Literature overview nutritional components and their effect on the immune system via G-protein–coupled receptors
| Receptor | Nutritional Activator | Concentration and Mode of Administration | Type of Study | Model | Stimulant/Disease Model | Effect | Reference |
|---|---|---|---|---|---|---|---|
| GPR41 | High-fiber diet or low-fiber diet supplemented with acetylated, propionylated, or butyrylated high-amylose maize starch | Ad libitum | In vivo | WT, GPR109A−/− and Igα−/− C57BL6/J mice | DSS-induced colitis | Butyrate improved gut barrier function and increased colonic IgA. Upregulation of Aldh1a2 in BMDC and integrin αvβ8 in BMDC and DCs induced by butyrate mediated via GPR41 and GPR109A | (Isobe et al., 2020) |
| Acetate and propionate | 200 mM acetate in drinking water or 10 nM acetate or 1 mM propionate (cell culture) | In vivo/in vitro | WT, GPR41−/−, and GPR43−/− C57BL/6 mice and murine intestinal cells | Induction of intestinal inflammation with ethanol and TNBS or infection with C. rodentium (mice). LPS or commensal bacterial extract and pertussis toxin, a GPR, such as GPR41 and GPR43, activation blocker (cells) | GPR41−/− and GPR43−/− mice exhibited reduced inflammatory responses/slower immune response against infection. Increased expression of IL-6, CXCL-1, and CXCL-10 | (Kim et al., 2013) | |
| High-fiber diet | Not specified | In vivo | WT and GPR41−/− C57BL/6J mice | High-fiber diet during pregnancy and lactation | Increased number of Treg cells in the thymus of offspring via enhancement of Aire expression | (Nakajima et al., 2017a) | |
| Propionate or acetate. Low-fiber diet or high-fiber diet | 1 g/kg i.p. propionate or 200 mM acetate or propionate in drinking water. High-fiber diet containing 30% cellulose or 30% pectin | In vivo | WT, GPR41−/−, and GPR43−/− C57BL/6 mice | HDM-induced allergic airway inflammation | Reduction of airway inflammation in a GPR41-dependent manner (propionate) | (Trompette et al., 2014) | |
| GPR43 | Acetate, butyrate, and propionate | 10 nM acetate or propionate, 5 nM butyrate | In vitro | Mouse glomerular mesangial cells and VERSUS-40 MES 13 | GPR43 overexpression and siRNA-GPR43 | Inhibition of phosphorylated NF-κB and MCP-1 expression via GPR43–β-arrestin-2 pathway | (Huang et al., 2020) |
| Acetate and propionate | 200 mM acetate in drinking water or 10 nM acetate or 1 mM propionate (cell culture) | In vivo/in vitro | WT, GPR41−/− and GPR43−/− C57BL/6 mice and murine intestinal cells | Induction of intestinal inflammation with ethanol and TNBS or infection with C. rodentium (mice). LPS or commensal bacterial extract and pertussis toxin, a GPR, such as GPR41 and GPR43, activation blocker (cells) | GPR41−/− and GPR43−/− mice exhibited reduced inflammatory responses/slower immune response against infection. Increased expression of IL-6, CXCL-1, and CXCL-10 | (Kim et al., 2013) | |
| Acetate | 100, 200, or 300 mM in drinking water | In vivo | WT, GPR43−/− and GPR109A−/− C57BL/6 mice | DSS-induced colitis | Improvement of clinical scores, histologic scores, and colon length via activation of NLPR3 inflammasome dependent on GPR109A and GPR43 signaling | (Macia et al., 2015) | |
| Acetate | 150 mM in drinking water | In vivo/ex vivo | WT, GPR43−/− C57BL/6 mice and germ-free mice, murine bone-marrow neutrophils ex vivo | Inflammatory arthritis and OVA-induced acute allergic airway inflammation, DSS-induced colitis | Exacerbated colitis in germ-free mice is ameliorated by acetate. GPR43−/− showed more severe inflammation, whereas acetate reduced the inflammation (inflammatory arthritis). GPR43-dependent effects of acetate on neutrophil function | (Maslowski et al., 2009) | |
| Acetate | 10 mM | Ex vivo | Macrophages from WT, GPR43−/− and aP2-Gpr43TG C57BL/6 mice | — | No changes in M1/M2 polarization but higher TNF-α expression dependent on MAPK signaling in M2 phenotype | (Nakajima et al., 2017b) | |
| Butyrate and propionate | 10 nM | In vivo/ex vivo | Neutrophilic granulocytes (polymorphonuclear leukocytes) from WT and GPR43−/− C57BL/6 mice | DSS-induced colitis | GPR43−/− mice showed diminished intestinal migration of polymorphonuclear leukocytes but protection against inflammatory tissue destruction. GPR43 deficiency caused inhibited SCFA-induced chemotactic activity (p38 MAPK-dependent) and influenced l-selectin shedding | (Sina et al., 2009) | |
| SCFAs or propionate | 150 mM SCFAs or propionate in drinking water | In vivo | WT, GPR43−/− C57BL/6 and germ-free mice | — | SCFAs restored Treg population in colon in germ-free mice and GPR43 mediated SCFA-induced effects on Treg cells, which is probably through HDAC inhibition | (Smith et al., 2013) | |
| SCFAs | 0.1–100 mM | Ex vivo | Bone marrow–derived neutrophils from WT and GPR43−/− C57BL/6 × 129 mice | — | Induction of neutrophil chemotaxis via PI3Kγ, Rac2, and MAPKs | (Vinolo et al., 2011) | |
| Acetate | 300 mM in drinking water | In vivo | WT and GPR43−/− C57BL/6 mice | — | Promotion of intestinal IgA via induction of Aldh1a1 in splenic dendritic cells | (Wu et al., 2017) | |
| Butyrate | 100 mM in drinking water | In vivo and ex vivo | WT and GPR43−/− C57BL/6 mice, and ex vivo intestinal epithelial cells | Antibiotic treatment to eliminate gut microbiota | Promotion of antimicrobial peptide expression (RegIIIγ and β-defensins 1, 3, and 4) in intestinal epithelial cells via activation of mTOR and STAT3 | (Zhao et al., 2018) | |
| GPR109A | Niacin | 0.1 mM | In vitro | Human monocytes and TCP-1 | LPS or Lysteria monocytogenes and siRNA-GPR109A | Reduction of TNF-α, IL-6, and MCP-1 via NF-κB inhibition | (Digby et al., 2012) |
| High-fiber diet or low-fiber diet supplemented with acetylated, propionylated, or butyrylated high-amylose maize starch | Ad libitum | In vivo | WT, GPR109A−/− and Igα−/− C57BL6/J mice | DSS-induced colitis | Butyrate improved gut barrier function and increased colonic IgA. Upregulation of Aldh1a2 in BMDC and integrin αvβ8 in BMDC and DCs induced by butyrate mediated via GPR41 and GPR109A | (Isobe et al., 2020) | |
| Niacin | 100 µM | In vitro | Human mature blood neutrophils | Pertussis toxin, a GPR activation blocker | Acceleration of apoptosis in mature neutrophils due to less decreased cAMP leading to reduced Bad phosphorylation | (Kostylina et al., 2008) | |
| Acetate | 100, 200, or 300 mM in drinking water | In vivo | WT, GPR43−/− and GPR109A−/− C57BL/6 mice | DSS-induced colitis | Improvement of clinical scores, histologic scores, and colon length via activation of NLPR3 inflammasome dependent on GPR109A and GPR43 signaling | (Macia et al., 2015) | |
| β-Hydroxybutyrate | 100 mg/kg (administration route unknown) ketogenic diet | In vivo | WT and GPR109A−/− C57BL/6 mice | Left middle cerebral artery occlusion | Reduction of consequences of ischemic stroke due to activation of anti-inflammatory microglia cells | (Rahman et al., 2014) | |
| Butyrate and niacin | 25 mM in drinking water | In vivo/ex vivo | WT, IL18−/−, Apc-/+ and GPR109A+/− Apc−/− C57BL/6 mice, murine macrophages, and DCs | DSS-induced colitis and azoxymethane-induced colon cancer | GPR109A+/− mice showed enhanced risk for colon cancer and colitis. Induction of IL-10 and Aldh1a1, reduction of IL-17 in murine macrophages and DCs leading to an increase in Treg cells (by butyrate and niacin), GPR109A-dependent | (Singh et al., 2014) | |
| Acetate, propionate, and butyrate | 200 mM acetate, 100 mM propionate, or 100 mM butyrate in drinking water | In vivo | WT and GPR109A−/− C57BL/6 mice | Intragastric administration of peanut extract | Enhancement of CD103+ DCs with increased expression of Aldh1a2 and increase in Treg populations | (Tan et al., 2016) | |
| GPR120 | DHA | 30 mg/kg i.p. for in vivo and 10 µM ex vivo | In vivo and ex vivo | WT and GPR120 KO Balb/c mice | Naphthalene-induced airway injury | Accelerated resolving of airway injury by proliferation and migration of club cells | (Lee et al., 2017) |
| DHA | 100 µM | In vitro | RAW-264.7 cells | LPS and siRNA-GPR120 | Suppression of NF-κB resulting in an anti-inflammatory response | (Liu et al., 2014) | |
| EPA | 10, 20, or 30 mg/kg oral 20 µM (in vitro) | In vivo/in vitro | Nlpr3−/− and double-KO Gpr40−/− Gpr120−/− C57BL/6 mice BV2 microglia cells | Right middle cerebral artery occlusion (in vivo). Oxygen-glucose deprivation, shRNA-GPR120, and shRNA-GPR40 (in vitro) | Reduction of ischemic brain injury by upregulation of IL-1β and suppression of inflammasome NLRP3 (in vivo) Blocking of IL-1β maturation, IL-18 secretion, and caspase-1 cleavage (in vitro), both mediated via GPR40 and GPR120 | (Mo et al., 2020) | |
| High-fat diet and high-fat diet enriched with Ω-3 PUFAs DHA (in vitro) | Ω-3 PUFAs containing 16% EPA and 9%, DHA 100 µM DHA (in vitro) | In vivo/in vitro | WT and GPR120 KO C57BL/6J mice RAW-264.7 cells | High-fat diet LPS and siRNA-GPR120 | Anti-inflammatory effects in high-fat diet–fed mice in adipose tissue. Increase in macrophage chemotaxis, M2 phenotype and decrease in M1in adipose tissue Downregulation of TNF-α, IL-6, and MCP-1 via GPR120/β -arrestin-2 | (Oh et al., 2010) | |
| DHA | 50 and 100 µM | In vitro | Human THP-1 cells and PBMC | LPS and siRNA-GPR120 | Decreased NLRP3, AIM2, and NAIP/NLCR4 inflammasome activation | (Williams-Bey et al., 2014) | |
| DHA, EPA, and α-linolenic acid | 20 µM | In vitro | Human THP-1 cells | shRNA-GPR120 and shRNA-GPR40 | Inhibition of IL-1β and caspase 1 activity via NLRP3 inflammasome mediated via both GPR120 and GPR40 | (Yan et al., 2013) | |
| GPR40 | Palmitic acid | 100 µM | In vitro | Mouse primary hepatocytes and RAW264.7 cells | LPS and GPR40-specific antagonist GW1100 | Synergistic work of LPS and palmitic leading to increased inflammation (increase in MCP-1, CD86, CSF-3, IL-1α, IL-1β, IL-6, and COX-2) in hepatocytes dependent on both GPR40 and CD36 | (Li et al., 2018) |
| Oleic and linoleic acid | 200 µM oleic acid or 100 µM linoleic acid | In vitro | Human neutrophils | GPR40-specific antagonist GW1100 | Increase in CXCL-8, COX-2, and MMP-9 dependent on the MEK1/2-ERK1/2 pathway. | (Mena et al., 2016) | |
| 10-Hydroxy-cis-12-octadecenoic acid | 50 µM | In vitro | Caco-2 and HEK293 | IFN-γ and TNF-α, GPR40-specific antagonist GW1100 | Improved barrier function by upregulation of ZO-1, ZO-2, and claudin-3 after INF-γ– and TNF-α–induced epithelial damage via MEK-ERK pathway | (Miyamoto et al., 2015) | |
| EPA | 10, 20 or 30 mg/kg oral 20 µM (in vitro) | In vivo/in vitro | Nlpr3−/− and double-KO Gpr40−/−; Gpr120−/− C57BL/6 mice BV2 microglia cells | Right middle cerebral artery occlusion (in vivo). Oxygen-glucose deprivation, shRNA-GPR120, and shRNA-GPR40 (in vitro) | Reduction of ischemic brain injury by upregulation of IL-1β and suppression of inflammasome NLRP3 (in vivo) Blocking of IL-1β maturation, IL-18 secretion, and caspase-1 cleavage (in vitro), both mediated via GPR40 and GPR120 | (Mo et al., 2020) | |
| DHA, EPA, and α-linolenic acid | 20 µM | In vitro | Human THP-1 cells | shRNA-GPR120 and shRNA-GPR40 | Inhibition of IL-1β and caspase 1 activity via NLRP3 inflammasome, mediated via both GPR120 and GPR40 | (Yan et al., 2013) | |
| GPR81 | |||||||
| Lactate | 150 µM at 30 µl/g i.p. 15 mM (in vitro) | In vivo/in vitro | C57BL/6N mice primary mouse macrophages, human monocytes, RAW 246.7 and Kupffer cells. | Acute hepatitis (administration of LPS and d-galactosamine), acute pancreatitis (administration of LPS and caerulin). siRNA-GPR81 and siRNA-ARRB2 | In vivo protection against immune hepatitis and acute pancreatitis, GPR81-dependent. Suppression of LPS-induced pro-IL-1β, NLRP3, caspase 1, and pro-IL-18 via inhibition of NF-κB mediated via GPR81/ARRB2 (in vitro). | (Hoque et al., 2014) | |
| Lactate | 10 mM | In vivo/ex vivo | Primary myometrial smooth muscle cells and uterine explants from timed-pregnant CD-1 mice, GPR81−/−, and GPR81 knocked-down mice | Intraperitoneal injection LPS, IL-1β ex vivo | Anti-inflammatory effects of lactate, including decreased mRNA expression of IL-1β, IL-6, MCP-1, and PGHS-2, via receptor GPR81 in the uterus during labor. | (Madaan et al., 2017) | |
| T2R | Flavones (apigenin, chrysin, and wogonin) | 10 µM | In vitro | A549 and 16HBE cells, and primary sinonasal epithelial cell cilia | Stimulation with phorbol 12-myristate 13-acetate, inducible NOS, or TNF-α, global PKC inhibitor Gö6983 | Reduction inflammation via downregulation of IL-18, granulate colony-stimulating factor, and granulocyte macrophage colony-stimulating factor | (Hariri et al., 2017) |
| Quinine | 56 µM | In vitro | Human sinonasal epithelial cells from healthy individuals and patients with chronic rhinosinusitis | — | Stimulation of the airway innate immune defense observed by an increase in nitric oxide and acceleration of ciliary beating related to T2R activation | (Workman et al., 2018) |
HEK, Human Embryonic Kidney; MAPK, Mitogen-Activated Protein Kinase; mTOR, mammalian target of rapamycin; shRNA, short hairpin RNA; STAT, signal transducer and activator of transcription; THP-1, human monocytic leukemia.