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Microbial genes and pathways in inflammatory bowel disease

Abstract

Perturbations in the intestinal microbiome are implicated in inflammatory bowel disease (IBD). Studies of treatment-naive patients have identified microbial taxa associated with disease course and treatment efficacy. To gain a mechanistic understanding of how the microbiome affects gastrointestinal health, we need to move from census to function. Bacteria, including those that adhere to epithelial cells as well as several Clostridium species, can alter differentiation of T helper 17 cells and regulatory T cells. Similarly, microbial products such as short-chain fatty acids and sphingolipids also influence immune responses. Metagenomics and culturomics have identified strains of Ruminococcus gnavus and adherent invasive Escherichia coli that are linked to IBD and gut inflammation. Integrated analysis of multiomics data, including metagenomics, metatranscriptomics and metabolomics, with measurements of host response and culturomics, have great potential in understanding the role of the microbiome in IBD. In this Review, we highlight current knowledge of gut microbial factors linked to IBD pathogenesis and discuss how multiomics data from large-scale population studies in health and disease have been used to identify specific microbial strains, transcriptional changes and metabolic alterations associated with IBD.

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Fig. 1: Inflammatory bowel disease and the microbiota.
Fig. 2: Phylogenetic tree of bacterial species associated with inflammatory bowel disease.
Fig. 3: Microbiome-based therapies for inflammatory bowel disease.

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Acknowledgements

The authors thank T. Reimels for editorial assistance and for help with figure design. R.J.X. received funding from the US National Institutes of Health (P30 DK043351 and R01 AT009708), the Crohn’s and Colitis Foundation of America, and the Center for Microbiome Informatics and Therapeutics at MIT.

Reviewer information

Nature Reviews Microbiology thanks J. Faith, C. Manichanh, and other anonymous reviewer(s), for their contribution to the peer review of this work.

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M.S., A.G., H.V., and R.J.X. conceived and wrote the article. All authors substantially contributed to discussion of content and reviewed/edited the manuscript before submission. M.S. generated Fig. 2.

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Correspondence to Melanie Schirmer or Hera Vlamakis or Ramnik J. Xavier.

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R.J.X. is a consultant to Nestle and Novartis. All other authors declare no competing interests.

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Inflammatory Bowel Disease Multi’omics Database. https://ibdmdb.org/

Supplementary information

Glossary

Microbiota

The collection of microorganisms in a particular environment.

Microbiome

The genes, genomes and products of the microbiota.

Barrier function

Epithelial cell–cell junctions plus the mucosal layer that permit nutrients and prevent luminal contents from accessing the rest of the body.

Glycaemic response

The glycaemic response to food describes its effect on blood glucose levels after consumption.

Non-caseating granulomas

Granulomas are clusters of immune cells that form during infection, inflammation or in the presence of a foreign substance to prevent a systemic spread. The absence of necrosis is a defining feature of non-caseating granulomas. In Crohn’s disease, non-caseating granulomas are formed during inflammation without an obvious infectious trigger.

Hygiene hypothesis

According to the hygiene hypothesis, a lack of early childhood microbial exposure affects the development of the immune system. This has been ascribed to the increase of allergic and autoimmune diseases in Western countries.

Mannan

A mannose polymer and component of fungal and plant cell walls.

Atypical perinuclear anti-neutrophil cytoplasmic antibody

Anti-neutrophil cytoplasmic antibodies are classified based on staining patterns. Cytoplasmic anti-neutrophil cytoplasmic antibody (ANCA) refers to staining of the entire cytoplasm, and perinuclear ANCA refers to staining of the area around the nucleus. Perinuclear ANCAs have been implicated in inflammatory bowel disease; however, their target antigens are unknown and they are therefore described as atypical perinuclear ANCA.

Laminaribioside

A glucose disaccharide building block of laminarin and a component of the cell walls of fungi and algae.

Chitobioside

A building block of the N-acetylglucosamine-based glycan chitin and a component of the cell walls of microorganisms.

Mannobioside

A disaccharide of mannose.

Colectomy

A surgical procedure removing all or part of the colon.

Strains

The classical microbiological definition of strain is a single bacterial isolate. In the context of metagenomic data, it refers to a combination of single-nucleotide polymorphisms that are computationally predicted to be linked and originating from an individual strain genome.

Metatranscriptome

All of the RNA in an environment.

Culturomics

The process of using classical microbiological techniques to culture and identify unknown bacteria that inhabit a given environment.

Indole metabolites

Indole metabolites derive from microbial metabolism of tryptophan and can be recognized by several host receptors that regulate host–microbial homeostasis.

Metagenomes

All the genetic material present in an environment, consisting of the genomes of numerous organisms.

RORγt+ Treg cells

Regulatory T cells that express the transcription factor RORγt, a nuclear hormone receptor and critical regulator of antimicrobial immunity.

Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy

An autoimmune disease characterized by destruction of endocrine tissues, chronic mucocutaneous candidiasis and ectodermal disorders.

16S ribosomal RNA (rRNA) gene

A gene conserved among bacteria often used for taxonomic classification.

Keystone taxa

Species with high connectivity in microbial networks (built based on statistical associations), suggesting that they are a key component of the ecosystem and their removal would result in drastic changes to the microbial ecosystem.

Anti-tumour necrosis factor therapy

Drugs that target tumour necrosis factor to decrease inflammation are often used to treat autoimmune diseases and inflammatory bowel disease.

Irritable bowel syndrome

A chronic condition, which affects the large intestine and causes abdominal pain, cramping and shifts in bowel movement patterns. In contrast to inflammatory bowel disease, irritable bowel syndrome is not associated with mucosal inflammation, ulcers or other damage to the bowel.

Chromogranins and secretogranins

A family of water-soluble acidic glycoproteins that are mainly produced by endocrine cells, such as the enteroendocrine cells of the gut. Also known as granins, they are precursors of biologically active peptides involved in inflammation.

Metabolome

All of the metabolites in an environment.

Probiotic

An organism or multiple organisms that confer beneficial effects to the host.

Postbiotic

A bacterial metabolic product that mediates benefits to the host.

Prebiotic

A certain food or food component that confers a beneficial effect by providing a competitive advantage to beneficial commensal bacteria capable of metabolizing these substrates or by augmenting the production of metabolic products that result from their fermentation.

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Schirmer, M., Garner, A., Vlamakis, H. et al. Microbial genes and pathways in inflammatory bowel disease. Nat Rev Microbiol 17, 497–511 (2019). https://doi.org/10.1038/s41579-019-0213-6

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