Purpose of review Recent technological advancements and expanded efforts have led to a tremendous growth in the collective knowledge of the human microbiome. This review will highlight some of the important recent findings in this area of research. Recent findings Studies have described the structure and functional capacity of the bacterial microbiome in the healthy state and in a variety of disease states. Downstream analyses of the functional interactions between the host and its microbiome are starting to provide mechanistic insights into these interactions. These data are anticipated to lead to new opportunities for diagnosis, prognosis, and treatment of a variety of human diseases. Summary There is a fast growing collection of data describing the structure and functional capacity of the microbiome in a variety of conditions available to the research community for consideration and further exploration. Ongoing efforts to further characterize the functions of the microbiome and the mechanisms underlying host-microbe interactions will provide a better understanding of the role of the microbiome in health and disease.

This article is available online at http://dmd.aspetjournals.org ABSTRACT:Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches, to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (P450) probe substrates, inhibitors and inducers and for the development of classification systems to improve the communication of risk to health care providers and to patients. While existing guidances cover mainly P450-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently, and should also be addressed. This article was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.Drug-drug interactions can lead to severe side effects and have resulted in early termination of development, refusal of approval, severe prescribing restrictions, and withdrawal of drugs from the market. Regulators, including the U.S. Food and Drug Administration (FDA 1 ) have therefore issued guidances for in vitro and in vivo drug interaction studies to be conducted during development. These guidances, however, do not address the specific designs of the studies, and there is a desire by regulatory authorities to harmonize approaches and study designs to allow for a better assessment and comparison of different drugs. In addition, the existing guidances cover mainly cytochrome P450 (P450)-mediated drug interactions and the importance of other mechanisms, such as transporters, has been recognized only recently. To address these issues, workshops have been held in

OBJECTIVES Patients who are immunocompromised (IC) are at increased risk of Clostridium difficile infection (CDI), which has increased to epidemic proportions over the past decade. Fecal microbiota transplantation (FMT) appears effective for the treatment of CDI, although there is concern that IC patients may be at increased risk of having adverse events (AEs) related to FMT. This study describes the multicenter experience of FMT in IC patients. METHODS A multicenter retrospective series was performed on the use of FMT in IC patients with CDI that was recurrent, refractory, or severe. We aimed to describe rates of CDI cure after FMT as well as AEs experienced by IC patients after FMT. A 32-item questionnaire soliciting demographic and pre- and post-FMT data was completed for 99 patients at 16 centers, of whom 80 were eligible for inclusion. Outcomes included (i) rates of CDI cure after FMT, (ii) serious adverse events (SAEs) such as death or hospitalization within 12 weeks of FMT, (iii) infection within 12 weeks of FMT, and (iv) AEs (related and unrelated) to FMT. RESULTS Cases included adult (75) and pediatric (5) patients treated with FMT for recurrent (55%), refractory (11%), and severe and/or overlap of recurrent/refractory and severe CDI (34%). In all, 79% were outpatients at the time of FMT. The mean follow-up period between FMT and data collection was 11 months (range 3–46 months). Reasons for IC included: HIV/AIDS (3), solid organ transplant (19), oncologic condition (7), immunosuppressive therapy for inflammatory bowel disease (IBD; 36), and other medical conditions/medications (15). The CDI cure rate after a single FMT was 78%, with 62 patients suffering no recurrence at least 12 weeks post FMT. Twelve patients underwent repeat FMT, of whom eight had no further CDI. Thus, the overall cure rate was 89%. Twelve (15%) had any SAE within 12 weeks post FMT, of which 10 were hospitalizations. Two deaths occurred within 12 weeks of FMT, one of which was the result of aspiration during sedation for FMT administered via colonoscopy; the other was unrelated to FMT. None suffered infections definitely related to FMT, but two patients developed unrelated infections and five had self-limited diarrheal illness in which no causal organism was identified. One patient had a superficial mucosal tear caused by the colonoscopy performed for the FMT, and three patients reported mild, self-limited abdominal discomfort post FMT. Five (14% of IBD patients) experienced disease flare post FMT. Three ulcerative colitis (UC) patients underwent colectomy related to course of UC > 100 days after FMT. CONCLUSIONS This series demonstrates the effective use of FMT for CDI in IC patients with few SAEs or related AEs. Importantly, there were no related infectious complications in these high-risk patients.

Background & Aims The efficacy of treatment of Helicobacter pylori infection has decreased steadily due to increasing resistance to clarithromycin, metronidazole, and levofloxacin. Resistance to amoxicillin is generally low, and high intragastric pH increases the efficacy of amoxicillin, so we investigated whether a combination of a high-dose proton-pump inhibitor and amoxicillin (dual therapy) was more effective than standard first-line or rescue therapies in eradicating H pylori. Methods We performed a large-scale, multi-hospital trial to compare the efficacy of a high-dose dual therapy (HDDT) with that of standard therapies in treatment-naïve (n=450) or treatment-experienced (n=168) patients with H pylori infection. Treatment-naïve patients were randomly assigned to groups given HDDT (rabeprazole 20 mg and amoxicillin 750 mg, 4 times/day for 14 days; group A1), sequential therapy for 10 days (group B1), or clarithromycin-containing triple therapy for 7 days (group C1). Treatment-experienced patients were randomly assigned to groups given HDDT for 14 days (group A2), sequential therapy for 10 days (B2), or levofloxacin-containing triple therapy for 7 days (C2). H pylori infection was detected using the 13C–urea breath test. We evaluated factors associated with treatment outcomes. Results In the intention-to-treat treat analysis, H pylori was eradicated in 95.3% of patients in group A1 (95% confidence interval [CI], 91.9%–98.8%), 85.3% in B1 (95% CI, 79.6%–91.1%), and 80.7% in group C1 (95% CI, 74.3%–87.1%). Infection was eradicated in 89.3% of patients in group A2 (95% CI, 80.9%–97.6%), 51.8% in group B2 (95% CI, 38.3%–65.3%), and 78.6% (95% CI, 67.5%–89.7%). The efficacy of HDDT was significantly higher than that of currently recommended regimens, irrespective of CYP2C19 genotype. Bacterial resistance to drugs was associated with treatment failure. There were no significant differences between groups in adverse events or patient adherence. Conclusions HDDT is superior to standard regimens as empiric first-line or rescue therapy for H pylori infection, with similar safety profiles and tolerability. ClinicalTrials.gov no: NCT01163435.

Background & Aims Helicobacter pylori infection increases gastric Treg response, which may contribute to H pylori immune escape. We hypothesize that H pylori directs Treg skewing by way of dendritic cells and thus inhibits Th17 immunity. Methods Two-photon microscopy was used to locate dendritic cells in gastric lamina propria of mice. The induction of Th17 and Treg responses by bacteria-pulsed murine bone marrow–derived dendritic cells was analyzed by cytokine production and stimulation of T cell proliferation. The effect of VacA, CagA, TGF-β, and IL-10 on Th17/Treg balance was assessed. The in vivo significance of Tregs on the H pylori–specific Th17 response and H pylori density was determined using anti-CD25 neutralizing antibodies to deplete Tregs in mice. Results We showed that mucosal CD11c+ dendritic cells are located near the surface of normal gastric epithelium and their number increased after H pylori infection. Study of the direct interaction of dendritic cells with H pylori revealed a Treg-skewed response. The Treg skewing was independent of H pylori VacA and CagA and dependent on TGF-β and IL-10. In vivo Treg skewing by adoptive transfer of H pylori–pulsed DCs reduces the ratio of gastric IL-17/Foxp3 mRNA expressions. The depletion of CD25+ Tregs results in early reduction of H pylori density, which is correlated with enhanced peripheral H pylori–specific Th17, but not Th1, response. Conclusions Overall, our study indicates that H pylori alters the DC-polarized Th17/Treg balance towards a Treg-biased response, which suppresses the effective induction of H pylori–specific Th17 immunity.