Probiotics, Nuclear Receptor Signaling, and Anti-Inflammatory
Pathways
Table 1
Summary for molecular mechanisms and probiotics.
Involved pathways
Probiotics
In vitro system
In vivo system
Summary
Ref.
NF-B
(i) L. casei Shirota (LcS)
(i) THP-1
(i) Rat
(i) L-lactic acid and LcS culture supernatant inhibited NF-κB activation, TNF-α mRNA expression increase, and TNF-α protein secretion in cells treated with lipopolysaccharide (LPS)
(i) VSL#3 inhibited the proinflammatory NF-κB pathway and induced the expression of cytoprotective heat shock proteins (HSPs) in intestinal epithelial cells
(i) Caco-2 cells preincubated with LP-L2 showed attenuation of monocyte chemotactic protein-1(MCP-1) protein production and mRNA expression and also prevented IκBα degradation in TNF-α-stimulated Caco-2 cells
(i) Lc downregulated the transcription of genes encoding proinflammatory effectors and adherence molecules induced by invasive S. flexneri resulting in anti-inflammation mediated by the inhibition of the NF-κB pathway
(i) In vivo, Sb protected mice from Salmonella enterica serovar-Typhimurium-(ST-) induced death and prevented hepatic bacterial translocation (ii) In T84 human colorectal cancer cells, Sb incubation abolished Salmonella invasion, preserved barrier function, and decreased ST-induced IL-8 synthesis (iii) Sb had an inhibitory effect on ST-induced activation of the MAPKs, extracellular regulated kinase (ERK) 1/2, p38 and JNK, and NF-κB
(i) E. coli Nissle 1917 (ECN) (ii) L. fermentum (iii) L. acidophilus (La) (iv) Pediococcus pentosaceus (v) L. paracasei (vi) VSL#3
(i) CaCo-2
(i) CaCo-2 cells treated with probiotic had peak of human β defensins-2 (hBD-2) mRNA expression at 6 h incubation (ii) Promoter activation via probiotics was abolished with the deletion of NF-κB- and activator-protein-1- (AP-1-) binding sites on the hBD-2 promoter (iii) Induction of hBD-2 depends on MAPK, ERK 1/2, p38, and c-Jun N-terminal kinase (JNK), to varying degrees
(i) ECN (ii) Various E. coli strains (iii) Various Lactobacilli strains
(i) CaCo-2
(i) Active and heat-inactivated ECN and several other probiotic bacteria potently induced hBD-2 in intestinal epithelial cells (ii) hBD-2 promoter activation was abolished by mutation of the two NF-kB sites in the hBD-2 promoter upon treatment with ECN (iii) ECN-inducted activation of AP-1 may be regulated by JNK kinase pathway
(i) LGG-CM induced Hsp25 and Hsp72 in time- and concentration-dependent manner (ii) LGG-CM-induced HSP72 induction was blocked by the Inhibitors of p38 and JNK
(i) Upon exposure to Sb, HER-2, HER-3, insulin-like growth factor-1 receptor, and EGFR were inactivated (ii) In HT-29 cells, Sb promoted apoptosis, prevented EGF-induced proliferation, and reduced cell colony formation (iii) Sb decreased intestinal tumor growth and dysplasia in C57BL/6J Min/+ (Apc(Min)) mice
(i) Commensal-origin DNA enhanced expression of TLR9 in HT-29 and T84 cells (ii) This was associated with attenuation of TNF-α-induced NF-κB activation by reducing IκBα degradation and p38 phosphorylation (iii) LGG DNA decreased the TNF-α-induced reduction in transepithelial electrical resistance (TER)
(i) HT29 cells incubated with lactobacilli showed upregulation of TLR2 and TLR9 transcription levels (ii) Protein expression levels of TLR2 and TLR5 were enhanced
(i) Intragastric administration of gamma-irradiated probiotics significantly ameliorated the severity of DSS-induced colitis in TLR2- and TLR4-deficient mice but not in TLR9-deficient mice
(i) ECN decreased colitis and proinflammatory cytokine secretion in WT but not TLR2- or TLR4-knockout mice (ii) ECN resulted in reduction of interferon (IFN)-γ secretion in TLR2 knockout (iii) Cytokine secretion was almost undetectable and not modulated by ECN in TLR-4-knockout mice (iv) Increased TLR2 and TLR4 protein expression and NF-κB activity via TLR2 and TLR4 was seen with ECN and human T-cell coculture
(i) LP strongly induced IL-10 and weakly induced IL-12; Lc strongly induced IL-12 and weakly induced IL-10 (ii) LP, compared to Lc, demonstrated more rapid and strong activation of MAPKs, especially of ERK (iii) Blocking LP-induced ERK activation resulted in decreased IL-10 production and increased IL-12 production (iv) Combined stimulation with LP and Lc resulted in synergistic induction of IL-10 production; this was triggered by the key factors: cell wall teichoic acid and lipoteichoic acids (v) Teichoic-acid-induced IL-10 production was mediated by TLR2-dependent ERK activation
(i) LGG-produced soluble proteins (p40 and p75) diminished the hydrogen-peroxide-induced decrease in TER and increase in inulin permeability and induced increase in membrane translocation of protein kinase C (PKC) beta I, PKC epsilon, and level of phospho-ERK1/2 in the detergent-insoluble fractions (ii) LGG-produced soluble proteins (p40 and p75) prevented hydrogen-peroxide-induced redistribution of occludin, zonula occludens (ZO)-1, E-cadherin, and beta-catenin from intercellular junctions and their dissociation from the detergent-insoluble fractions (iii) p40- and p75-mediated reduction of hydrogen-peroxide-induced tight junction disruption and inulin permeability was attenuated by U0126 (a MAP kinase inhibitor)
(i) B. infantis-conditioned medium (BiCM) increased TER, ZO-1, and occludin expression and decreased claudin-2 expression; this was associated with increased phospho-ERK and decreased phospho-p38 (ii) TNF-α- and IFN-γ-induced drops in TER and rearrangement of TJ proteins were prevented by BiCM (iii) Inhibition of ERK attenuated the protection from TNF-α and IFN-γ and prevented BiCM-induced increase in TER (iv) In vivo, oral BiCM reduced colonic permeability, in IL-10-deficient mice, long-term BiCM decreased colonic and splenic IFN-γ secretion, attenuated inflammation, and normalized colonic permeability
(i) LP MB452 increased TER across Caco-2 cell monolayers in dose-dependent manner (ii) Altered expression of several tight-junction-related genes (including occludin and associated plaque proteins) was seen in response to LP MB452 (iii) LP MB452 caused changes in gene expression levels of tubulin and proteasome (iv) LP MB452-treated cells showed increased fluorescence intensity of the four tight junction proteins when compared to untreated controls
(i) Unconjugated bilirubin (UCB) caused decreased PKC activity, serine phosphorylated occluding, and ZO-1 levels (ii) High concentrations of UCB caused cytotoxicity and decreased TER (iii) Treatment with LP mitigated the effects of UCB on TER and apoptosis, prevented aberrant expression and rearrangement of TJ proteins, and partially restored PKC activity and serine phosphorylated TJ protein levels
(i) LP DSM 2648 reduced the deleterious effect of Escherichia coli (enteropathogenic E. coli (EPEC)) O127:H6 (E2348/69) on TER and adherence with simultaneous or prior coculture compared with EPEC incubation alone
(i) LP induced translocation of ZO-1 to the TJ region in an in vitro model, but the effects on occludin were minor compared with effects seen in vivo (ii) LP activated TLR2 signaling, and treatment with TLR2 agonist Pam(3)-Cys-SK4(PCSK), increased fluorescent staining of occludin in the TJ (iii) Phorbol-ester-induced dislocation of ZO-1 and occludin and associated increase in epithelial permeability were attenuated with pretreatment with LP or PCSK
(i) B. bifidum decreased the incidence of necrotizing enterocolitis (NEC), normalized IL-6, mucin-3, and Tff3 levels in the ileum of NEC rats, and normalized the expression and localization of TJ and adherens junction (AJ) proteins in the ileum compared with animals with NEC (ii) B. bifidum did not affect reduced mucin-2 production in the NEC rats
(i) VSL#3 treatment prevented the increase in epithelial permeability in acute colitis, decrease in expression and redistribution of occludin, ZO-1, and claudin-1, claudin-3, claudin-4, and claudin-5, and increase of epithelial apoptotic ratio
(i) Pretreatment with combination of Lr and La significantly prevented decrease in the membrane-bound ATPases and reduced expression of tight junction proteins in the membrane
(i) B. lactis 420 (ii) B. lactis HN019 (iii) La NCFM (iv) L. salivarius Ls-33
(i) CaCo-2
(i) B. lactis 420 and Escherichia coli O157:H7 (EHEC) supernatant had opposite effects in tight junction integrity; B. lactis 420 supernatant protected the tight junctions from EHEC-induced damage when administered before EHEC supernatant (ii) EHEC and probiotics had reverse effects upon cyclo-oxygenase expression
(i) ECN colonization of gnotobiotic mice resulted in upregulation of ZO-1 mRNA and protein levels in IECs (ii) ECN administration reduced loss of body weight and colon shortening in DSS-treated mice (iii) ECN inoculation ameliorates the infiltration of the colon with leukocytes
(i) EPEC with ECN coincubation: addition of ECN after EPEC infection restored barrier integrity and abolished barrier disruption (ii) ECN altered the expression, distribution of ZO-2 protein and of distinct PKC isotypes; ZO-2 expression was increased in parallel to its redistribution towards the cell boundaries (iii) ECN induces restoration of a disrupted epithelial barrier; this is transmitted by PKCzeta silencing and ZO-2 redistribution
(i) EHEC-induced decrease in electrical resistance and the increase in barrier permeability assays were attenuated by probiotic pretreatment (ii) LGG protected epithelial monolayers against EHEC-induced redistribution of claudin-1 and ZO-1 proteins (iii) Heat-inactivated LGG did not affect EHEC binding or disruption of barrier function
(i) Streptococcus thermophilus (ST)/La or the commensal Bacteroides thetaiotaomicron (BT) prevented the TNF-α- and IFN-γ-induced reduction in TER and increase in epithelial permeability (ii) ST/La or BT prevented IFN-γ inhibition of agonist-stimulated chloride secretion (iii) ST/La or BT restoration of Cl(-) secretion was blocked by inhibitors of p38 MAPK, ERK1, 2, and PI3K (iv) ST/La pretreatment reversed the IFN-γ-induced downregulation of the cystic fibrosis transmembrane conductance regulator (CFTR) and the NKCC1 cotransporter (v) The effects of ST/La or BT on TER and permeability were potentiated by a Janus kinase (JAK) inhibitor but not by p38, ERK1, 2, or PI3K inhibition (vi) Reduced activation of suppressor of cytokine signaling (SOCS)3 and STAT1,3 was seen only in probiotic-treated epithelial cells exposed to cytokines
(i) LcS improved chronic ileitis in SAMP1/Yit mice (ii) Lcs improved murine chronic colitis, and this was associated with decreased IL-6 production by large intestinal lamina propria mononuclear cells ( LI-LPMCs) and downregulation of proinflammatory cytokines such as IL-6 and IFN-γ production in LPMC (iii) IL-6 release in LPS-activated LI-LPMC, RAW264.7, and ulcerative colitis-peripheral blood mononuclear cells (UC-PBMCs) was inhibited by LcS-derived polysaccharide-peptidoglycan complex (PSPG) (iv) In lipopolysaccharide- (LPS-) stimulated LI-LPMC and RAW264.7 cells, LcS inhibited the production of IL-6; other strains of Lactobacillus did not (v) Nuclear translocation of NF-κB was downregulated by LcS
(i) After EHEC O157:H7 infection, STAT-1 activation was reduced compared to uninfected cells (ii) Preincubation with L. helveticus R0052 (but not boiled L. helveticus R0052, an equal concentration of viable Lr R0011, or surface-layer proteins) followed by EHEC infection abrogated disruption of IFN-γ-STAT-1 signaling
(i) After Salmonella challenge, S. cerevisiae 905 inhibited weight loss and increased survival rate (ii) Levels of proinflammatory cytokines were decreased, and activation of mitogen-activated protein kinases (p38 and JNK, but not ERK1/2), NF-κB, and AP-1 was modulated by S. cerevisiae 905
(i) Probiotics resulted in downregulation of CXCL9, CXCL10, CCL5, T-cell activation and IRGM (ii) Probiotic treatment decreased the number of CCL5+ CD3+ double-positive T cells consistent with reduction in integrins and upregulated galectin2 (iii) Lipid- and PPAR-signaling-associated genes were also upregulated (iv) Altered microbial diversity was noted in probiotic-treated mice (v) Inflammation in IL10-KO mice showed differential regulation of various signaling pathways( inflammatory, nuclear receptor, lipid, and xenobiotic)
(i) La (ii) L. gasseri (iii) L. amylovorus (iv) L. gallinarum (v) L. johnsonii
(i) CaCo-2
(i) Exposure to bacteria-free supernatants of La cultured in chemically defined media (CDM) with 110 mM fructose increased glucose accumulation; exposure to a suspension of the bacteria had no effect (ii) Heat-denaturing the supernatant diminished the increase in glucose accumulation (iii) Supernatants prepared with anaerobic culture of L. gasseri, L. amylovorus, L. gallinarum, and L. johnsonii in the CDM with fructose increased glucose accumulation
(i) LGG induced ROS generation in intestinal epithelia in vitro and in vivo (ii) Increased glutathione (GSH) oxidation and cullin-1 deneddylation was seen in the intestines of mice fed LGG, showing local ROS generation and the resultant Ubc12 inactivation (iii) Prefeeding LGG prevented TNF-α-induced activation of intestinal NF-κB
