The effect of pyridostigmine on small intestinal bacterial overgrowth (SIBO) and plasma inflammatory biomarkers in HIV-associated autonomic neuropathies.

Small intestinal bacterial overgrowth (SIBO) is common among patients with HIV-associated autonomic neuropathies (HIV-AN) and may be associated with increased bacterial translocation and elevated plasma inflammatory biomarkers. Pyridostigmine is an acetylcholinesterase inhibitor which has been used to augment autonomic signaling. We sought preliminary evidence as to whether pyridostigmine could improve proximal gastrointestinal motility, reduce SIBO, reduce plasma sCD14 (a marker of macrophage activation and indirect measure of translocation), and reduce the inflammatory cytokines IL-6 and TNFα in patients with HIV-AN. Fifteen participants with well-controlled HIV, HIV-AN, and SIBO were treated with 8 weeks of pyridostigmine (30 mg PO TID). Glucose breath testing for SIBO, gastric emptying studies (GES) to assess motility, plasma sCD14, IL-6, and TNFα, and gastrointestinal autonomic symptoms were compared before and after treatment. Thirteen participants (87%) experienced an improvement in SIBO following pyridostigmine treatment; with an average improvement of 50% (p = 0.016). There was no change in gastrointestinal motility; however, only two participants met GES criteria for gastroparesis at baseline. TNFα and sCD14 levels declined by 12% (p = 0.004) and 19% (p = 0.015), respectively; there was no significant change in IL-6 or gastrointestinal symptoms. Pyridostigmine may ameliorate SIBO and reduce levels of sCD14 and TNFα in patients with HIV-AN. Larger placebo-controlled studies are needed to definitively delineate how HIV-AN affects gastrointestinal motility, SIBO, and systemic inflammation in HIV, and whether treatment improves clinical outcomes.

Performing colonic mast cell counts in patients with chronic diarrhea of unknown etiology has limited diagnostic use.

CONTEXT: Mastocytic enterocolitis is a recently described entity defined by chronic diarrhea of unknown etiology and normal colon biopsy results with increased mast cells (MCs) seen on special stains. These patients may benefit from mast cell stabilizers; however, the clinical utility of MC counts remains unknown. OBJECTIVE: To determine the clinical utility of colonic MC counts on normal biopsies in patients with chronic diarrhea of unknown etiology. DESIGN: Blinded MC counts using a c-Kit stain were performed in 76 consecutive patients with chronic diarrhea of unknown etiology who had normal colon biopsy results and in 89 consecutive control patients presenting for screening colonoscopy. Mast cells were counted per single high-power field in the highest-density area. A t test was used to compare the counts, and receiver operating characteristic curves were generated to examine sensitive and specific cutoff values. RESULTS: Overall, MC counts averaged 31 MCs per high-power field in the study group versus 24 MCs per high-power field in the control group (P < .001). When stratified by location, a significant increase was seen in biopsies from the left colon only. Receiver operating characteristic analysis revealed that overall MC counts, left-sided MC counts, and the difference between right- and left-sided MC counts did not yield discriminatory cutoff values (area under the curve, 0.68, 0.74, and 0.81, respectively). CONCLUSIONS: Mast cell counts were increased in patients with chronic diarrhea of unknown etiology, primarily in the left colon. However, receiver operating characteristic analysis demonstrates no discriminatory cutoff values. Quantitative MC stains yield little useful diagnostic information, and further studies are necessary to determine whether mastocytic enterocolitis truly represents a distinct entity.

Small Intestinal Transit Time Is Delayed in Small Intestinal Bacterial Overgrowth.

BACKGROUND: Altered small intestinal motility is thought to contribute to the development of small intestinal bacterial overgrowth (SIBO). The clinical manifestations of SIBO and consequent malabsorption are wide ranging and include abdominal pain, bloating, diarrhea, weight loss, and nutritional deficiencies. However, due to the nonspecific nature of symptoms, the diagnosis may often be overlooked. To date, few studies have illustrated a direct relationship between impaired small intestinal motility and SIBO. In addition, further study has been limited by the technical challenges and lack of widespread availability of antroduodenal manometry. The development of a wireless motility capsule (WMC) (SmartPill) that evaluates pressure, pH, and temperature throughout the GI tract offers the potential to identify patients with small bowel transit delays who may be at risk for bacterial overgrowth. AIMS: The primary aims of this study were to: (1) characterize the relationship of prolonged small bowel transit time (SBTT) in patients undergoing WMC with SIBO as based on a positive lactulose breath testing (LBT); and (2) to assess the relationship of prolonged gastric, colonic, and whole gut transit times (WGTT) and additional motility parameters with SIBO (positive LBT). We also sought to evaluate the relationship of small bowel motility parameters (SB motility index, contractions per minute, and SB peak amplitudes) with LBT results. METHODS: We performed a retrospective study of consecutive patients who were referred for wireless motility testing at a single, tertiary care institution from April 2009 to December 2012. Of the 72 total patients identified, 34 underwent both WMC and LBT. Gastric, small bowel, colonic, WGTT, and SB motility parameters were measured and correlated with LBT results. Statistical methods utilized for data analysis include ANOVA, 2-sample t tests, nonparametric Kruskal Wallis test, Wilcoxon rank-sum test, and the Fisher exact test. RESULTS: Of the 37 patients who underwent both WMC and LBT, 24 (65%) were LBT positive. The mean SBTT among those who were LBT positive was 6.6 hours as compared with 4.2 hours in those who were LBT negative (P=0.04). Among patients who were LBT positive, 47.6% had prolonged SBTT (≥6 h), whereas only 7.7% of those who were LBT negative had a delay in their SBTT (P=0.01). In addition, patients who were LBT positive were more likely to have prolongation of both colonic and WGTT versus those who were LBT negative (CTT: positive LBT=64.4 h vs. negative LBT=35.5 h, P=0.02; WGTT: positive LBT=70.5 h vs. negative LBT=44.1 h, P=0.02). However, there were no statistical differences observed between the groups for gastric emptying times or other small intestinal motility parameters (SB motility index, contractions per minute, and peak amplitudes) between the 2 groups. CONCLUSIONS: Patients with underlying SIBO have significant delays in SBTT as compared with those without. The association between prolonged SBTT and positive LBT may be useful in identifying those patients with SIBO diagnosed by LBT and potentially target therapeutic options for those refractory to standard therapy. Interestingly, patients with positive LBT did not necessarily have a generalized gastrointestinal motility (similar GETs among groups), suggesting that small bowel transit specifically predisposes to the development of SIBO. Future, prospective studies are needed to further characterize intestinal dysmotility and other contributing pathophysiological mechanisms in SIBO and to investigate the potential benefits of prokinetics in this challenging patient population.

Herbal therapy is equivalent to rifaximin for the treatment of small intestinal bacterial overgrowth.

OBJECTIVE: Patients with small intestine bacterial overgrowth (SIBO) have chronic intestinal and extraintestinal symptomatology which adversely affects their quality of life. Present treatment of SIBO is limited to oral antibiotics with variable success. A growing number of patients are interested in using complementary and alternative therapies for their gastrointestinal health. The objective was to determine the remission rate of SIBO using either the antibiotic rifaximin or herbals in a tertiary care referral gastroenterology practice. DESIGN: One hundred and four patients who tested positive for newly diagnosed SIBO by lactulose breath testing (LBT) were offered either rifaximin 1200 mg daily vs herbal therapy for 4 weeks with repeat LBT post-treatment. RESULTS: Three hundred ninety-six patients underwent LBT for suspected SIBO, of which 251 (63.4%) were positive 165 underwent treatment and 104 had a follow-up LBT. Of the 37 patients who received herbal therapy, 17 (46%) had a negative follow-up LBT compared to 23/67 (34%) of rifaximin users (P=.24). The odds ratio of having a negative LBT after taking herbal therapy as compared to rifaximin was 1.85 (CI=0.77-4.41, P=.17) once adjusted for age, gender, SIBO risk factors and IBS status. Fourteen of the 44 (31.8%) rifaximin non-responders were offered herbal rescue therapy, with 8 of the 14 (57.1%) having a negative LBT after completing the rescue herbal therapy, while 10 non-responders were offered triple antibiotics with 6 responding (60%, P=.89). Adverse effects were reported among the rifaximin treated arm including 1 case of anaphylaxis, 2 cases of hives, 2 cases of diarrhea and 1 case of Clostridium difficile. Only one case of diarrhea was reported in the herbal therapy arm, which did not reach statistical significance (P=.22). CONCLUSION: SIBO is widely prevalent in a tertiary referral gastroenterology practice. Herbal therapies are at least as effective as rifaximin for resolution of SIBO by LBT. Herbals also appear to be as effective as triple antibiotic therapy for SIBO rescue therapy for rifaximin non-responders. Further, prospective studies are needed to validate these findings and explore additional alternative therapies in patients with refractory SIBO.

Low ileocecal valve pressure is significantly associated with small intestinal bacterial overgrowth (SIBO).

BACKGROUND: Small intestinal bacterial overgrowth (SIBO) is a significant and increasingly recognized syndrome. While the development may be multifactorial, impairment of the ileocecal valve (ICV), small bowel motility, and gastric acid secretion have been hypothesized to be risk factors. ICV dysfunction remains largely unexplored using standard technology. The wireless motility capsule (WMC) that evaluates pressure, pH, and temperature throughout the GI tract provides the ability to assess these parameters. AIMS: The primary aims of this study were to assess the relationship of ICV pressures, small bowel transit time (SBTT) and intestinal pH with lactulose hydrogen breath testing (LBT) results in subjects with suspected SIBO. METHODS: We retrospectively studied consecutive patients referred to our institution for WMC and LBT from 2010-2012. Ileocecal junction pressures (IJP), as a surrogate for ICV pressures, were defined as the highest pressure over a 4-min window prior to the characteristic ileocecal pH drop. SBTT and pH were calculated and compared with LBT results. RESULTS: Twenty-three patients underwent both WMC and LBT, with positive results observed in 15 (65.2%). IJP were significantly higher in LBT(-) negative vs. LBT(+) (79.9 vs. 45.1, p < 0.01). SBTT was significantly longer in LBT(+) versus LBT(-) (5.82 vs. 3.81 h, p = 0.05). Among LBT(+) subjects, gastric pH was significantly higher versus LBT(-) subjects (2.76 vs. 1.63, p = 0.01). There was poor correlation between IJP and other parameters (SBTT, small bowel pH, and gastric pH). CONCLUSIONS: Low IJP is significantly associated with SIBO. While this is physiologically plausible, to our knowledge, this is the first study to make this connection. Prolonged SBTT and higher pH are also independently associated with SIBO. Our findings add value of the WMC test as a diagnostic tool in patients with functional gastrointestinal complaints and suggest re-focus of attention on the ileocecal valve as a prominent player in intestinal disorders.

Long non-coding RNA HNF1A-AS1 regulates proliferation and migration in oesophageal adenocarcinoma cells.

OBJECTIVES: Long non-coding RNAs (lncRNA) have been shown to play important roles in the development and progression of cancer. However, functional lncRNAs and their downstream mechanisms are largely unknown in the molecular pathogenesis of oesophageal adenocarcinoma (EAC) and its progression. DESIGN: lncRNAs that are abnormally upregulated in EACs were identified by RNA-sequencing analysis, followed by quantitative RT-PCR (qRTPCR) validation using tissues from 25 EAC patients. Cell biological assays in combination with small interfering RNA-mediated knockdown were performed in order to probe the functional relevance of these lncRNAs. RESULTS: We discovered that a lncRNA, HNF1A-AS1, is markedly upregulated in human primary EACs relative to their corresponding normal oesophageal tissues (mean fold change 10.6, p<0.01). We further discovered that HNF1A-AS1 knockdown significantly inhibited cell proliferation and anchorage-independent growth, suppressed S-phase entry, and inhibited cell migration and invasion in multiple in vitro EAC models (p<0.05). A gene ontological analysis revealed that HNF1A-AS1 knockdown preferentially affected genes that are linked to assembly of chromatin and the nucleosome, a mechanism essential to cell cycle progression. The well known cancer-related lncRNA, H19, was the gene most markedly inhibited by HNF1A-AS1 knockdown. Consistent to this finding, there was a significant positive correlation between HNF1A-AS1 and H19 expression in primary EACs (p<0.01). CONCLUSIONS: We have discovered abnormal upregulation of a lncRNA, HNF1A-AS1, in human EAC. Our findings suggest that dysregulation of HNF1A-AS1 participates in oesophageal tumorigenesis, and that this participation may be mediated, at least in part, by modulation of chromatin and nucleosome assembly as well as by H19 induction.

Jet injection of dyed saline facilitates efficient peroral endoscopic myotomy.

BACKGROUND AND STUDY AIMS: Peroral endoscopic myotomy (POEM) is technically challenging and time consuming. Repeated injection of dyed saline during tunneling is performed to enhance the demarcation between the submucosal layer and the muscularis propria. This process requires exchanging the knife for a catheter to spray dyed saline and is time consuming. This study aimed to describe a new method of injecting dyed saline through an integrated water jet channel during POEM. PATIENTS AND METHODS: POEM was performed using a triangular tip knife. Repeated jet injection of saline mixed with indigo carmine was performed whenever the submucosal dissection plane became unclear. RESULTS: The study cohort consisted of nine patients (8 achalasia, 1 Jackhammer esophagus). All procedures were technically feasible and successful without any complications and resulted in the patients' Eckhardt's scores returning to normal. The mean submucosal tunnel length was 13.3 cm and the mean myotomy length was 9.9 cm. The mean procedure time was 127 minutes. CONCLUSION: The modified POEM technique with use of jet injection of dyed saline is simple and may render POEM easier and more efficient than the standard dissection method.