APC: antigen-presenting cell
5-ASA: 5-aminosalicylic acid, mesalamine
CNS: central nervous system
FDA: Food and Drug Administration
GPCR: G protein-coupled receptor
HGPRT: hypoxanthine-guanine phosphoribosyl transferase
HPA: hypothalamic-pituitary-adrenal (axis)
5HT: 5-hydroxytryptamine (serotonin)
IBD: inflammatory bowel disease
JAK: Janus kinase
MAO: monoamine oxidase
NF-κB: nuclear factor-κB
NSAID: nonsteroidal anti-inflammatory drug
PPAR-γ: peroxisome proliferator-activated receptor gamma
STAT: signal transducer and activator of transcription
TGF: transforming growth factor
TH: T helper (lymphocyte)
TNF: tumor necrosis factor
TPMT: thiopurine methyltransferase
TYK2: tyrosine kinase 2
XO: xanthine oxidase
INFLAMMATORY BOWEL DISEASE
Inflammatory bowel disease is a spectrum of remitting and relapsing, chronic, inflammatory intestinal conditions. IBD causes significant GI symptoms that include diarrhea, abdominal pain, bleeding, anemia, and weight loss. IBD conventionally is divided into two major subtypes: ulcerative colitis and Crohn’s disease.
Ulcerative colitis is characterized by confluent mucosal inflammation of the colon starting at the anal verge and extending proximally for a variable extent (e.g., proctitis, left-sided colitis, or pancolitis). Crohn’s disease, by contrast, is characterized by transmural inflammation of any part of the GI tract but most commonly the area adjacent to the ileocecal valve. The inflammation in Crohn’s disease is not necessarily confluent, frequently leaving “skip areas” of relatively normal mucosa. The transmural nature of the inflammation may lead to fibrosis and strictures or fistula formation. IBD is often associated with extraintestinal manifestations involving the joints, skin, or eyes (Ott and Scholmerich, 2013). IBD is also increasingly recognized to have comorbid psychological manifestations, notably anxiety and depression (Graff et al., 2009; Taft et al., 2017). Primary sclerosing cholangitis is a serious but infrequent extraintestinal manifestation of IBD, usually ulcerative colitis, in which inflammation and fibrostenosis occur in the intra- and extrahepatic biliary tree (Williamson and Chapman, 2014). Chronic, severe IBD is associated with an increased risk for the development of colorectal cancer (Beaugerie and Itzkowitz, 2015).
A summary of proposed pathogenic events and potential sites of therapeutic intervention is shown in Figure 55–1. Both diseases are associated with an aberrant immune response to the commensal microbiota of the gut in genetically susceptible individuals. Evidence of dysbiosis of the microbiome in IBD supports this theory (Lee and Chang, 2020). Nevertheless, Crohn’s disease and ulcerative colitis result from distinct pathogenic mechanisms at the level of mucosal immune activation (Xavier and Podolsky, 2007). Histologically, the transmural lesions in Crohn’s disease exhibit marked infiltration of lymphocytes and macrophages, granuloma formation, and submucosal fibrosis, whereas the superficial lesions in ulcerative colitis have lymphocytic and neutrophilic infiltrates.
Proposed pathogenesis of IBD and target sites for pharmacological intervention. Shown are the interactions among bacterial antigens in the intestinal lumen and immune ...