Signaling of free fatty acid receptors 2 and 3 differs in colonic mucosa following selective agonism or coagonism by luminal propionate

Tough, Iain R.; Forbes, Sarah; Cox, Helen

doi:10.1111/nmo.13454

Cited by 30 publications

(42 citation statements)

References 50 publications

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“…Indeed, two‐thirds of all patients reported constipation, which was associated with rapid GE2 and slow colon transit. One possible explanation is that rapid GE is associated with exaggerated release of humoral mediators of the ileal brake (ie, GLP‐1, PYY, NPY, leptin, and amylin), which may also delay colonic transit …”

Section: Discussionmentioning

confidence: 99%

“…One possible explanation is that rapid GE is associated with exaggerated release of humoral mediators of the ileal brake (ie, GLP-1, PYY, NPY, leptin, and amylin), which may also delay colonic transit. 21,[36][37][38][39][40] Only 20% of patients with rapid GE had conditions (ie, autonomic neuropathy or POTS, diabetes mellitus, celiac disease) that have been associated with rapid GE. [5][6][7] Among patients with an autonomic neuropathy or POTS, gastric emptying is more likely to be rapid than delayed.…”

Section: (25)mentioning

confidence: 99%

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Clinical features and disturbances of gastrointestinal transit in patients with rapid gastric emptying

Kuwelker

Muthyala

O’Connor

et al. 2020

Neurogastroenterology Motil

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Aims Some patients with upper gastrointestinal symptoms have rapid gastric emptying (GE). We aimed to compare patients with normal and rapid GE and to identify phenotypes among patients with rapid GE. Methods Among 2798 patients who underwent GE scintigraphy, we compared patients with normal and rapid GE and separately, patients with rapid GE at 1 hour (GE1), 2 hours (GE2), or both (GE12). Results In 2798 patients, GE was normal (74%), delayed (18%), or rapid (8%). Among 211 patients with rapid GE, patterns were rapid GE1 (48%), 2 hours (17%), or 1 and 2 hours (35%); 42 (20%) had diseases that explain rapid GE. A combination of upper and lower gastrointestinal symptoms (54%) was more common that isolated upper (17%) or lower (28%) gastrointestinal symptoms (P < .001). Constipation was more prevalent in patients with rapid GE 2 (72%) than rapid GE 1 (47%) or rapid GE12 hours (67%) (P < .05). Among 179 diabetes mellitus (DM) patients, 15% had rapid GE, which was not associated with the DM phenotype. By multivariable analysis, insulin therapy (odds ratio [OR], 0.36; 95% confidence interval [CI], 0.15‐0.88), and weight loss (OR, 0.10; 95% CI, 0.01‐0.78) were associated with a lower risk of rapid than normal GE in DM. Conclusions Eight percent of patients undergoing scintigraphy had rapid GE, which is most frequently associated with upper and lower gastrointestinal symptoms; constipation is common. Insulin therapy and weight loss were associated with a lower risk of rapid than normal GE in DM patients.

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Section: Discussionmentioning

confidence: 99%

Section: (25)mentioning

confidence: 99%

Clinical features and disturbances of gastrointestinal transit in patients with rapid gastric emptying

Kuwelker

Muthyala

O’Connor

et al. 2020

Neurogastroenterology Motil

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“…Previous in vivo studies had indicated that administration of SCFAs into the gut (gavage) accelerated gut transit 32 . However, a more recent ex vivo study on isolated colon showed the opposite, where C3, possibly acting via FFA2, decreased gut transit 33 . We resolved this issue using the hFFA2-DREADD-HA mice.…”

Section: An In Vivo Role For Ffa2 In Glp-1 Release and Gut Transitmentioning

confidence: 92%

Chemogenetics defines receptor-mediated functions of short chain free fatty acids

et al. 2019

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Differentiating actions of Short Chain Fatty Acids (SCFAs) at Free Fatty Acid receptor 2 (FFA2) from other free fatty acid-responsive receptors, and from non-receptor mediated effects, has been challenging. Using a novel chemogenetic and knockin strategy whereby an engineered variant of FFA2 (FFA2-DREADD) that is unresponsive to natural SCFAs but instead is activated by sorbic acid replaced the wild type receptor we determined that activation of FFA2 in differentiated adipocytes and colonic crypt enteroendocrine cells of mouse accounts fully for SCFA-regulated lipolysis and release of the incretin glucagon like peptide-1 (GLP-1) respectively. In vivo studies confirmed the specific role of FFA2 in GLP-1 release and also demonstrated a direct role for FFA2 in accelerating gut transit. Thereby we establish the general principle that such a chemogenetic knockin strategy can successfully define novel GPCR biology and both provide target validation and establish therapeutic potential of a 'hard to target' GPCR.

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“…One of the more uncertain aspects of mechanisms behind local effects of SCFA in the gut following their production has been on gut transit time. For example, both (31) and (32) observed SCFAs to reduce gut transit. By contrast Bolognini et al, (19) showed that in wild type C57BL/6 mice provision of C3 in the drinking water resulted in enhanced gut transit.…”

Section: Ffa2 But Not Ffa3 Activation Promotes Gut Transit Timementioning

confidence: 99%

Chemogenetic analysis of how receptors for short chain fatty acids regulate the gut-brain axis

Tobin

Barki

Bolognini

et al. 2020

Preprint

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The gut-brain axis allows bi-directional communication between the enteric and central nervous systems. Short chain fatty acids (SCFAs) generated by the gut microbiota are important regulators of this interface. However, defining mechanisms by which SCFAs do so has been challenging because, amongst various roles, they co-activate both of a pair of closely related and poorly characterized G protein-coupled receptors, FFA2 and FFA3.Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) can provide an important approach in defining receptor-specific functions. By screening a library of carboxylate-containing small molecules we identified 4-methoxy-3-methyl-benzoic acid (MOMBA) as a specific agonist of a DREADD variant of FFA2 which is not activated by SCFAs. Using mice engineered to replace FFA2 with this FFA2-DREADD, whilst retaining FFA3 expression, combinations of MOMBA and the now FFA3 receptor selective SCFAs defined key, but distinct, roles of FFA2 and FFA3 in each of gut transit time, secretion of entero-endocrine hormones, and communication from the gut to each of autonomic and somatic sensory ganglion cells and the spinal cord. These studies map mechanisms and signalling pathways by which each of FFA2 and FFA3 act to link the gut and the brain and provide both animal models and novel tool compounds to further explore this interface. IntroductionThe gut-brain axis allows bi-directional communication between the enteric and central nervous systems. Growing evidence highlights the role that the intestinal microbiota may play in such interactions (1) and in the development of disease (2). The microbiota generates a wide array of metabolites that can modulate host cells and their functions (3-4).Among these short chain fatty acids (SCFAs), particularly acetate (C2) and propionate (C3), are generated in prodigious amounts by fermentation of fibre and other non-digestible 3 carbohydrates in the lower gut. The SCFAs play central roles in homeostasis at the interface between metabolism and immunity (5-6) and also within the gut-brain axis (7)(8). Although a range of their key effects are believed to be produced by activation of G protein-coupled receptors (GPCRs), both locally in the lower gut and following uptake into the systemic circulation, which of these roles are generated directly by individual receptors and via which signalling pathways remains uncertain.Over the course of evolution genes encoding many ancestral forms of GPCRs have multiplied and diversified to provide enhanced flexibility of signalling and integration of responses to either the same or closely related ligands. An example of this is within the family of receptors that are activated by the binding of free fatty acids. In human, genes encoding the FFA1, FFA2 and FFA3 receptors cluster at chromosomal location 19q13.1 and in mouse, in a similar manner, at chromosomal location 7 A3 (9). Each receptor is closely related and whilst FFA1 is activated by saturated and unsaturated fatty acids of chain length C10 and above, both FFA2 and ...

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Signaling of free fatty acid receptors 2 and 3 differs in colonic mucosa following selective agonism or coagonism by luminal propionate

Cited by 30 publications

References 50 publications

Clinical features and disturbances of gastrointestinal transit in patients with rapid gastric emptying

Clinical features and disturbances of gastrointestinal transit in patients with rapid gastric emptying

Chemogenetics defines receptor-mediated functions of short chain free fatty acids

Chemogenetic analysis of how receptors for short chain fatty acids regulate the gut-brain axis

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