Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, has multifactorial aetiology with complex interactions between genetic and environmental factors. Over 150 genetic loci are associated with IBD. The genetic contribution of the majority of those loci towards explained heritability is low. Recent studies have reported an increasing spectrum of human monogenic diseases that can present with IBD-like intestinal inflammation. A substantial proportion of patients with those genetic defects present with very early onset of intestinal inflammation. The 40 monogenic defects with IBD-like pathology selected in this review can be grouped into defects in intestinal epithelial barrier and stress response, immunodeficiencies affecting granulocyte and phagocyte activity, hyper- and autoinflammatory disorders as well as defects with disturbed T and B lymphocyte selection and activation. In addition, there are defects in immune regulation affecting regulatory T cell activity and interleukin (IL)-10 signalling. Related to the variable penetrance of the IBD-like phenotype, there is a likely role for modifier genes and gene-environment interactions. Treatment options in this heterogeneous group of disorders range from anti-inflammatory and immunosuppressive therapy to blockade of tumour necrosis factor α and IL-1β, surgery, haematopoietic stem cell transplantation or gene therapy. Understanding of prototypic monogenic 'orphan' diseases cannot only provide treatment options for the affected patients but also inform on immunological mechanisms and complement the functional understanding of the pathogenesis of IBD.

The microbiota in inflammatory bowel disease

“…The increasing prevalence of IBD worldwide also supports the primacy of environmental risk factors [7,8] in the development of IBD, except in rare cases of monogenic disease [9]. The most consistent epidemiological feature of both UC and CD is the increase in incidence and prevalence when a society transitions from developing to developed [10].…”

Exploring the microbiome in health and disease

“…164,199 IBD and the microbiome IBD is a group of disorders characterized by chronic inflammation of the gastrointestinal tract, of which the two main disease manifestations, ulcerative colitis (UC) and Crohn's disease (CD), each have distinctive clinical and pathological features. [200][201][202][203] Both CD and UC result from a complex interplay among environmental factors, genetics, and intestinal microbiota composition. 204,205 The important role of the microbiome in IBD pathogenesis has been elucidated by a study where germ-free animals showed less inflammation than controls in response to dextran sulfate sodium (DSS)-induced colitis.…”

Repurposing Miltefosine for the Treatment of Immune-Mediated Disease?

“…These findings may make miltefosine an attractive candidate for the treatment of IBD. Although the cause of IBD remains unclear, there are many indications that suggest that a reduced function of the innate immune system predisposes to an excessive response of the adaptive immune response to intestinal microbiota (Marks et al, 2006;Hayee et al, 2010;Uhlig, 2013). Given the results discussed above, miltefosine may have a dual therapeutic effect in IBD by both stimulating macrophagemediated innate immunity and reducing excessive activation of T cell-mediated adaptive immunity.…”