Modulation of the PI3K/Akt/mTOR signaling pathway by probiotics as a fruitful target for orchestrating the immune response

Figures & data

Table 1. List of probiotics strain and their effect on different disorders

Probiotic	Model	Mechanism	Effect	Year	Reference
B. coagulans 09.712	In vivo	Up-regulation of Foxp3 and down-regulation the phosphorylation of Akt, 4E-BP1, STAT3, SGK1, p70S6K and mTOR	Amelioration of allergic inflammation	2017	29
L. plantarum	In vitro	Up-regulation of PTEN, BAX, TLR4, and down-regulation of Akt genes	Induction of apoptosis and inhibition of H. pylori-related gastric cancer	2020	30
	In vivo	Reduction of lipid accumulation, FASN expression, and hepatic weight, and elevation of IRS-1/AKT/eNOS pathway expression and phosphorylation	Improvement of lipogenesis and restoring hepatic and renal dysregulation	2020	31
	In vitro	Inhibition of melanogenic enzymes and cellular activity of tyrosinase, and activation of PI3K/Akt and ERK pathways	Prevention of melanogenesis	2015	32
L. plantarum KY1032	In vivo	Inhibition of Akt/mTOR/NF-κB phosphorylation and activation of p53, p16, and COX-2 expression	Returning the alternation of age reduced spontaneous and amelioration of lipidemia	2015	33
L. plantarum WCFS1	In vitro and in vivo	Up-regulation of PKC and PI3K/Akt anti-apoptotic pathways	Regulation of TJ and actin cytoskeleton, and promotion of general immune tolerance	2021	34
L. plantarum H31	In vitro	Up-regulation of Akt-2, AMPK, and GLUT-4 expression	Prevention of pancreas α-amylase activity, and alleviation of diabetes mellitus	2020	35
S. cerevisiae	In vitro	Down-regulation of p-Akt1, Bcl-XL, pro-caspase-3 and 9 expressions, and up-regulation of BAX, cleavedcaspase-3 and 9	Induction of apoptosis in colon cancer	2020	36
B. amyloliquefaciens SC06	In vitro and in vivo	Inhibition of PI3K/Akt pathway	Alleviation of oxidative stress	2019	37
B. licheniformis SC08	In vitro and in vivo	Inhibition of PI3K/Akt pathway	Alleviation of oxidative stress	2019	37
E. faecalis	In vitro	Inhibition of Akt and mTOR phosphorylation	Induction macrophages autophagy	2018	38
L. fermentum	In vitro	Reduction of senescence markers, NF-κB activation and DNA damage, and down-regulating the phosphorylation of PI3K/Akt/mTOR pathway	Prevention of senescence progression	2020	39
L. fermentum L930BB	In vitro and in vivo	Up-regulation of PKC and PI3K/Akt anti-apoptotic pathways	Regulation of TJ and actin cytoskeleton, and promotion of general immune tolerance	2021,2018	34,40
L. rhamnosus	In vivo	Down-regulation of PI3K/mTOR/NF-κB pathways	Reduction of autophagy and inflammation, and improvement of alcoholic hepatitis	2019	41
L. rhamnosus GG	In vitro and In vivo	Down-regulation of p38 MAPK and up-regulation of PI3K/Akt cascade	Prevention of cytokine-induced apoptosis	2007	42
	In vivo	Enhancing mTOR signaling pathway expression, antioxidant activities and tight junction, and attenuating apoptosis and autophagy	Protection of LPS-induced intestinal barrier dysfunction	2017	43
	In vitro	Suppression of PI3K/Akt signal pathway over-activation	Regulation of Salmonella induced IL-8 response and prevention of Salmonella infection	2016	44
	In vivo	Suppression of Akt/mTOR and ERK1/2 pathways phosphorylation	Improvement of OSA	2019	45
L. acidophilus NCFM	In vivo	Down-regulation of Akt1, p38 and cytosolic group IV PLA2 phosphorylation, and up-regulation of ERK1/2 phosphorylation	Reduction of T-cell-induced colitis	2011	46
	In vitro	Down-regulation of JNK and mTOR pathways, and up-regulation of p53 and p21 proteins expression, and ROS formation	Induction of autophagic cell death and anti-cancer effect	2019	47
K. marxianus	In vitro	Prevention of mTOR, JAK-1, and Akt-1 pathways	Induction of apoptosis	2020	48
P. kudriavzevii	In vitro	Prevention of mTOR, JAK-1, and Akt-1 pathways	Induction of apoptosis	2020	48
L. reuteri	In vivo	Elevation of active-β-catenin and TGFβ1 expression, and PI3K/Akt phosphorylation	Stimulation of GMSCs function and healing of wound	2019	49
L. reuteri ZJ617	In vivo	Enhancing mTOR signaling pathway expression, antioxidant activities and tight junction, and attenuating apoptosis and autophagy	Protection of LPS-induced intestinal barrier dysfunction	2017	43
L. reuteri GMNL-263	In vivo	Down-regulation of Fas ligand and up-regulation of IGF-IR/PI3K/Akt cell survival pathway	Reduction of hyperlipidaemic and cardiac apoptosis	2015	50
B. bifidum	In vitro	Inhibition of LPS-induced autophagy and punctate distribution of GFP-mCherry-LC3, and decreasing of LC3-II/LC3-I ratio	Maintaining epithelial barrier function	2016	51
C. butyricum	In vivo	Up-regulation of TJ-related proteins expression, and Akt/mTOR, and p70S6k phosphorylation	Reduction of intestinal mucosal permeability, and colitis symptoms	2020	20
	In vivo	Increasing the levels of Bcl-2, BDN, and Akt phosphorylation and decreasing the level of BAX	Reduction of neuronal apoptosis and improvement of VaD	2015	52
C. butyricum MIYAIRI 588	In vitro and in vivo	Reduction of hepatic lipid deposition and improvement of triglyceride, insulin resistance, and hepatic inflammatory indexes, and elevation of lipolysis or lipogenesis, Akt, and hepatic AMPK expression	Prevention of NAFLD progression	2013	53
L. gasseri JM1	In vitro	Activation of the TLR2 and NOD2-mediated PI3K/Akt signaling pathway	Alleviation of inflammation	2020	54
L. paragasseri K7	In vitro and in vivo	Up-regulation of PKC and PI3K/Akt anti-apoptotic pathways	Regulation of TJ and actin cytoskeleton, and promotion of general immune tolerance	2020	34
B. lactis Bb-12	In vivo	up-regulation of insulin receptor substrate 1 and insulin receptor beta, Akt, certain adipocytokines, IκBα, and IKKα expression, and down-regulation of mTOR and p66Shc signaling pathway	Improve glucose homeostasis	2018	55
B. animalis subsp. lactis BI-04	In vitro	Up-regulation of PI3K/Akt pathways and down-regulation of p53 gene expression	Postpone the BaP-induced apoptosis	2020	56
B. animalis subsp. lactis DSM10140	In vitro	Suppression of PI3K/Akt signal pathway over-activation	Regulation of Salmonella induced IL-8 response and prevention of Salmonella infection	2016	44
B. animalis subsp. animalis (IM386)	In vitro and in vivo	Up-regulation of PKC and PI3K/Akt anti-apoptotic pathways	Regulation of TJ and actin cytoskeleton, and promotion of general immune tolerance	2021	34
B. breve B-3	In vivo	Promotion of AMPK and Akt/mTOR signaling phosphorylation	Elevation muscle mass	2020	57
B. breveC50 (BbC50sn)	In vitro	Induction of PI3K/Akt, p38MAPK, and ERK pathways	reduction of allergic and inflammatory disorders	2008	58
L. johnsonii N6.2	In vivo	Reduction of mTORC1-activating phosphorylation of pAKT-T308 and pAKT-S473	Reduction of metabolic syndrome disease	2018	59
L. casei	In vitro	Down-regulation of PI3K/Akt/NF-κB phosphorylation	Induction of apoptosis and inhibition of gastric cancer	2013	60
L. casei Zhang (LCZ)	In vivo	Decreasing inflammatory cytokines, and inhibiting the hyperactivation of PI3K/Akt/NF-κB and p-STAT3 pathways	Prevention and treatment of ulcerative colitis	2019	95
L. paracasei subp. paracasei X12	In vitro	Down-regulation mTOR/4E-BP1 pathway and cyclin E1, and up-regulating of p27	Blocking cell cycle of colon cancer cells	2016	61
L. paracasei TD062	In vitro and in vivo	Increasing the level of IRS-2, PI3K and Akt and decreasing the level of GSK-3β	Improvement of glucose homeostasis and insulin resistance, and inhibition of T2DM	2018	62
VSL#3	In vivo	Inhibiting the PI3K/Akt and NF- κB pathway, iNOS, COX-2, NF-κB, TNF-α, IL-6, and p-Akt expression, and increasing of IL-10	Prevention and treatment of ulcerative colitis	2013	63
L. mesenteroides	In vitro	Inactivation of NF-κB, Akt, and Bcl-XL expressions, and up-regulation of MAPK1, BAX, and caspase-3	Promotion of apoptosis in colon cancer	2017	64
L. salivarius Ren	In vitro and in vivo	Inactivation of Akt signaling cascades, cyclinD1, and COX-2	Suppression of cell proliferation and CRC formation, and induction of cell apoptosis	2020	65
L. salivarius AR809	In vivo	Inhibition of TLR/PI3K/Akt/mTOR/NF-κB pathway, and elevation of autophagic protein level	Inhibition of inflammatory response caused by S. aureus	2020	66
L. curvatus HY7601	In vivo	Inhibition of Akt/mTOR/NF-κB phosphorylation and activation and p53, p16, and COX-2 expression	Returning the alternation of age reduced spontaneous	2015	33
L. pentosus var. plantarum C29	In vivo	Suppression of p16, COX-2, and inducible nitric oxide synthase expression, and activation of Akt, mTOR, and NF-κB	Returning the alternation of age reduced spontaneous	2015	67
E. faecium L-15	In vivo	Activation of PI3K/Akt pathway	Improvement of self-renewal and proliferation of SKPs	2020	6

Figure 1. Schematic representation of the complex crosstalk between probiotics and the PI3K/AKT/mTOR signaling network, whereby extracellular and intracellular signals converge to orchestrate canonical upstream and downstream pathways to modulate a wide range of biological processes involved in various disorders. A detailed description of these interactions is provided in the text. Right: Up-regulation of PI3K/AKT/mTOR signaling cascade by probiotics. Left: Down-regulation of hyperactivated PI3K/AKT/mTOR signaling pathway by probiotics. Arrows indicate positive regulation (activation/stimulation), bar-headed lines indicate negative regulation (inhibition). The abbreviations shown in the figure can be found in the main text. (Figure was designed by https://biorender.com)

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