mTOR Signaling Pathway and Gut Microbiota in Various Disorders: Mechanisms and Potential Drugs in Pharmacotherapy
Abstract
:1. Introduction
2. mTOR (Mechanistic Target of Rapamycin)
2.1. mTORC1 and mTORC2 Structure
2.2. Upstream Regulation of mTORC1
2.3. Substrates and Functions of mTORC1
2.4. Upstream Regulation of mTORC2
2.5. Substrates and Functions of mTORC2
3. Gut Microbiota
3.1. Gut Microbiota, mTOR, and Intestinal Diseases
3.2. Gut Microbiota, mTOR, and Liver Diseases
3.3. Gut Microbiota, mTOR, and Heart Disease
3.4. Gut Microbiota, mTOR, and Other Diseases
3.5. Gut Microbes and mTOR in the Analysis of Big Data
4. Application of Multiple Drugs Affecting Gut Microbes and mTOR in the Treatment of Different Diseases
4.1. Treatment of Intestinal Diseases
4.2. Treatment of Liver Diseases
4.3. Treatment of Other Diseases
Name | Disease | Pathway Affected | Changes of Gut Microbiota | Cell Response |
---|---|---|---|---|
Maltol [162] | —— | ↑AMPK ↓mTOR | ↑Firmicutes, ↓Bacteroidetes | ↓Apoptosis |
HQD [163] | UC | ↑PI3K/AKT/mTOR | ↑Firmicutes, Bacteroidetes | ↑amino acid metabolism, p-S6 and p-4EBP1 ↓Apoptosis |
Rhein [165] | UC | ↓PI3K/AKT/mTOR | ↑Unspecified-S24-7, Rikenellaceae ↓Enterobacteriaceae, Turicibacter | ↓pro-inflammatory cytokines |
P. ginseng [164] | IBD | ↓mTOR, TLR4, NF-kB | ↓Gram-negative bacteria | ↑Autophagy ↓p62 |
SCFAs [129] | CD and UC | ↑mTOR, STAT3 | against enteric infection of Citrobacter rodentium | ↑HIF1α, AhR, IL-22 ↓Gpr41, HDAC |
TB [168] | CRC | ↓PI3K/AKT/mTOR | ↓Bacteroidceae and Bacteroides ↑Prevotellaceae and Alloprevotella | ↑cyclin D1 protein, cleaved caspase 3 |
SCFAs [183] | —— | ↑mTOR, STAT3 | —— | ↑AMP, RegIIIγ, β-defensins |
L. reuteri + MTZ [169] | NAFLD | ↓mTOR, AKT | ↑Akkermansia muciniphila, Firmicutes, butyrate | ↑Autophagy, LC-3II ↓LPS, NF-kB, TNF-α |
AB23A [141] | NAFLD | ↓mTOR, TLR4, NF-kB | ↓Firmicutes/Bacteroidaeota, Actinobacteriota/Bacteroidaeota | ↑ZO-1, occludin |
LGG-s and BMMSC [142] | Alcoholic liver disease | ↓PI3K/mTOR, PI3K/NF-kB | —— | ↑Autophagy ↓NKB cells, TFH cells |
LF2 [170] | METS | ↓PI3K/AKT/mTOR | ↑Verrucomicrobia, Akkermansia muciniphila | ↓SREBP-1c, PPARγ |
Butyrate [143] | HCC | ↓mTOR, AKT | —— | ↑ROS, Autophagy: beclin 1, ATG 5, LC3-II |
Curcumin [172] | HCC | ↓PI3K/AKT/mTOR | ↑family Helicobacteraceaeorder, order Campylobacterales, and genus Helicobacter and Campylobacteria | ↑apoptosis |
PFT [173] | AD | ↑PI3K/AKT ↓mTOR, GSK-3β | —— | ↓oxidative stress, inflammation |
AMP [174] | Brain aging | ↑PI3K/AKT/mTOR ↓AMPK/SIRT1/NF-κB | ↑Bacteroides ↓Firmicutes | ↓apoptosis, NLRP3 |
MogV and 11-oxo-mogrol [175] | neuronal damages | ↑AKT/mTOR | —— | ↑neurite outgrowth ↓apoptosis, [Ca2+]i release |
OPD [176] | atherosclerosis | ↓mTOR/SREBP1/SCD1 | ↑Bacteroidetes, Faecalibaculum ↓Firmicutes, Ileibacterium | ↑insulin resistance ↓lipid metabolism |
HMB [177] | Obesity | ↑AMPKα, Sirt1, and FoxO1 ↓mTOR | ↑Bacteroidetes, acetic acid | ↓lipid metabolism |
XXT [149] | Obesity | ↑AMPK ↓mTOR | ↑key synthetic enzymes of SCFAs | ↑energy expenditure:PGC-1α, UCP-2 ↓energy intake |
FVP [178] | Heart | ↑mTOR, etc ↓AMPK, PI3K-Akt, etc | ↑Bacteroidetes, Muribaculaceae | ↑Immunity |
BO [179] | TNBC | ↑mTOR | ↑Candidatus Melainabacteria bacterium MEL.A1, Ndongobacter massiliensis, Prevotella ruminicola | ↓Autophagy Regulate amino acid metabolism |
GRh2 [180] | T-ALL | ↓PI3K/AKT/mTOR | ↑Bacteroidetes, Verrucomicrobia ↓Firmicutes, Proteobacteria | ↑Immunity, tight junction proteins, antimicrobial peptides, IgA |
ERS Diet [181] | PC | ↓mTOR, ERK1/2 | ↑diversity of microbiota ↑Formate, Lactate ↓Propionate | ↓Proliferation |
Resveratrol [155] | Obesity and Diabetes | ↓mTOR | ↓Lactococcus, Clostridium XI, Oscillibacter, and Hydrogenoanaerobacterium | ↑insulin resistance |
ERapa [156] | Longevity | ↓mTOR | Alteration of gut metagenomes | Regulate T, B, myeloid, and innate lymphoid cells |
5. Conclusions and Future Perspective
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
Abbreviations
4E-BPs | 4E-binding proteins |
AB23A | Alisol B 23-acetate |
AD | Alzheimer’s disease |
AMP | Aronia melanocarpa polysaccharide |
AMPK | AMP-activated protein kinase |
AMPK | AMP-activated protein kinase |
AOM | Azomethane |
ASD | Autism spectrum disorder |
ATF4 | Activating transcription factor 4 |
BMMSCs | Bone marrow mesenchymal stem cells |
BMMSCs | Bone marrow mesenchymal stem cells |
BO | Bruceae fructus oil |
CASTOR1 | Cellular arginine sensor for mTORC1 |
CD | Crohn’s disease |
CTSK | Cathepsin K |
DAP1 | Death-associated protein 1 |
DDiT4L | DNA-damage-inducible transcript 4-like |
DEPTOR | DEP domain-containing mTOR-interacting protein |
DSS | Dextran sodium sulfate |
eIF4E | Eukaryotic translation initiation factor 4E |
ERS | Engineered Resistant-Starch |
FLCN | Folliculin |
FoxO1/3a | Forkhead box O1/3a |
FVP | Flammulina velutipes polysaccharide |
GAP | GTPase-activating protein |
GATOR2 | GAP activity toward Rags |
GI | Gastrointestinal tract |
Grb10 | Growth factor receptor-bound protein 10 |
GSK3 | Glycogen synthase kinase 3 |
HCC | Hepatocellular Carcinoma |
HK-II | Hexokinase-II |
HMB | β-hydroxy-β-methylbutyrate |
HQD | Huangqin decoction |
IBD | Inflammatory bowel disease |
IEC | Intestinal epithelial cells |
IGF1 | Insulin and insulin-like growth factor 1 |
IKKβ | IκB kinase β |
L. reuteri | Lactobacillus reuteri DSM 17938 |
LGG-s | Lactobacillus rhamnosus culture supernatant |
LI | Large intestine |
LPS | Lipopolysaccharide |
METS | Metabolic syndrome |
mLST8 | Mammalian lethal with SEC13 protein 8 |
MogV | MogrosideV |
mSIN1 | Mammalian stress-activated protein kinase interacting protein 1 |
MST1 | Mammalian sterile 20-like kinase |
MTF | Metformin |
MTHFD2 | Methylenetetrahydrofolate dehydrogenase 2 |
mTOR | The mammalian or mechanistic target of rapamycin |
mTORC | mTOR complex |
NAFLD | Non-alcoholic fatty liver disease |
NDRG1 | N-myc downstream regulated gene 1 |
NKB | Natural killer B cell |
OPD | Ophiopogonin D |
P. ginseng | Polysaccharides from Panax ginseng C. A. Meyer |
PC | Pancreatic cancer |
PDCD4 | Programmed cell death 4 |
PFT | Probiotics fermentation technology |
PGC-1α | Proliferator-activated receptor gamma coactivator 1-alpha |
PI3K | Phosphoinositide 3-kinase |
PIKK | Phosphoinositide 3-kinase related protein kinase |
PKC-α | Protein kinase C-α |
PPAR-γ | Peroxisome proliferator-activated receptor γ |
PRAS40 | Proline-rich substrate of 40 kDa |
PROTOR1/2 | Protein observed with RICTOR 1/2 |
Rags | Ras-related GTPases |
RAPTOR | Regulatory-associated protein of mTOR |
Redd1 | Regulation of DNA damage response 1 |
Rheb | Ras homolog enriched in the brain |
ROS | Reactive oxygen species |
RSK | Ribosomal S6 kinase |
S6K1 | S6 kinase 1 |
SAM | S-adenosylmethionine |
SCFAs | Short chain fatty acids |
SGK1 | Serum and glucocorticoid-induced protein kinase 1 |
SI | Small intestine |
SREBP1/2 | Sterol regulatory element binding protein 1/2 |
SRPK2 | SR protein kinase 2 |
STZ | Streptozotocin |
T-ALL | T-cell acute lymphoblastic leukemia |
TB | Theabrownin |
TFH | Follicular helper T cell |
TLR4 | Toll-like receptor 4 |
TNBC | Triple-negative breast cancer |
TNF-α | Tumor necrosis factor-α |
Trx1 | Thioredoxin 1 |
TSC | Tuberous sclerosis complexes |
UC | Ulcerative colitis |
UCP-2 | Uncoupling protein-2 |
ULK1 | Unc-51-like autophagy-activating kinase 1 |
XXT | Xiexin Tang |
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Gao, Y.; Tian, T. mTOR Signaling Pathway and Gut Microbiota in Various Disorders: Mechanisms and Potential Drugs in Pharmacotherapy. Int. J. Mol. Sci. 2023, 24, 11811. https://doi.org/10.3390/ijms241411811
Gao Y, Tian T. mTOR Signaling Pathway and Gut Microbiota in Various Disorders: Mechanisms and Potential Drugs in Pharmacotherapy. International Journal of Molecular Sciences. 2023; 24(14):11811. https://doi.org/10.3390/ijms241411811
Chicago/Turabian StyleGao, Yuan, and Tian Tian. 2023. "mTOR Signaling Pathway and Gut Microbiota in Various Disorders: Mechanisms and Potential Drugs in Pharmacotherapy" International Journal of Molecular Sciences 24, no. 14: 11811. https://doi.org/10.3390/ijms241411811