mTOR and Gut Microbiota in Various Diseases: Comparison
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The mammalian or mechanistic target of rapamycin (mTOR) integrates multiple intracellular and extracellular upstream signals involved in the regulation of anabolic and catabolic processes in cells and plays a key regulatory role in cell growth and metabolism. The activation of the mTOR signaling pathway has been reported to be associated with a wide range of human diseases. A growing number of in vivo and in vitro studies have demonstrated that gut microbes and their complex metabolites can regulate host metabolic and immune responses through the mTOR pathway and result in disorders of host physiological functions.

  • mTOR
  • gut microbes
  • metabolites
  • therapy

1. Treatment of Intestinal Diseases

Some drugs have already been proven to have a potential role in animal models of intestinal diseases such as inflammatory bowel disease (IBD) and CRC. Ming-hui Jin et al. used polystyrene nanoplastics (PS) to stimulate enterotoxicity in mice, resulting in intestinal microbial disruption and colonic tissue damage. Maltol treatment promoted AMP-activated protein kinase (AMPK)K phosphorylation activity and inhibited mechanistic target of rapamycin (mTOR)TOR phosphorylation in the colon after PS exposure, promoting translocation of transcription factor EB (TFEB)TFEB entry into the nucleus to mitigate autophagy-dependent apoptosis. In addition, oral maltol decreased the relative abundance of Bacteroidetes but increased the relative abundance of Firmicutes and restored the number of known single-chain fatty acid (SCFA)SCFA-producing bacteria, thereby restoring gut microbial composition [1]. Mu Xia Li et al. revealed the mechanism of Huangqin decoction (HQD) in the treatment of gastrointestinal diseases such as UC. As a traditional Chinese medicine therapy, HQD could improve the clinical performance of the DSS-induced UC model, inhibit the inflammatory response in vivo, and rebalance the gut microbiota. HQD treatment activated PI3K/AKT/mTOR signaling by upregulating amino acid metabolism and improved the barrier function of the intestinal epithelial [2][3]. In contrast, Rhein inhibited pro-inflammatory factors by inhibiting the PI3K/AKT/mTOR pathway, thereby alleviating enteritis. In the process, Lingling Dong et al. found that Rhein treatment resulted in the downregulation of Enterobacteriaceae and Turicibacter and the upregulation of Unspecified-S24-7 and Rikenellaceae, which were correlated with pro-inflammatory factors [4]. Dandan Wang et al. found that a polysaccharide isolated from Panax ginseng (GP) reduced the intestinal injury of DSS-induced colitis in rats. GP treatment increased the diversity of the microbial community, improved the compositions of gut microbiota, reduced the phosphorylation level of mTOR, and activated autophagy to inhibit inflammation [3]. In addition, SCFAs and metformin (MTF) can regulate intestinal immunity to prevent colitis and have potential therapeutic applications [5][6].
The PI3K/AKT/MTOR signaling pathway plays a key role in a variety of cancers, including CRC, such as cell proliferation, cell metastasis, and cell survival [7][8]. Theabrownin (TB) inhibited the development of CRC by decreasing Bacteroidceae and Bacteroides associated with CRC and increasing the production of SCFAs, thereby inhibiting cell proliferation through the suppression of PI3K/AKT/mTOR phosphorylation [9].

2. Treatment of Liver Diseases

In the HFD-induced rat model of non-alcoholic fatty liver disease (NAFLD), fecal levels of Firmicutes, Bacteroidetes, and short-chain fatty acids returned to normal with treatment with L. reuteri + MTZ alone or in combination with MTF. More precisely, combined therapy prevented steatosis and the progression of liver injury by inducing autophagy via p-AKT/mTOR/LC-3Ⅱ pathways in the liver [10]. Fan Xia et al. found that AB23A not only reduced the abundance of Firmicutes/Bacteroidaeota and Actinobacteriota/Bacteroidaeota but also decreased the activities of mTOR and TLR4 to prevent the progress of NAFLD [11]. Furthermore, the combined LGG-s and BMMSC treatment also inhibited the PI3K/mTOR signal to accelerate autophagy, which has the potential to alleviate alcoholic steatohepatitis [12]. Interestingly, in the HFD-induced metabolic syndrome, Zhenzhen Deng et al. found that low-molecular-weight fucoidan fraction LF2 and MTF have similar effects on gut microbiota, increasing the proportion of Verrucomicrobia and enriching the abundance of Akkermansia muciniphila. LF2 promoted the phosphorylation of PI3K and AKT in a dose-dependent manner but reversed the over-activation of mTOR, thereby improving lipid metabolism [13].
According to the report, the gut microbiota can regulate the immune response of hepatocellular carcinoma (HCC); thus, readjusting the gut microbiota could be a potential option for HCC treatment [14]. Butyrate, considered as a potential candidate drug for the treatment of liver cancer, could inhibit the phosphorylation of AKT and mTOR through reactive oxygen species, resulting in the upregulation of autophagy proteins beclin 1, ATG 5, and LC3-Ⅱ, thereby promoting the formation of autophagy bodies [15]. Curcumin can significantly sensitize hepatoma cells to 5-FU cytotoxicity and increase the apoptosis rate through synergistic effects. The gut microbiota facilitates the oral utilization of curcumin in vivo and enhances the chemo-sensitivity of hepatocellular carcinoma cells to 5-FU by blocking the PI3K/AKT/mTOR signaling pathway in vitro [16].

3. Treatment of Other Diseases

Probiotics regulate the PI3K/AKT/mTOR signaling pathway, which is beneficial for coordinating the immune response. Probiotics fermentation technology (PFT) activated the PI3K/AKT signal transduction pathway but inhibited the glycogen synthase kinase-3β (GSK-3β) and mTOR signal; its potential role in the treatment of Alzheimer’s disease was parallel to that of pioglitazone [17]. Additionally, there are reports that Aronia melanocarpa polysaccharide (AMP) activates PI3K/AKT/mTOR signaling pathway and its downstream apoptotic protein family, inhibits brain-cell apoptosis, and enriches intestinal beneficial bacteria to delay aging, which had a similar function to MogrosideV and its metabolite 11-oxo-mogrol [18][19]. In contrast to the mechanism of action of AMP, Xiexin Tang (XXT) ameliorates obesity by promoting the activity of key enzymes for the synthesis of SCFAs and inhibiting AMPK while activating mTOR signaling [20].
Ophiopogonin D (OPD) can increase the abundance of Bacteroidetes, reduce the relative abundance of Firmiuts, inhibit the phosphorylation of mTOR and the expression of SREBP1 and SCD1 to alleviate fat metabolism, and result in the prevention of atherosclerosis and metabolic syndrome [21]. The mechanism in which β-hydroxyβ-methylbutyrate (HMB) functions through the Bacteroidetes–acetic acid–AMPKα axis to reduce the lipid metabolism of Bama Xiang mini-pigs was somewhat similar [22]. In addition, Flammulina velutipes polysaccharide (FVP) affected the abundance of gut microbiota, especially the Bacteroidetes phylum and the Muribaculaceae family, and upregulated the mTOR signaling pathway in cardiac tissue [23]. However, the specific mechanism remains to be determined.
The oral administration of the bruceae Frutus oil (BO), under the influence of gut microbiota, inhibited breast cancer. At the same time, BO changed the dominant strains of gut microbiota and promoted mTOR activity, leading to the inhibition of autophagy [24]. In contrast, 20 (s)-ginsenoside Rh2 (grh2) played an anti-tumor role by inhibiting PI3K/AKT/mTOR signal [25]. Both an engineered resistant starch (ERS) diet and a ketogenic diet (KD) reduced mTOR phosphorylation and regulated microorganisms [26][27]. Diet may serve as a synergistic approach to improve the treatment of diseases.
The direct interaction between mTOR and intestinal microorganisms provides potential ideas for treatment. Firstly, microencapsulated rapamycin (eRapa), the best pharmacological mTOR inhibitor studied in the study of lifespan and health extension, had strong immune effects and could gently change intestinal metagenes, which is worthy of further study [28]. Then, resveratrol, a specific inhibitor of mTOR complex 1, alleviated the changes in intestinal microflora in diet-induced obese mice [29]. Furthermore, the microflora metabolite SCFAs activated mTOR and STAT3 of IEC to produce antimicrobial peptides to balance the intestinal environment [30].
Overall, in view of the limitations of current treatment, more drugs can only be used as a potential choice for disease treatment, which has broad clinical application prospects in the future.
Table 1. List of drugs affecting the microbiota and the mTOR signaling pathway in different disorders.
Name Disease Pathway Affected Changes of Gut Microbiota Cell Response
Maltol

[1]		 —— ↑AMPK

↓mTOR		 ↑Firmicutes,

↓Bacteroidetes		 ↓Apoptosis
HQD

[2]		 UC ↑PI3K/AKT/mTOR ↑Firmicutes,

Bacteroidetes		 ↑amino acid metabolism,

p-S6 and p-4EBP1

↓Apoptosis
Rhein

[4]		 UC ↓PI3K/AKT/mTOR ↑Unspecified-S24-7, Rikenellaceae

↓Enterobacteriaceae, Turicibacter		 ↓pro-inflammatory cytokines
P. ginseng

[3]		 IBD ↓mTOR, TLR4, NF-kB ↓Gram-negative bacteria ↑Autophagy

↓p62
SCFAs

[5]		 CD and UC ↑mTOR, STAT3 against enteric infection of

Citrobacter rodentium		 ↑HIF1α, AhR, IL-22

↓Gpr41, HDAC
TB

[9]		 CRC ↓PI3K/AKT/mTOR ↓Bacteroidceae and Bacteroides

↑Prevotellaceae and Alloprevotella		 ↑cyclin D1 protein, cleaved caspase 3
SCFAs

[30]		 —— ↑mTOR, STAT3 —— ↑AMP, RegIIIγ,

β-defensins
L. reuteri + MTZ [10] NAFLD ↓mTOR, AKT ↑Akkermansia muciniphila,

Firmicutes, butyrate		 ↑Autophagy, LC-3II

↓LPS, NF-kB, TNF-α
AB23A

[11]		 NAFLD ↓mTOR, TLR4, NF-kB ↓Firmicutes/Bacteroidaeota, Actinobacteriota/Bacteroidaeota ↑ZO-1, occludin
LGG-s and BMMSC

[12]		 Alcoholic liver disease ↓PI3K/mTOR,

PI3K/NF-kB		 —— ↑Autophagy

↓NKB cells, TFH cells
LF2

[13]		 METS ↓PI3K/AKT/mTOR ↑Verrucomicrobia,

Akkermansia muciniphila		 ↓SREBP-1c, PPARγ
Butyrate

[15]		 HCC ↓mTOR, AKT —— ↑ROS, Autophagy: beclin 1,

ATG 5, LC3-II
Curcumin

[16]		 HCC ↓PI3K/AKT/mTOR ↑family Helicobacteraceaeorder,

order Campylobacterales, and genus Helicobacter and Campylobacteria		 ↑apoptosis
PFT

[17]		 AD ↑PI3K/AKT

↓mTOR, GSK-3β		 —— ↓oxidative stress, inflammation
AMP

[18]		 Brain aging ↑PI3K/AKT/mTOR

↓AMPK/SIRT1/NF-κB		 ↑Bacteroides

↓Firmicutes		 ↓apoptosis, NLRP3
MogV and 11-oxo-mogrol [19] neuronal damages ↑AKT/mTOR —— ↑neurite outgrowth

↓apoptosis, [Ca2+]i release
OPD

[21]		 atherosclerosis ↓mTOR/SREBP1/SCD1 ↑Bacteroidetes, Faecalibaculum

↓Firmicutes, Ileibacterium		 ↑insulin resistance

↓lipid metabolism
HMB

[22]		 Obesity ↑AMPKα, Sirt1, and FoxO1

↓mTOR		 ↑Bacteroidetes, acetic acid ↓lipid metabolism
XXT

[20]		 Obesity ↑AMPK

↓mTOR		 ↑key synthetic enzymes of SCFAs ↑energy expenditure:PGC-1α, UCP-2

↓energy intake
FVP

[23]		 Heart ↑mTOR, etc

↓AMPK, PI3K-Akt, etc		 ↑Bacteroidetes, Muribaculaceae ↑Immunity
BO

[24]		 TNBC ↑mTOR ↑Candidatus Melainabacteria bacterium MEL.A1, Ndongobacter massiliensis, Prevotella ruminicola ↓Autophagy

Regulate amino acid metabolism
GRh2

[25]		 T-ALL ↓PI3K/AKT/mTOR ↑Bacteroidetes, Verrucomicrobia

↓Firmicutes, Proteobacteria		 ↑Immunity, tight junction proteins, antimicrobial peptides, IgA
ERS Diet

[26]		 PC ↓mTOR, ERK1/2 ↑diversity of microbiota

↑Formate, Lactate

↓Propionate		 ↓Proliferation
Resveratrol

[29]		 Obesity and Diabetes ↓mTOR ↓Lactococcus, Clostridium XI, Oscillibacter, and Hydrogenoanaerobacterium ↑insulin resistance
ERapa

[28]		 Longevity ↓mTOR Alteration of gut metagenomes Regulate T, B, myeloid, and innate lymphoid cells
Arrows indicate upregulation or downregulation.

References

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