the failing heart, persistent β-adrenergic receptor (βAR) activation is thought to induce myocyte death by protein kinase A (PKA)-dependent and PKA-independent activation of calcium/calmodulin-dependent kinase II (CaMKII). β-Adrenergic signaling pathways are also capable of activating cardioprotective mechanisms. Objective This study used a novel PKA inhibitor peptide (PKI) to inhibit PKA activity to test the hypothesis that βAR signaling causes cell death through PKA-dependent pathways and cardioprotection through PKA-independent pathways. Methods and Results In PKI transgenic mice, chronic isoproterenol (ISO) failed to induce cardiac hypertrophy, fibrosis, myocyte apoptosis and depressed cardiac function. In cultured adult feline ventricular myocytes (AFVMs), PKA inhibition protected myocytes from death induced by β1-AR agonists by preventing cytosolic and SR Ca2+ overload and CaMKII activation. PKA inhibition revealed a cardioprotective role of β-adrenergic signaling via cAMP/EPAC /Rap1/Rac/ERK pathway. Selective PKA inhibition causes protection in the heart after myocardial infarction (MI) that was superior to β-blocker therapy. Conclusion These results suggest that selective block of PKA could be a novel heart failure therapy.