Acotiamide (Z-338), a Novel Gastroprokinetic Agent for the Treatment of Functional Dyspepsia, Restores Delayed Gastric Emptying Induced by Restraint Stress via the Vagal Afferent Pathway in Rats

adults (13 weeks of age) (infant+/adult+) and 2) rats gavaged with vehicle only as infants and subsequent gavage with 108 cfu wild-type C. jejuni as adults (infant-/adult+). After inoculation with C. jejuni (as infants or adults), stool was collected daily and scored on a 1-4 scale based on consistency. Stools were cultured for C. jejuni on Campylobacter-selective blood agar. Clearance of infection was defined as two consecutive days with negative culture. Rats were euthanized 3 months after clearance of the adult acute infection in both groups. RT-PCR using all bacteria primers were performed on DNA extracted from the luminal contents of the ileum, jejunum, and duodenum (Qiagen QIAamp stool kit). Small intestinal bacterial overgrowth (SIBO) was defined as RT-PCR results >2 standard deviations higher than the mean healthy control rat bowel segments. Results: First exposure to C. jejuni yielded a greater length of C. jejuni colonization in infants (43.4±1.7 days) compared to infant-/adult+ (30.4±3.5 days) (P<0.01). Exposure as an infant appeared to confer subsequent protection to second exposure as adult of 10.5±1.7 days (P<0.0001). RT-PCR of luminal DNA demonstrated SIBO in 26% of infant-/adult+ rats three months after clearance of infection. However, significantly more infant+/adult+ rats (46%) had SIBO (P=0.019). Additionally, diarrhea was a risk factor during acute C. jejuni infection. Of the infant+/adult+ rats, 50% of those that had diarrhea as infants developed SIBO as an adult compared to 18% of infants with normal stool consistency (p<0.05). Among infant-/adult+, rats who developed SIBO had more days of diarrhea acutely (4.5±0.57) compared to those that did not develop SIBO (1.7±0.28) (P<0.001). Interestingly, rats with SIBO among the infant-/ adult+ rats had greater alteration in stool consistency as evidenced by stool wet weight (P<0.01). Conclusions: Although early exposure to C. jejuni mitigates the acute effects of future infection, second exposure increased the development of SIBO. Risk factors for SIBO were the presence and duration of loose stool during acute C. jejuni infection.