Explore the vast range of titles available.

Maintaining a healthy balance of gut bacteria can promote good health. Leonardi et al. show that fungi can also interact with gut immune cells to maintain intestinal well-being. CX3CR1 + mononuclear phagocytes (MNPs) patrol the intestine and promote antifungal immunity. Genetic deletion of CX3CR1 in MNPs caused colitis-like symptoms in mice. CX3CR1 polymorphisms were detected in Crohn's disease patients that were unable to produce antibodies against multiple fungal species. Thus, commensal fungi may be as important as bacteria in maintaining gut health, and antifungal therapy could hold promise for treating intestinal inflammation. Science , this issue p. 232 Phagocytes police the fungal microbiome. Intestinal fungi are an important component of the microbiota, and recent studies have unveiled their potential in modulating host immune homeostasis and inflammatory disease. Nonetheless, the mechanisms governing immunity to gut fungal communities (mycobiota) remain unknown. We identified CX3CR1 + mononuclear phagocytes (MNPs) as being essential for the initiation of innate and adaptive immune responses to intestinal fungi. CX3CR1 + MNPs express antifungal receptors and activate antifungal responses in a Syk-dependent manner. Genetic ablation of CX3CR1 + MNPs in mice led to changes in gut fungal communities and to severe colitis that was rescued by antifungal treatment. In Crohn’s disease patients, a missense mutation in the gene encoding CX3CR1 was identified and found to be associated with impaired antifungal responses. These results unravel a role of CX3CR1 + MNPs in mediating interactions between intestinal mycobiota and host immunity at steady state and during inflammatory disease.

Inflammatory bowel disease (IBD) is associated with risk variants in the human genome and dysbiosis of the gut microbiome, though unifying principles for these findings remain largely undescribed. The human commensal Bacteroides fragilis delivers immunomodulatory molecules to immune cells via secretion of outer membrane vesicles (OMVs). We reveal that OMVs require IBD-associated genes, ATG16L1 and NOD2, to activate a noncanonical autophagy pathway during protection from colitis. ATG16L1-deficient dendritic cells do not induce regulatory T cells (Tregs) to suppress mucosal inflammation. Immune cells from human subjects with a major risk variant in ATG16L1 are defective in Treg responses to OMVs. We propose that polymorphisms in susceptibility genes promote disease through defects in \"sensing\" protective signals from the microbiome, defining a potentially critical gene-environment etiology for IBD.

The intestinal microflora, typically equated with bacteria, influences diseases such as obesity and inflammatory bowel disease. Here, we show that the mammalian gut contains a rich fungal community that interacts with the immune system through the innate immune receptor Dectin-1. Mice lacking Dectin-1 exhibited increased susceptibility to chemically induced colitis, which was the result of altered responses to indigenous fungi. In humans, we identified a polymorphism in the gene for Dectin-1 (CLEC7A) that is strongly linked to a severe form of ulcerative colitis. Together, our findings reveal a eukaryotic fungal community in the gut (the \"mycobiome\") that coexists with bacteria and substantially expands the repertoire of organisms interacting with the intestinal immune system to influence health and disease.

Publicly available ulcerative colitis (UC) gene expression datasets from observational studies and clinical trials include inherently heterogeneous disease characteristics and methodology. We used meta-analysis to identify a robust UC gene signature from inflamed biopsies. Eight gene expression datasets derived from biopsy tissue samples from noninflammatory bowel disease (IBD) controls and areas of active inflammation from patients with UC were publicly available. Expression- and meta-data were downloaded with GEOquery. Differentially expressed genes (DEG) in individual datasets were defined as those with fold change > 1.5 and a Benjamini–Hochberg adjusted P value < .05. Meta-analysis of all DEG used a random effects model. Reactome pathway enrichment analysis was conducted. Meta-analysis identified 946 up- and 543 down-regulated genes in patients with UC compared to non-IBD controls (1.2 and 1.7 times fewer up- and down-regulated genes than the median of the individual datasets). Top-ranked up- and down-regulated DEG were LCN2 and AQP8 . Multiple immune-related pathways (e.g., ‘Chemokine receptors bind chemokine’ and ‘Interleukin-10 signaling’) were significantly up-regulated in UC, while ‘Biological oxidations’ and ‘Fatty acid metabolism’ were downregulated. A web-based data-mining tool with the meta-analysis results was made available ( https://premedibd.com/genes.html ). A UC inflamed biopsy disease gene signature was derived. This signature may be an unbiased reference for comparison and improve the efficiency of UC biomarker studies by increasing confidence for identification of disease-related genes and pathways.

Owing to advances in genomics that enable differentiation of molecular aetiologies, patients with monogenic inflammatory bowel disease (mIBD) potentially have access to genotype-guided precision medicine. In this Expert Recommendation, we review the therapeutic research landscape of mIBD, the reported response to therapies, the medication-related risks and systematic bias in reporting. The mIBD field is characterized by the absence of randomized controlled trials and is dominated by retrospective observational data based on case series and case reports. More than 25 off-label therapeutics (including small-molecule inhibitors and biologics) as well as cellular therapies (including haematopoietic stem cell transplantation and gene therapy) have been reported. Heterogeneous reporting of outcomes impedes the generation of robust therapeutic evidence as the basis for clinical decision making in mIBD. We discuss therapeutic goals in mIBD and recommend standardized reporting (mIBD REPORT (monogenic Inflammatory Bowel Disease Report Extended Phenotype and Outcome of Treatments) standards) to stratify patients according to a genetic diagnosis and phenotype, to assess treatment effects and to record safety signals. Implementation of these pragmatic standards should help clinicians to assess the therapy responses of individual patients in clinical practice and improve comparability between observational retrospective studies and controlled prospective trials, supporting future meta-analysis.In this Expert Recommendation, Uhlig and colleagues review the therapeutic landscape for monogenic inflammatory bowel disease and propose recommendations for standardized reporting of clinical outcomes.

Crohn's disease (CD) patients demonstrate distinct intestinal microbial compositions and metabolic characteristics compared to unaffected controls. However, the impact of inflammation and underlying genetic risk on these microbial profiles and their relationship to disease phenotype are unclear. We used lavage sampling to characterize the colonic mucosal-luminal interface (MLI) microbiome of CD patients in endoscopic remission and unaffected controls relative to obesity, disease genetics, and phenotype. Cecum and sigmoid colon were sampled from 110 non-CD controls undergoing screening colonoscopy who were stratified by body mass index and 88 CD patients in endoscopic remission (396 total samples). CD polygenic risk score (GRS) was calculated using 186 known CD variants. MLI pellets were analyzed by 16S ribosomal RNA gene sequencing, and supernatants by untargeted liquid chromatography-mass spectrometry. CD and obesity were each associated with decreased cecal and sigmoid MLI bacterial diversity and distinct bacterial composition compared to controls, including expansion of Escherichia/Shigella. Cecal and sigmoid dysbiosis indices for CD were significantly greater in obese controls than non-overweight controls. CD, but not obesity, was characterized by altered biogeographic relationship between the sigmoid and cecum. GRS was associated with select taxonomic shifts that overlapped with changes seen in CD compared to controls including Fusobacterium enrichment. Stricturing or penetrating Crohn's disease behavior was characterized by lower MLI bacterial diversity and altered composition, including reduced Faecalibacterium, compared to uncomplicated CD. Taxonomic profiles including reduced Parasutterella were associated with clinical disease progression over a mean follow-up of 3.7 years. Random forest classifiers using MLI bacterial abundances could distinguish disease state (area under the curve (AUC) 0.93), stricturing or penetrating Crohn's disease behavior (AUC 0.82), and future clinical disease progression (AUC 0.74). CD patients showed alterations in the MLI metabolome including increased cholate:deoxycholate ratio compared to controls. Obesity, CD in endoscopic remission, and high CD genetic risk have overlapping colonic mucosal-luminal interface (MLI) microbiome features, suggesting a shared microbiome contribution to CD and obesity which may be influenced by genetic factors. Microbial profiling during endoscopic remission predicted Crohn's disease behavior and progression, supporting that MLI sampling could offer unique insight into CD pathogenesis and provide novel prognostic biomarkers.

Patients with immune-mediated inflammatory diseases such as inflammatory bowel disease (IBD) on immunosuppressive and biologic therapies were largely excluded from severe acute respiratory syndrome coronavirus-2 messenger RNA vaccine trials. We evaluated adverse events (AE) after messenger RNA vaccination in 246 adults with IBD participating in a longitudinal vaccine registry. In general, AE frequency was similar to that reported in the general population. AEs were more common among younger patients and those with previous COVID-19. AEs were less common in individuals receiving advanced therapies with biologics or small-molecule inhibitors. Those with IBD and other immune-mediated inflammatory diseases can be reassured that the AE risk is likely not increased, and may be reduced, while on advanced therapies.

Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes ( n  = 13), direct disruption of transcription-factor binding sites ( n  = 3), and tissue-specific epigenetic marks ( n  = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn’s disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms. Results of fine-mapping 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals and several new fine-mapping methods. Fine-mapping IBD loci Genome-wide association studies for inflammatory bowel disease (IBD) have identified over 200 associated loci but the causal variants at only several of these individual loci have been resolved. Here, Hailiang Hang and colleagues report fine-mapping of 94 of these IBD susceptibility loci using high-density genotyping in 67,852 individuals. They apply several new fine-mapping methods and identify 139 independent associations, 18 of which are resolved to a single causal variant with >95% certainty. This provides an example of how fine-mapping with high-density genotyping in large sample sizes is able to resolve causal variants at GWAS loci, an approach that may be used for other complex traits. To review the detailed fine-mapping results and annotations, a customizable browser is available at http://finemapping.broadinstitute.org .

The recently identified member of the TNF superfamily TL1A (TNFSF15) increases IFN-gamma production by T cells in peripheral and mucosal CCR9+ T cells. TL1A and its receptor DR3 are up-regulated during chronic intestinal inflammation in ulcerative colitis and Crohn's disease (CD). TL1A gene haplotypes increase CD susceptibility in Japanese, European, and US cohorts. Here we report that the presence of TL1A gene haplotype B increases risk in Jewish CD patients with antibody titers for the E. coli outer membrane porin C (OmpC+) (Haplotype B frequency in Jewish CD patients: 24.9% for OmpC negative and 41.9% for OmpC positive patients, respectively, P< or =0.001). CD14+ monocytes isolated from Jewish OmpC+ patients homozygous for TL1A gene haplotype B express higher levels of TL1A in response to FcgammaR stimulation, a known inducing pathway of TL1A, as measured by ELISA. Furthermore, the membrane expression of TL1A is increased on peripheral monocytes from Jewish but not non-Jewish CD patients with the risk haplotype. These findings suggest that TL1A gene variation exacerbates induction of TL1A in response to FcgammaR stimulation in Jewish CD patients and this may lead to chronic intestinal inflammation via overwhelming T cell responses. Thus, TL1A may provide an important target for therapeutic intervention in this subgroup of IBD patients.

Inflammatory bowel disease (IBD) is a group of chronic diseases of the digestive tract that affects millions of people worldwide. Genetic, environmental and microbial factors have been implicated in the onset and exacerbation of IBD. However, the mechanisms associating gut microbial dysbioses and aberrant immune responses remain largely unknown. The integrative Human Microbiome Project seeks to close these gaps by examining the dynamics of microbiome functionality in disease by profiling the gut microbiomes of >100 individuals sampled over a 1-year period. Here, we present the first results based on 78 paired faecal metagenomes and metatranscriptomes, and 222 additional metagenomes from 59 patients with Crohn’s disease, 34 with ulcerative colitis and 24 non-IBD control patients. We demonstrate several cases in which measures of microbial gene expression in the inflamed gut can be informative relative to metagenomic profiles of functional potential. First, although many microbial organisms exhibited concordant DNA and RNA abundances, we also detected species-specific biases in transcriptional activity, revealing predominant transcription of pathways by individual microorganisms per host (for example, by Faecalibacterium prausnitzii ). Thus, a loss of these organisms in disease may have more far-reaching consequences than suggested by their genomic abundances. Furthermore, we identified organisms that were metagenomically abundant but inactive or dormant in the gut with little or no expression (for example, Dialister invisus ). Last, certain disease-specific microbial characteristics were more pronounced or only detectable at the transcript level, such as pathways that were predominantly expressed by different organisms in patients with IBD (for example, Bacteroides vulgatus and Alistipes putredinis ). This provides potential insights into gut microbial pathway transcription that can vary over time, inducing phenotypical changes that are complementary to those linked to metagenomic abundances. The study’s results highlight the strength of analysing both the activity and the presence of gut microorganisms to provide insight into the role of the microbiome in IBD. Analysis of paired metagenomes and metatranscriptomes associated with patients with inflammatory bowel disease (IBD) and non-IBD controls over time provides some insights into microbial community variation and potential pathways influencing IBD symptoms.