Page 157 - Human Bile Acid Metabolism: a Postprandial Perspective

also on T lymphocytes (figures 2, 3).7,75 Initially, exposure of macrophages to bile acids was thought to dampen the proinflammatory cytokine response, but TGR5 also modulates inflammatory signals in other ways.7,75−77 Controlling postprandial inflammatory responses in the intestine and liver might be required for a normal physiological response to food intake.
Preclinical data
In vitro, TGR5 activation in Kupffer cells decreases expression of interleukins
and TNFα after stimulation with lipopolysaccharide.9 This effect was mediated
by inhibition of the NfκB pathway.78 Additionally, TGR5 stimulation reduces lipopolysaccharide-induced liver inflammation in mice.79 Without the presence
of an inflammatory stimulus, TGR5 might actually increase the expression of
interleukin 1β and TNFα.80 This theory is disputed by most other studies, which
have found an anti-inflammatory effect.13 Treatment with the cholic acid derivative
INT777 led to increased NfκB-mediated cytokine release in primary cultures of
macrophages isolated from wild-type and Tgr5–/– mice, but not in those from Tgr5-overexpressing mice.13 TGR5 activation also showed antiatherogenic effects
in a mouse model of atherogenesis.13 Similarly, TGR5 activation increased the ratio
between the anti-inflammatory interleukin 10 and proinflammatory interleukin 12
in human macrophages,81,82 and monocyte-derived dendritic cells produced less
interleukin 12 and TNFα after contact with bacterial pathogens when cultured
with a TGR5 agonist.83 By contrast, one report showed increased bile acid-induced inflammatory responses in a human monocyte line that could have been species- 8 dependent.84 Finally, TGR5 activates the Akt-mTOR signalling pathway, which
attenuates the inflammatory chemokine response of macrophages.85
Clinical data
Cipriani and colleagues86 and Yoneno and colleagues87 showed increased Tgr5 expression in lamina propria mononuclear cells in ex-vivo colonic samples from patients with Crohn’s disease with colonic inflammation. Here, Tgr5 expression might be upregulated in response to inflammatory cells or luminal antigens. Polymorphisms in the Tgr5 gene are associated with primary sclerosing cholangitis, further suggesting a link with inflammatory conditions.88
Food intake has been shown to evoke a postprandial inflammatory response;89–91 this response depends on the fat content of the meal and is characterised by increased
Review: clinical relevance of TGR5
155