Page 159 - Human Bile Acid Metabolism: a Postprandial Perspective

TGR5-mediated itch is present in human beings as well as mice, which seems likely given the overlap between human and rodent tissue distribution of the receptor, it could prove a major barrier in implementing TGR5-targeted therapy.
Some reports have shown increased cell proliferation in response to TGR5 activation. In in-vitro models of gastric98 and endometrial cancer,99 stimulation with high doses of TGR5 agonists promoted cell proliferation. Increased TGR5 expression on tumour cells has also been correlated with worsening clinical prognosis in patients with oesophageal and gastric adenocarcinoma.100,101 Adverse effects have mainly been reported in cell cultures or animal models under extreme conditions and await further investigation. Regardless, these side-effects raise concern that systemic TGR5 agonists will not be tolerated therapeutically.
Conclusion
Since the discovery of bile acid-mediated activation of TGR5, many preclinical studies have been done to elucidate the physiology of this receptor and its potential as a therapeutic target in type 2 diabetes, obesity, and non-alcoholic steatohepatitis. However, profound interspecies differences in the biology of bile acids and their receptors in different cells and tissues exist, which hampers the translation of preclinical findings to human pathophysiology.
Studies in rodents point to an important role for TGR5 in GLP-1 secretion,
insulin sensitivity, and energy expenditure. Targeting the immune system 8 through TGR5 could also prove beneficial in inflammatory conditions. Studies
of administration of natural bile acids and bile acid-sequestering agents, and
models of bariatric surgery provide only limited mechanistic clues, as a result
of the complex dynamics of the multi-compartmental enterohepatic circulation.
Although we acknowledge that molecular mechanisms in human beings are
harder to understand than those in rodents, future studies should aim to study
the equivalent processes in human beings.
Studies in human beings should focus on TGR5 activation within the enterohepatic cycle and its potential role in GLP-1 secretion and modulation of inflammation. TGR5-mediated increases in energy expenditure via BAT and white adipose tissue browning would require systemic administration, which is unlikely to be achievable in human beings because no safe systemic TGR5 agonists exist. Non-absorbable
Review: clinical relevance of TGR5
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