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Understanding the interplay between genetic susceptibility, the microbiome, the environment and the immune system in Crohn's Disease (CD) is essential for developing optimal therapeutic strategies. We sought to examine the dynamics of the relationship between inflammation, the ileal microbiome, and host genetics in murine models of ileitis. We induced ileal inflammation of graded severity in C57BL6 mice by gavage with Toxoplasma gondii, Giardia muris, low dose indomethacin (LDI; 0.1 mg/mouse), or high dose indomethacin (HDI; 1 mg/mouse). The composition and spatial distribution of the mucosal microbiome was evaluated by 16S rDNA pyrosequencing and fluorescence in situ hybridization. Mucosal E. coli were enumerated by quantitative PCR, and characterized by phylogroup, genotype and pathotype. Moderate to severe ileitis induced by T. gondii (day 8) and HDI caused a consistent shift from >95% gram + Firmicutes to >95% gram - Proteobacteria. This was accompanied by reduced microbial diversity and mucosal invasion by adherent and invasive E. coli, mirroring the dysbiosis of ileal CD. In contrast, dysbiosis and bacterial invasion did not develop in mice with mild ileitis induced by Giardia muris. Superimposition of genetic susceptibility and T. Gondii infection revealed greatest dysbiosis and bacterial invasion in the CD-susceptible genotype, NOD2(-/-), and reduced dysbiosis in ileitis-resistant CCR2(-/-) mice. Abrogating inflammation with the CD therapeutic anti-TNF-α-mAb tempered dysbiosis and bacterial invasion. Acute ileitis induces dysbiosis and proliferation of mucosally invasive E. coli, irrespective of trigger and genotype. The identification of CCR2 as a target for therapeutic intervention, and discovery that host genotype and therapeutic blockade of inflammation impact the threshold and extent of ileal dysbiosis are of high relevance to developing effective therapies for CD.

Digital health is poised to transform health care and redefine personalized health. As Internet and mobile phone usage increases, as technology develops new ways to collect data, and as clinical guidelines change, all areas of medicine face new challenges and opportunities. Inflammatory bowel disease (IBD) is one of many chronic diseases that may benefit from these advances in digital health. This review intends to lay a foundation for clinicians and technologists to understand future directions and opportunities together. This review covers mobile health apps that have been used in IBD, how they have fit into a clinical care framework, and the challenges that clinicians and technologists face in approaching future opportunities. We searched PubMed, Scopus, and ClinicalTrials.gov to identify mobile apps that have been studied and were published in the literature from January 1, 2010, to April 19, 2019. The search terms were (\"mobile health\" OR \"eHealth\" OR \"digital health\" OR \"smart phone\" OR \"mobile app\" OR \"mobile applications\" OR \"mHealth\" OR \"smartphones\") AND (\"IBD\" OR \"Inflammatory bowel disease\" OR \"Crohn's Disease\" (CD) OR \"Ulcerative Colitis\" (UC) OR \"UC\" OR \"CD\"), followed by further analysis of citations from the results. We searched the Apple iTunes app store to identify a limited selection of commercial apps to include for discussion. A total of 68 articles met the inclusion criteria. A total of 11 digital health apps were identified in the literature and 4 commercial apps were selected to be described in this review. While most apps have some educational component, the majority of apps focus on eliciting patient-reported outcomes related to disease activity, and a few are for treatment management. Significant benefits have been seen in trials relating to education, quality of life, quality of care, treatment adherence, and medication management. No studies have reported a negative impact on any of the above. There are mixed results in terms of effects on office visits and follow-up. While studies have shown that digital health can fit into, complement, and improve the standard clinical care of patients with IBD, there is a need for further validation and improvement, from both a clinical and patient perspective. Exploring new research methods, like microrandomized trials, may allow for more implementation of technology and rapid advancement of knowledge. New technologies that can objectively and seamlessly capture remote data, as well as complement the clinical shift from symptom-based to inflammation-based care, will help the clinical and health technology communities to understand the full potential of digital health in the care of IBD and other chronic illnesses.

The fungal microbiota (mycobiota) is an integral part of the complex multikingdom microbial community colonizing the mammalian gastrointestinal tract and has an important role in immune regulation 1 – 6 . Although aberrant changes in the mycobiota have been linked to several diseases, including inflammatory bowel disease 3 – 9 , it is currently unknown whether fungal species captured by deep sequencing represent living organisms and whether specific fungi have functional consequences for disease development in affected individuals. Here we developed a translational platform for the functional analysis of the mycobiome at the fungal-strain- and patient-specific level. Combining high-resolution mycobiota sequencing, fungal culturomics and genomics, a CRISPR–Cas9-based fungal strain editing system, in vitro functional immunoreactivity assays and in vivo models, this platform enables the examination of host–fungal crosstalk in the human gut. We discovered a rich genetic diversity of opportunistic Candida albicans strains that dominate the colonic mucosa of patients with inflammatory bowel disease. Among these human-gut-derived isolates, strains with high immune-cell-damaging capacity (HD strains) reflect the disease features of individual patients with ulcerative colitis and aggravated intestinal inflammation in vivo through IL-1β-dependent mechanisms. Niche-specific inflammatory immunity and interleukin-17A-producing T helper cell (T H 17 cell) antifungal responses by HD strains in the gut were dependent on the C. albicans -secreted peptide toxin candidalysin during the transition from a benign commensal to a pathobiont state. These findings reveal the strain-specific nature of host–fungal interactions in the human gut and highlight new diagnostic and therapeutic targets for diseases of inflammatory origin. Genetically diverse Candida albicans strains in patients with inflammatory bowel disease secrete a toxin and aggravate IL-1β-dependent intestinal inflammation.

Background:Pregnancy outcomes in patients with inflammatory bowel disease with quiescent disease are similar to those in the general population. Data from the Pregnancy Inflammatory bowel disease And Neonatal Outcomes registry have demonstrated the safety of antitumor necrosis factor (TNF) α agents and thiopurines in pregnancy. The objective of this study was to provide information from the Pregnancy Inflammatory bowel disease And Neonatal Outcomes registry on maternal and fetal outcomes in patients exposed to the newer biologics ustekinumab (UST) and vedolizumab (VDZ).Methods:In this multicenter prospective observational study, we included pregnant women with singleton pregnancies and a diagnosis of inflammatory bowel disease. Questionnaires were administered to women at study intake, each subsequent trimester, delivery, and 4, 9, and 12 months after birth. Bivariate analyses were used to determine the independent effects of specific drug classes on outcomes. The exposure cohorts were VDZ, UST, anti-TNF, immunomodulators, and combination with anti-TNF and immunomodulators. All were compared with no exposure and with biologics/immunomodulators.Results:There were 1,669 completed pregnancies with 1,610 live births. The maternal mean age was 32.1 (SD 4.6) years at delivery with 66 VDZ exposed and 47 UST exposed. Women on UST were more likely to have Crohn's disease. There was no increased risk of spontaneous abortion, small for gestational age, low birth weight, neonatal intensive care unit stay, congenital malformations, or intrauterine growth restriction with in utero VDZ or UST exposure. The rate of preterm birth was lower (0.0%) for the UST-exposed cohort when compared with other cohorts including VDZ (13.8%), anti-TNF (8.2%), combination therapy (14.2%), immunomodulators (12.3%), and unexposed (9.7%) (P = 0.03). Rates of serious infections at birth, 4 months, and within the first 12 months of life were comparable among all cohorts. Nonserious infections were lower at 12 months in UST-exposed pregnancies. There was no increased risk signal for placental complications in the VDZ cohort. UST infant concentrations at birth were increased whereas VDZ concentrations were overall decreased compared with maternal serum drug concentration.DISCUSSION:This analysis of UST and VDZ exposure during pregnancy suggests no increase in complications compared with TNF, immunomodulators, and combination TNF/immunomodulators. No signal was found for increased placental events with either therapy. Continuation of UST and VDZ throughout pregnancy is recommended.

Perturbations of the intestinal microbiome, termed dysbiosis, are linked to intestinal inflammation. Isolation of adherent-invasive Escherichia coli (AIEC) from intestines of patients with Crohn's disease (CD), dogs with granulomatous colitis, and mice with acute ileitis suggests these bacteria share pathoadaptive virulence factors that promote inflammation.MethodsTo identify genes associated with AIEC, we sequenced the genomes of phylogenetically diverse AIEC strains isolated from people with CD (4), dogs with granulomatous colitis (2), and mice with ileitis (2) and 1 non-AIEC strain from CD ileum and compared them with 38 genome sequences of E. coli and Shigella. We then determined the prevalence of AIEC-associated genes in 49 E. coli strains from patients with CD and controls and correlated genotype with invasion of intestinal epithelial cells, persistence within macrophages, AIEC pathotype, and growth in standardized conditions.ResultsGenes encoding propanediol utilization (pdu operon) and iron acquisition (yersiniabactin, chu operon) were overrepresented in AIEC relative to nonpathogenic E. coli. PduC (propanediol dehydratase) was enriched in CD-derived AIEC, correlated with increased cellular invasion, and persistence in vitro and was increasingly expressed in fucose-containing media. Growth of AIEC required iron, and the presence of chuA (heme acquisition) correlated with persistence in macrophages. CD-associated AIEC with lpfA154 (long polar fimbriae) demonstrated increased invasion of epithelial cells and translocation across M cells.ConclusionsOur findings provide novel insights into the genetic basis of the AIEC pathotype, supporting the concept that AIEC are equipped to exploit and promote intestinal inflammation and reveal potential targets for intervention against AIEC and inflammation-associated dysbiosis.

INTRODUCTION:Ulcerative colitis (UC) is a chronic condition that may require long-term treatment. We report the final efficacy and safety results of the UNIFI long-term extension study of ustekinumab in patients with UC through 4 years.METHODS:Ustekinumab induction responders who completed 44 weeks of maintenance treatment and agreed to enter the long-term extension continued their subcutaneous maintenance therapy (90 mg ustekinumab every 8 or 12 weeks [q8w or q12w] or placebo). Starting at week 56, randomized patients could receive dose adjustment to 90 mg q8w. Symptoms and adverse events were assessed through the study; endoscopic assessment was conducted at week 200.RESULTS:Of the 348 patients randomized to subcutaneous ustekinumab at maintenance baseline (q8w and q12w combined), 55.2% were in symptomatic remission at week 200. A greater proportion of biologic-naive patients (67.2% [117/174]) were in symptomatic remission than those with a history of biologic failure (41.6% [67/161]). Among patients in symptomatic remission at week 200, 96.4% were corticosteroid-free. Of the 171 patients with endoscopic evaluation at week 200, 81.6% (71/87) in the q12w group and 79.8% (67/84) in the q8w group had endoscopic improvement. From weeks 156 to the final safety visit (up to week 220), no deaths, major adverse cardiovascular events, or tuberculosis occurred in patients receiving ustekinumab. Nasopharyngitis, UC worsening, and upper respiratory tract infections were the most frequently reported adverse events.DISCUSSION:The long-term efficacy of ustekinumab maintenance in patients with UC was confirmed through 4 years. No new safety signals were observed. ClinicalTrials.gov number NCT02407236.

INTRODUCTION:Tofacitinib is a Janus kinase (JAK) inhibitor shown to be effective in several inflammatory conditions, though it has limited efficacy in luminal Crohn’s Disease (CD). Here, we report the case of a woman with refractory CD-associated arthritis that improved markedly on tofacitinib.CASE DESCRIPTION/METHODS:A 38-year-old woman with history of CD and enterocutaneous fistula status post right hemicolectomy presented with severe sacroiliitis and arthritis for 20 years. Her Harvey Bradshaw Index (HBI) was 7, notable for “terrible wellbeing” secondary to arthritis and 2 soft stools daily. Her CD-associated arthritis was refractory to sulfasalazine, mycophenolate mofetil, methotrexate, adalimumab and ustekinumab. Family history was notable for a father with rheumatoid arthritis. Exam demonstrated sacral spine tenderness, bilateral knee effusions, and right ankle effusion. Laboratory work-up was notable for negative HLA-B27, rheumatoid factor and double stranded DNA antibody. MRI lumbosacral spine showed fluid signal in the right sacroiliac joint, concerning for sacroiliitis. Based on her CD and imaging, she met criteria for ankylosing spondylitis. Given her continued joint pain, she was initiated on tofacitinib 10 mg twice daily. Within one month of treatment, the patient noted significant improvement in joint pain and stiffness, with HBI now 2, only notable for two soft stools daily. Five months after initiating tofacitinib, her CD-associated arthritis was still in remission.DISCUSSION:Tofacitinib, an oral JAK inhibitor, has been shown to have efficacy in rheumatoid arthritis, psoriasis, and ulcerative colitis (UC). In UC, tofacitinib improves clinical and endoscopic response and remission. By contrast, tofacitinib has been shown to have limited efficacy in inducing clinical response and remission in CD, although it has been associated with decreased CRP and fecal calprotectin. Yet, there are case reports detailing tofacitinib’s use for extraintestinal manifestations of CD, including pyoderma gangrenosum. Despite its use in other inflammatory arthritides, to our knowledge, this is one of the first case reports characterizing improvement of CD-associated arthritis with tofacitinib. This case demonstrates that tofacitinib can quickly improve CD-associated arthritis refractory to other biologic therapy. Although tofacitinib may have a limited role in luminal treatment of CD, future studies should evaluate its use for extraintestinal manifestations of CD, including CD-associated arthritis.

Short chain fatty acids (SCFA), principally acetate, propionate, and butyrate, are produced by fermentation of dietary fibers by the gut microbiota. SCFA regulate the growth and virulence of enteric pathogens, such as enterohemorrhagic E. coli (EHEC), Klebsiella and Salmonella. We sought to investigate the impact of SCFA on growth and virulence of pathosymbiont E. coli associated with inflammatory bowel disease (IBD) and colorectal cancer (CRC), and their role in regulating host responses to bacterial infection in vitro. We found that under ileal conditions (pH = 7.4; 12 mM total SCFA), SCFA significantly (p < 0.05) potentiate the growth and motility of pathosymbiont E. coli. However, under colonic conditions (pH = 6.5; 65 to 123 mM total SCFA), SCFA significantly (p < 0.05) inhibit growth in a pH dependent fashion (up to 60%), and down-regulate virulence gene expression (e.g., fliC, fimH, htrA, chuA, pks). Functional analysis reveals that colonic SCFA significantly (p < 0.05) inhibit E. coli motility (up to 95%), infectivity (up to 60%), and type 1 fimbria-mediated agglutination (up to 50%). In addition, SCFA significantly (p < 0.05) inhibit the activation of NF-κB, and IL-8 production by epithelial cells. Our findings provide novel insights on the role of the regional chemical microenvironment in regulating the growth and virulence of pathosymbiont E. coli and opportunities for therapeutic intervention.

Abstract Background Infliximab and adalimumab concentrations are associated with important outcomes in inflammatory bowel disease (IBD). Antibodies to infliximab (ATI) and adalimumab (ATA) are associated with reduced drug concentrations and worse outcomes. Because the efficacy of dose escalation to overcome antibodies is unclear, we assessed the impact of this strategy to overcome immunogenicity in IBD. Methods Infliximab and adalimumab dosing, drug, and antibody concentrations were extracted from a database of patients with IBD having specimens collected for therapeutic drug monitoring. The primary outcome compared proportions with either infliximab ≥5 μg/mL or adalimumab ≥7.5 μg/mL and undetectable antibodies between dose-escalated and non-escalated patients. Area under the receiver operating characteristic curve analyses determined antibody concentrations below which dose escalation was associated with the primary outcome. Results The study included 63,176 patients treated with infliximab and 46,429 patients treated with adalimumab. We detected ATI and ATA in 23.6% (n = 14,900) of patients treated with infliximab and 19.6% (n = 9101) of patients treated with adalimumab. In patients with ATI, infliximab dose escalation (n = 453) yielded higher proportions achieving the primary outcome (47.5% vs 30.9%; P < 0.001), greater drug concentration increases (5.9 μg/mL vs 0.2 μg/mL; P < 0.001), and ATI reductions (4.3 U/mL vs 1.9 U/mL; P = 0.002) compared to no escalation (n = 204). An ATI threshold of 8.55 U/mL was associated with achieving the primary outcome with dose escalation (area under the curve = 0.66). For patients with ATI ≤8.55 U/mL (n = 274), higher proportions (59.1% vs 29.6%; P < 0.001) achieved the primary outcome compared with those with ATI >8.55 U/mL (n = 179). No patients treated with adalimumab achieved the primary outcome (0/390), regardless of dose escalation (n = 87). Conclusion Dose escalation increased drug concentrations and eliminated antibodies with infliximab but not adalimumab. Initial ATI ≤8.55 U/mL was associated with increased efficacy of dose escalation using this assay.