Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca2+-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.

Fecal Microbiota Transplantation Donor Screening Updates and Research Gaps for Solid Organ Transplant Recipients.

In this review, we discuss stool donor screening considerations to mitigate potential risks of pathogen transmission through fecal microbiota transplant (FMT) in solid organ transplant (SOT) recipients. SOT recipients have a higher risk for Clostridioides difficile infection (CDI) and are more likely to have severe CDI. FMT has been shown to be a valuable tool in the treatment of recurrent CDI (RCDI); however, guidelines for screening for opportunistic infections transmitted through FMT are underdeveloped. We review reported adverse effects of FMT as they pertain to an immunocompromised population and discuss the current understanding and recommendations for screening found in the literature while noting gaps in research. We conclude that while FMT is being performed in the SOT population, typically with positive results, there remain many unanswered questions which may have major safety implications and warrant further study.

Fecal Microbiota Transplantation Is Safe and Effective in Patients With Clostridioides difficile Infection and Cirrhosis.

BACKGROUND & AIMS: Clostridioides difficile infection (CDI) harms a large proportion of patients with cirrhosis. Fecal microbiota transplantation (FMT) is recommended for recurrent CDI, but its effects in patients with cirrhosis have not been established. We performed a multicenter observational study to evaluate the efficacy and safety of FMT for CDI in patients with cirrhosis. METHODS: We performed a retrospective study of 63 adults with cirrhosis (median model for end-stage liver disease score, 14.5; 24 patients with decompensated cirrhosis) who underwent FMT for CDI from January 2012 through November 2018 at 8 academic centers in the United States, Canada, and Italy. We collected data on patient demographics and characteristics of cirrhosis, CDI, and FMT from medical records and compared differences among patients with different severities of cirrhosis, and FMT successes vs failures at the 8-week follow-up evaluation. We also obtained data on adverse events (AEs) and severe AEs within 12 weeks of FMT. RESULTS: Patients underwent FMT for recurrent CDI (55 of 63; 87.3%), severe CDI (6 of 63; 9.5%), or fulminant CDI (2 of 63; 3.2%) primarily via colonoscopy (59 of 63; 93.7%) as outpatients (47 of 63; 76.8%). FMT success was achieved for 54 patients (85.7%). Among FMT failures, a higher proportion used non-CDI antibiotics at the time of FMT (44.4% vs 5.6%; P < .001), had Child-Pugh scores of B or C (100% vs 37.7%; P < .001), used probiotics (77.8% vs 24.1%; P = .003), had pseudomembranes (22.2% vs 0; P = .018), and underwent FMT as inpatients (45.5% vs 19%; P = .039), compared with FMT successes. In multivariable analysis, use of non-CDI antibiotics at the time of FMT (odds ratio, 17.43; 95% CI, 2.00-152.03; P = .01) and use of probiotics (odds ratio, 11.9; 95% CI, 1.81-78.3; P = .01) were associated with a greater risk of FMT failure. FMT-related AEs occurred in 33.3% of patients (21 of 63)-most were self-limited abdominal cramps or diarrhea. There were only 5 severe AEs that possibly were related to FMT; none involved infection or death. CONCLUSIONS: In a retrospective study, we found FMT to be safe and effective for the treatment of CDI in patients with cirrhosis.

Fecal microbiota transplantation for the treatment of recurrent and severe Clostridium difficile infection in solid organ transplant recipients: A multicenter experience.

Fecal microbiota transplant (FMT) is recommended for Clostridium difficile infection (CDI) treatment; however, use in solid organ transplantation (SOT) patients has theoretical safety concerns. This multicenter, retrospective study evaluated FMT safety, effectiveness, and risk factors for failure in SOT patients. Primary cure and overall cure were defined as resolution of diarrhea or negative C difficile stool test after a single FMT or after subsequent FMT(s) ± anti-CDI antibiotics, respectively. Ninety-four SOT patients underwent FMT, 78% for recurrent CDI and 22% for severe or fulminant CDI. FMT-related adverse events (AE) occurred in 22.3% of cases, mainly comprising self-limiting conditions including nausea, abdominal pain, and FMT-related diarrhea. Severe AEs occurred in 3.2% of cases, with no FMT-related bacteremia. After FMT, 25% of patients with underlying inflammatory bowel disease had worsening disease activity, while 14% of cytomegalovirus-seropositive patients had reactivation. At 3 months, primary cure was 58.7%, while overall cure was 91.3%. Predictors of failing a single FMT included inpatient status, severe and fulminant CDI, presence of pseudomembranous colitis, and use of non-CDI antibiotics at the time of FMT. These data suggest FMT is safe in SOT patients. However, repeated FMT(s) or additional antibiotics may be needed to optimize rates of cure with FMT.

Durability and Long-term Clinical Outcomes of Fecal Microbiota Transplant Treatment in Patients With Recurrent Clostridium difficile Infection.

Background: Fecal microbiota transplant (FMT) appears safe and effective for treatment of recurrent Clostridium difficile infection (RCDI). However, durability, long-term clinical outcomes, and patient satisfaction after FMT are not well described. Methods: Eligible patients who received FMT for RCDI at Emory Hospital between 1 July 2012 and 31 December 2016 were contacted via telephone for a follow-up survey. Of 190 eligible patients, 137 (72%) completed the survey. Results: Median time from last FMT to follow-up was 22 months. Overall, 82% (113/137) of patients at follow-up had no recurrence of C. difficile infection (CDI) post-FMT (non-RCDI group) and 18% (24/137) of patients had CDI post-FMT (RCDI group). Antibiotic exposure for non-CDI infections after FMT was more common in the RCDI group compared to the non-RCDI group (75% vs 38%, P = .0009). Overall, 11% of patients reported improvement or resolution of diagnoses not related to CDI post-FMT, and 33% reported development of a new medical condition or symptom post-FMT. Ninety-five percent of patients (122/128) indicated that they would undergo FMT again, and 70% of these 122 reported that they would prefer FMT to antibiotics as initial treatment if they were to have a CDI recurrence. Conclusions: In this follow-up survey of outcomes after FMT at a median of 22 months follow-up, 82% of patients had durable cure of CDI. Patients with recurrence had more post-FMT antibiotic exposure, underscoring the need for thoughtful antibiotic use and a potential role for prophylactic microbiome enrichment to reduce recurrence.

Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease.

BACKGROUND & AIMS: The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn's disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities. METHODS: We performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database). Single-nucleotide polymorphisms (SNPs) associated at P < 5.0 × 10-8 in meta-analysis with a nominal evidence (P < .05) in each scan were considered to have genome-wide significance. RESULTS: We detected SNPs at HLA-DRB1, and African-specific SNPs at ZNF649 and LSAMP, with associations of genome-wide significance for UC. We detected SNPs at USP25 with associations of genome-wide significance for IBD. No associations of genome-wide significance were detected for CD. In addition, 9 genes previously associated with IBD contained SNPs with significant evidence for replication (P < 1.6 × 10-6): ADCY3, CXCR6, HLA-DRB1 to HLA-DQA1 (genome-wide significance on conditioning), IL12B,PTGER4, and TNC for IBD; IL23R, PTGER4, and SNX20 (in strong linkage disequilibrium with NOD2) for CD; and KCNQ2 (near TNFRSF6B) for UC. Several of these genes, such as TNC (near TNFSF15), CXCR6, and genes associated with IBD at the HLA locus, contained SNPs with unique association patterns with African-specific alleles. CONCLUSIONS: We performed a genome-wide association study of African Americans with IBD and identified loci associated with UC in only this population; we also replicated IBD, CD, and UC loci identified in European populations. The detection of variants associated with IBD risk in only people of African descent demonstrates the importance of studying the genetics of IBD and other complex diseases in populations beyond those of European ancestry.

Tacrolimus concentration to dose ratio in solid organ transplant patients treated with fecal microbiota transplantation for recurrent Clostridium difficile infection.

Fecal microbiota transplantation (FMT) is increasingly being performed for Clostridium difficile infection in solid organ transplant (SOT) patients; however, little is known about the potential pharmacokinetic or pharmacomicrobial effects this may have on tacrolimus levels. We reviewed the medical records of 10 SOT patients from September 2012-December 2016 who were taking tacrolimus at time of FMT for recurrent C. difficile infection. We compared the differences in tacrolimus concentration/dose ratio (C/D ratio) 3 months prior to FMT vs 3 months after FMT. The mean of the differences in C/D ratio calculated as (ng/mL)/(mg/kg/d) was -17.65 (95% CI -1.25 to 0.58) (ng/mL)/(mg/kg/d), P-value .43 by Wilcoxon signed-rank test. The mean of the differences in C/D ratio calculated as (ng/mL)/(mg/d) was -0.33 (95% CI -1.25 to 0.58) (ng/mL)/(mg/d), P-value .28 by Wilcoxon signed-rank test. Of these patients, 2/10 underwent allograft biopsy for allograft dysfunction in the year after FMT, with no evidence of allograft rejection on pathology. These preliminary data suggest that FMT may not predictably alter tacrolimus levels and support its safety for SOT patients however further study in randomized trials is needed.

Laboratory Testing of Donors and Stool Samples for Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection.

Fecal microbiota transplantation is an efficacious and inexpensive therapy for recurrent Clostridium difficile infection, yet its safety is thought to depend on appropriate fecal donor screening. FDA guidance for regulation of this procedure is in flux, but screening and manufacture of fecal material from asymptomatic donors present many challenges to clinical laboratories. This minireview summarizes FDA regulatory changes, principles of donor selection, and recommended laboratory screening practices for fecal microbiota transplantation.

Pediatric short bowel syndrome and subsequent development of inflammatory bowel disease: an illustrative case and literature review.

Short bowel syndrome (SBS) in neonates is an uncommon but highly morbid condition. As SBS survival increases, physiologic complications become more apparent. Few reports in the literature elucidate outcomes for adults with a pediatric history of SBS. We present a case report of a patient, born with complicated gastroschisis resulting in SBS at birth, who subsequently developed symptoms and pathologic changes of inflammatory bowel disease (IBD) as an adult. The patient lived from age 7, after a Bianchi intestinal lengthening procedure, to age 34 independent of parenteral nutrition (PN), but requiring hydration fluid via G-tube. He was then diagnosed with IBD, after presenting with weight loss, diarrhea, and malabsorption, which required resumption of PN and infliximab treatment. This report adds to a small body of the literature which points to a connection between SBS in neonates and subsequent diagnosis of IBD. Recent evidence suggests that SBS and IBD have shared features of mucosal immune dysfunction and altered intestinal microbiota. We review current treatment options for pediatric SBS as well as multidisciplinary and coordinated transition strategies. We conclude that there may be an etiologic connection between SBS and IBD and that this knowledge may impact outcomes and approaches to care.

A Novel Microbiome Therapeutic Increases Gut Microbial Diversity and Prevents Recurrent Clostridium difficile Infection.

BACKGROUND: Patients with recurrent Clostridium difficile infection (CDI) have a ≥60% risk of relapse, as conventional therapies do not address the underlying gastrointestinal dysbiosis. This exploratory study evaluated the safety and efficacy of bacterial spores for preventing recurrent CDI. METHODS: Stool specimens from healthy donors were treated with ethanol to eliminate pathogens. The resulting spores were fractionated and encapsulated for oral delivery as SER-109. Following their response to standard-of-care antibiotics, patients in cohort 1 were treated with SER-109 on 2 consecutive days (geometric mean dose, 1.7 × 10(9) spores), and those in cohort 2 were treated on 1 day (geometric mean dose, 1.1 × 10(8) spores). The primary efficacy end point was absence of C. difficile-positive diarrhea during an 8-week follow-up period. Microbiome alterations were assessed. RESULTS: Thirty patients (median age, 66.5 years; 67% female) were enrolled, and 26 (86.7%) met the primary efficacy end point. Three patients with early, self-limiting C. difficile-positive diarrhea did not require antibiotics and tested negative for C. difficile at 8 weeks; thus, 96.7% (29 of 30) achieved clinical resolution. In parallel, gut microbiota rapidly diversified, with durable engraftment of spores and no outgrowth of non-spore-forming bacteria found after SER-109 treatment. Adverse events included mild diarrhea, abdominal pain, and nausea. CONCLUSIONS: SER-109 successfully prevented CDI and had a favorable safety profile, supporting a novel microbiome-based intervention as a potential therapy for recurrent CDI.

Characterization of genetic loci that affect susceptibility to inflammatory bowel diseases in African Americans.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) has familial aggregation in African Americans (AAs), but little is known about the molecular genetic susceptibility. Mapping studies using the Immunochip genotyping array expand the number of susceptibility loci for IBD in Caucasians to 163, but the contribution of the 163 loci and European admixture to IBD risk in AAs is unclear. We performed a genetic mapping study using the Immunochip to determine whether IBD susceptibility loci in Caucasians also affect risk in AAs and identify new associated loci. METHODS: We recruited AAs with IBD and without IBD (controls) from 34 IBD centers in the United States; additional controls were collected from 4 other Immunochip studies. Association and admixture loci were mapped for 1088 patients with Crohn's disease, 361 with ulcerative colitis, 62 with IBD type unknown, and 1797 controls; 130,241 autosomal single-nucleotide polymorphisms (SNPs) were analyzed. RESULTS: The strongest associations were observed between ulcerative colitis and HLA rs9271366 (P = 7.5 × 10(-6)), Crohn's disease and 5p13.1 rs4286721 (P = 3.5 × 10(-6)), and IBD and KAT2A rs730086 (P = 2.3 × 10(-6)). Additional suggestive associations (P < 4.2 × 10(-5)) were observed between Crohn's disease and IBD and African-specific SNPs in STAT5A and STAT3; between IBD and SNPs in IL23R, IL12B, and C2orf43; and between ulcerative colitis and SNPs near HDAC11 and near LINC00994. The latter 3 loci have not been previously associated with IBD, but require replication. Established Caucasian associations were replicated in AAs (P < 3.1 × 10(-4)) at NOD2, IL23R, 5p15.3, and IKZF3. Significant admixture (P < 3.9 × 10(-4)) was observed for 17q12-17q21.31 (IZKF3 through STAT3), 10q11.23-10q21.2, 15q22.2-15q23, and 16p12.2-16p12.1. Network analyses showed significant enrichment (false discovery rate <1 × 10(-5)) in genes that encode members of the JAK-STAT, cytokine, and chemokine signaling pathways, as well those involved in pathogenesis of measles. CONCLUSIONS: In a genetic analysis of 3308 AA IBD cases and controls, we found that many variants associated with IBD in Caucasians also showed association evidence with these diseases in AAs; we also found evidence for variants and loci not previously associated with IBD. The complex genetic factors that determine risk for or protection against IBD in different populations require further study.

Ulcerative Colitis: Update on Medical Management.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease whose pathogenesis is multifactorial and includes influences from genes, the environment, and the gut microbiome. Recent advances in diagnosis and treatment have led to significant improvement in managing the disease. Disease monitoring with the use of therapeutic drug monitoring, stool markers, and assessment of mucosal healing have garnered much attention. The recent approval of vedolizumab for treatment of moderate to severe UC has been a welcome addition. Newer biologics, including those targeting the Janus tyrosine kinase (JAK) pathway, are on the horizon to add to the current armamentarium of anti-TNF alpha and anti-integrin therapies. The recent publication of the SCENIC consensus statement on surveillance and management of dysplasia in UC patients supports the use of chromoendoscopy over random biopsies in detecting dysplasia. This review highlights these recent advances along with others that have been made with ulcerative colitis.

A comparison of abdominal surgical outcomes between African-American and Caucasian Crohn's patients.

BACKGROUND AND OBJECTIVE: Whether race affects the natural history of Crohn's disease is a matter of debate. The aim of the current study was to evaluate the differences in surgical outcomes between African-American (AA) and Caucasian (C) Crohn's patients undergoing surgery at a tertiary care referral center. METHODS: With Institutional Review Board approval, the medical records of our institution were queried to identify consecutive AA and C patients who underwent surgery for Crohn's disease from December 1, 2009 to December 15, 2011. A retrospective chart review was performed using electronic medical records. RESULTS: A total of 77 patients were included in this study, including 32 AA (41 %) and 45 C (59 %). No significant differences were seen with respect to age, gender, type of insurance, preoperative exposure to immunosuppressives, body mass index, or smoking history between the two populations (p > 0.05). There was a trend toward lower albumin in AAs (p = 0.09). AA and C patients who underwent their first Crohn's disease (CD)-related surgery had similar lag periods between diagnosis and surgery. No significant differences were seen in location of disease, indication for operation, and need for open laparotomy over laparoscopy. No significant differences were seen in need for a repeat operation within 90 days of the original surgery or major postoperative complications. There was a trend toward higher rate of minor complications in the AA group (p = 0.07). CONCLUSION: No significant differences were noted in the current study in several preoperative variables and surgical outcomes between AA and C.

Integration of Radiation Oncology Into the Preclinical Curriculum Through Problem-Based Learning.

PURPOSE: Early exposure to oncology care during the preclinical years of medical school may translate to increased student interest in oncology-related fields and improved understanding of oncologic treatment modalities, including radiation oncology. Many schools incorporate problem-based learning (PBL) into the medical school curriculum; this is an opportunity to immerse students in oncologic case management. We describe the effective incorporation of one course into the medical school curriculum that may be replicated at other institutions. METHODS AND MATERIALS: A PBL case regarding pancreatic cancer was created by a radiation oncology resident and faculty member in collaboration with the gastrointestinal course director for first-year medical students at a single institution. Pancreatic cancer was chosen based on curricular needs. Learning objectives were discussed to guide the creation of the case. RESULTS: All 140 first-year medical students participated in the 1-hour small group case focused on oncologic work up, multidisciplinary care, and radiation therapy concepts. Students were provided with a case prompt and resources to review prior to the PBL session. Volunteer radiation oncology facilitators attended a 30-minute educational meeting and were provided a detailed case guide 1 week before the PBL session. During the PBL case, facilitators guided students to achieve desired learning objectives. Among the 76 (54%) medical students who completed an optional post-PBL survey, the majority reported that the case motivated them to learn more about oncology (89%) and radiation oncology (82%). There was an increase in the number of subscribers to the Oncology Interest Group (43% increase from previous year) and preclinical students shadowing in the radiation oncology department. The PBL case was continued in future years for all first-year students and extended to 2 hours to promote additional discussion in response to student and facilitator feedback. CONCLUSIONS: A cancer-specific PBL case facilitated by radiation oncology educators is an effective avenue to integrate radiation oncology into the preclinical curriculum and stimulate interest in oncology among first-year medical students.

Vitamin D status and bone mineral density in African American children with Crohn disease.

BACKGROUND: Vitamin D deficiency and low bone mineral density (BMD) are complications of inflammatory bowel disease. Vitamin D deficiency is more prevalent among African Americans compared with whites. There are little data comparing differences in serum 25-hydroxyvitamin D (25OHD) concentrations and BMD between African American and white children with Crohn disease (CD). METHODS: We compared serum 25OHD concentrations of African American children with CD (n = 52) to white children with CD (n = 64) and healthy African American controls (n = 40). We also analyzed BMD using dual-energy x-ray absorptiometry results from our pediatric CD population. RESULTS: African American children with CD had lower serum 25OHD concentrations (16.1 [95% confidence interval, CI 14.5-17.9] ng/mL) than whites with CD (22.3 [95% CI 20.2-24.6] ng/mL; P < 0.001). African Americans with CD and controls exhibited similar serum 25OHD concentration (16.1 [95% CI 14.5-17.9] vs 16.3 [95% CI 14.4-18.4] ng/mL; NS). African Americans with CD exhibited no difference in serum 25OHD concentration when controlling for seasonality, disease severity, and surgical history, although serum 25OHD concentration was significantly decreased in overweight children (body mass index ≥85%, P = 0.003). Multiple regression analysis demonstrated that obese African American girls with CD had the lowest serum 25OHD concentrations (9.6 [95% CI 6.8-13.5] ng/mL). BMD was comparable between African American and white children with CD (z score -0.4 ± 0.9 vs -0.7 ± 1.2; NS). CONCLUSIONS: African American children with CD are more likely to have vitamin D deficiency compared with white children with CD, but have similar BMD. CD disease severity and history of surgery do not affect serum 25OHD concentrations among African American children with CD. African American children have low serum 25OHD concentrations, independent of CD, compared with white children. Future research should focus on how race affects vitamin D status and BMD in children with CD.

Intracolonic Neuropeptide Y Y1 Receptor Inhibition Attenuates Intestinal Inflammation in Murine Colitis and Cytokine Release in IBD Biopsies.

We have demonstrated that neuropeptide Y (NPY) can regulate pro-inflammatory signaling in the gut via cross-talk with the pro-inflammatory cytokine tumor necrosis factor (TNF). Here, we investigated if selective blocking of NPY receptors, NPY1R or NPY2R, using small molecule non-peptide antagonists (BIBP-3222 for NPY1R and BIIE-0246 for NPY2R) in the colon could attenuate intestinal inflammation by lowering TNF levels (BIBP - N-[(1R)]-4-[(Aminoiminomethyl)amino-1-[[[(4-hydroxyphenyl)methyl]amino]carbonyl]butyl-α-phenylbenzeneacetamide; BIIE - N-[(1S)-4-[(Aminoiminomethyl)amino]-1-[[[2-(3,5-dioxo-1,2-diphenyl-1,2,4-triazolidin-4-yl)ethyl]amino]carbonyl]butyl]-1-[2-[4-(6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-yl)-1-piperazinyl]-2-oxoethyl]-cyclopentaneacetamide). Colitis was induced using dextran sodium sulfate in drinking water for 7 days, or by adoptive T-cell transfer in RAG-/- mice. Colonic biopsies from healthy subjects (n = 10) and IBD patients (n = 34, UC = 20, CD = 14) were cultured ex vivo in presence or absence of NPY antagonists (100 µM, 20 h), and cytokine release into culture supernatants was measured by ELISA. Intracolonic administration of BIBP (but not BIIE) significantly reduced clinical, endoscopic, and histological scores, and serum TNF, interleukin (IL)-6, and IL-12p70 in DSS colitis; it also significantly attenuated histological damage and serum IL-6 in T-cell colitis (P < .05). Intracolonic administration of BIBP significantly reduced TNF and interferon (IFN)-γ release from UC biopsies, whereas BIIE downregulated only IFN-γ (P < .05). BIBP significantly reduced TNF and interferon (IFN)-γ release from UC biopsies, whereas BIIE downregulated only IFN-γ (P < .05). Our data suggest a promising therapeutic value for NPY1R inhibition in alleviating intestinal inflammation in UC, possibly as enemas to IBD patients.