Table 2.
Clinical and rodent studies assessing the role of gut-derived metabolites commonly involved in the pathogenesis of inflammatory bowel disease and co-morbid metabolic defects.
| Metabolites | Clinical Importance | Roles in IBD | Roles in Metabolic Disorders | ||
|---|---|---|---|---|---|
| Human | Rodent | Human | Rodent | ||
| BCAA (Leucine, Isoleucine, and Valine) |
Maintain the protein synthesis and muscle growth [110].Ensure the intestinal integrity and immune response [111]. | Increase the development and severity of pre-existing colitis [112]. Increase (high dose, >2.57%) intestinal immune response [112,113] by activating mTOR and NF-kB [114]. |
Worsen DSS-induced colitis following the diet containing animal-based protein [115]. May increase the severity of chemical-induced colitis through excessive activated colonic macrophages [116]. Promote systemic oxidative stress and the activation of inflammasome, leading to extensive intestinal inflammation [117]. |
Remodel lipid metabolism (increase LDL-C and triglycerides). Increase the risk and development of CVD [118,119], obesity [120,121,122], insulin resistance [122,123] and hepatic diseases [121,124]. |
Induce body weight gain, hyperglycemia, insulin resistance and accumulation of hepatic lipid droplets [125]. Impair insulin sensitivity, cardiac function (EF%) in mice received transverse aortic constriction [126]. |
| Tryptophan metabolites | Provide indirect assistance on maintaining intestinal permeability and epithelial integrity [127]. | Decrease in serum of patients with UC [128,129] and CD [128,130]. Stronger potential of tryptophan degradation in active IBD cases [128]. |
Attenuate severity of DSS-induced colitis by limiting the secretion of inflammatory markers [131,132]. Serve as a treatment (IPA) of active IBD remission in mice by enhancing anti-inflammatory responses [133]. Provide intestinal antifungal resistance by producing IL-22 [134]. |
Negatively correlates to insulin deficiency and glucose imbalance in diabetes patients [135]. Reduce serum tryptophan [136] and IPA [137] in patients with obesity and T2D.Improve overweight correlated inflammatory response [134]. |
Reduced body weight gain (IPA), improved glucose metabolism and insulin resistance in obese mice [138,139]. Ameliorate active colitis cases by enhancing T-cell dependent immunity and upregulating AhR [140]. Improve insulin sensitivity, glucose homeostasis and energy regulatory hormones (e.g.,: leptin and GLP-1) [141]. Protect against intestinal permeability and systemic immunity [142]. |
| SCFA | Control systemic energy metabolism and regulate intestinal immune response [143]. | Prevent incidence and development of IBD (butyrate and propionate) [144,145]. Increase risk of IBD (acetate and pyruvic) [146]. Enhance anti-inflammatory potential (butyrate), therefore improving the pre-existing IBD [147]. |
Improve IBD by suppressing T-cell mediated inflammatory responses (butyrate) [148]. Protect against colitis susceptibility and improve intestinal permeability in DSS-induced colitis model [149]. |
Provide protection on developing insulin resistance, obesity and diabetes (butyrate and propionate) [150]. Improve severity of obese, insulin resistance, diabetes and glucose homeostasis (propionate) [151,152]. Negatively correlates with hypercholesterolemia (butyrate) [153]. |
Protect against high fat-feeding induced liver steatosis and insulin resistance in mice and rats [154,155,156,157,158,159]. |
| Bile acid | Maintain enterohepatic circulation, systemic energy homeostasis and the balance of gut bacterial community [160]. | Decreased bile-acid transforming bacteria in IBD patients [161,162]. Negatively correlate with CD (SBA and conjugated bile acids), but not UC [1,4,5,163]. SBA and conjugated bile acids can be restored by applying anti-TNF-α treatment [164]. |
Protect against epithelial permeability and goblet cell loss by activating FXR-α [165,166]. Improve anti-inflammatory response by maintaining RORγ+ regulatory T cells in IBD mice [167]. |
Accumulate in patients (mostly primary bile acid) with liver dysfunction (hepatic steatosis, lobular and portal inflammation) [168] obesity [169] and diabetes [170], with interrupted bile acid negative feedback loops via FXR-α [143,160]. | Improve hepatic glucose metabolism and insulin resistance by upregulating FXR-α [164]. Improve insulin resistance [171] and lipid metabolism [172] via anti-obesity receptor in mice model with metabolic stress. |
| TMA/TMAO | Classic risk factor on inducing chronic diseases [173]. | Positively correlates with active UC and CD cases [174]. | Indicate disrupted gut bacterial ecology by overexpressing choline associated catabolic enzymes [175]. Accelerate the progression of IBD in colitis mice models [175,176]. |
Indicate the risk, incidence [177,178,179] and mortality rate [180] of cardiovascular diseases Increase platelet responsiveness [174].Increase the incidence of insulin resistance [181] and T2D [178]. |
Increase aortic lesion, platelets responsiveness [165,167], and microbiota dependent atherosclerosis [176] in mice supplemented with TMAO. Increase inflammatory biomarkers (e.g., NF-kB) [59], hyperglycemia [182].Induce the formation of ox-LDL [165] and NAFLD through disrupted choline metabolism [183]. |