Brucine alleviates fibroblast-like synoviocytes dysfunction and inflammation by regulating YY1 during rheumatoid arthritis.

Brucine is a weak alkaline indole alkaloid with wide pharmacological activities and has been identified to protect against rheumatoid arthritis (RA) process. Circular RNAs (circRNAs) are also reported to be involved in the pathogenesis of RA. Here, we aimed to probe the role and mechanism of Brucine and circ_0139658 in RA progression. The fibroblast-like synoviocytes of RA (RA-FLSs) were isolated for functional analysis. Cell proliferation, apoptosis, invasion, migration, as well as inflammatory response were evaluated by CCK-8 assay, EdU assay, flow cytometry, transwell assay, and ELISA analysis, respectively. qRT-PCR and western blotting analyses were utilized to measure the levels of genes and proteins. The binding between miR-653-5p and circ_0139658 or Yin Yang 1 (YY1), was verified using dual-luciferase reporter and RNA pull-down assays. Brucine suppressed the proliferation, migration, and invasion of RA-FLSs, and alleviated inflammation by reducing the release of pro-inflammatory factors and macrophage M1 polarization. RA-FLSs showed increased circ_0139658 and YY1 levels and decreased miR-653-5p levels. Circ_0139658 is directly bound to miR-653-5p to regulate YY1 expression. Brucine treatment suppressed circ_0139658 and YY1 expression but increased YY1 expression in RA-FLSs. Functionally, circ_0139658 overexpression reversed the suppressing effects of Brucine on RA-FLS dysfunction and inflammation. Moreover, circ_0139658 silencing alleviated the dysfunction and inflammation in RA-FLSs, which were reverted by YY1 overexpression. Brucine suppressed the proliferation, migration, invasion, and inflammation in RA-FLSs by decreasing YY1 via circ_0139658/miR-653-5p axis.

Cynaroside improved depressive-like behavior in CUMS mice by suppressing microglial inflammation and ferroptosis.

Depression is a common mental health disorder, and in recent years, the incidence of various forms of depression has been on the rise. Most medications for depression are highly dependency-inducing and can lead to relapse upon discontinuation. Therefore, novel treatment modalities and therapeutic targets are urgently required. Traditional Chinese medicine (TCM) offers advantages in the treatment of depression owing to its multi-target, multi-dimensional approach that addresses the root cause of depression by regulating organ functions and balancing Yin and Yang, with minimal side effects. Cynaroside (CNS), an extract from the traditional Chinese herb honeysuckle, is a flavonoid compound with antioxidant properties. In this study, network pharmacology identified 44 potential targets of CNS associated with depression and several highly correlated inflammatory signaling pathways. CNS alleviated LPS-induced M1 polarization and the release of inflammatory factors in BV-2 cells. Transcriptomic analysis and validation revealed that CNS reduced inflammatory polarization, lipid peroxidation, and ferroptosis via the IRF1/SLC7A11/GPX4 signaling pathway. In vivo experiments showed that CNS treatment had effects similar to those of fluoxetine (FLX). It effectively ameliorated anxiety-, despair-, and anhedonia-like states in chronic unpredictable mild stress (CUMS)-induced mice and reduced microglial activation in the hippocampus. Thus, we conclude that CNS exerts its therapeutic effect on depression by inhibiting microglial cells from polarizing into the M1 phenotype and reducing inflammation and ferroptosis levels. This study provides further evidence that CNS is a potential antidepressant, offering new avenues for the treatment of depression.

Brain microvascular endothelial cell-derived exosomes transmitting circ_0000495 promote microglial M1-polarization and endothelial cell injury under hypoxia condition.

Human brain microvascular endothelial cells (HBMVECs) and microglia play critical roles in regulating cerebral homeostasis during ischemic stroke. However, the role of HBMVECs-derived exosomes in microglia polarization after stroke remains unknown. We isolated exosomes (Exos) from oxygen glucose deprivation (OGD)-exposed HBMVECs, before added them into microglia. Microglia polarization markers were tested using RT-qPCR or flow cytometry. Inflammatory cytokines were measured with ELISA. Endothelial cell damage was assessed by cell viability, apoptosis, apoptosis-related proteins, oxidative stress, and angiogenic activity using CCK-8, flow cytometry, western blot, ELISA, and endothelial tube formation assay, respectively. We also established middle cerebral artery occlusion (MCAO) mice model to examine the function of circ_0000495 on stroke in vivo. Our study found that HBMVECs-Exos reduced M2 markers (IL-10, CD163, and CD206), increased M1 markers (TNF-α, IL-1ß, and IL-12), CD86-positive cells, and inflammatory cytokines (TNF-α and IL-1ß), indicating the promotion of microglial M1-polarization. Microglial M1-polarization induced by HBMVECs-Exos reduced viability and promoted apoptosis and oxidative stress, revealing the aggravation of endothelial cell damage. However, circ_0000495 silencing inhibited HBMVECs-Exos-induced alterations. Mechanistically, circ_0000495 adsorbed miR-579-3p to upregulate toll-like receptor 4 (TLR4) in microglia; miR-579-3p suppressed HBMVECs-Exos-induced alterations via declining TLR4; furthermore, Yin Yang 1 (YY1) transcriptionally activated circ_0000495 in HBMVECs. Importantly, circ_0000495 aggravated ischemic brain injury in vivo via activating TLR4/nuclear factor-κB (NF-κB) pathway. Collectively, OGD-treated HBMVECs-Exos transmitted circ_0000495 to regulate miR-579-3p/TLR4/NF-κB axis in microglia, thereby facilitating microglial M1-polarization and endothelial cell damage.

Polyporus umbellatus polysaccharide iron-based nanocomposite for synergistic M1 polarization of TAMs and combinational anti-breast cancer therapy.

M1 polarization of tumor-associated macrophages (TAMs) is a promising approach to breaking through therapeutic barriers imposed by the immunosuppressive tumor microenvironment (TME). As a clinically-used immunopotentiator for cancer patients after chemotherapies; however, the immunomodulatory mechanism and potential of polyporus polysaccharide (PPS) remains unclear. Here, we present mannose-decorated PPS-loaded superparamagnetic iron-based nanocomposites (Man/PPS-SPIONs) for synergistic M1 polarization of TAMs and consequent combinational anti-breast cancer therapy. Once internalized by M2-like TAMs, PPS released from Man/PPS-SPIONs induces the M1 polarization via IFN-γ secretion and downstream NF-κB pathway activating. The SPIONs within the nanocomposites mediate a Fenton reaction, producing OH· and activating the subsequent NF-κB/MAPK pathway, further facilitating the M1 polarization. The Man/PPS-SPIONs thereby establish a positive feedback loop of M1 polarization driven by the "IFN-γ-Fenton-NF-κB/MAPK" multi-pathway, leading to a series of anti-tumoral immunologic responses in the TME and holding promising potential in combinational anticancer therapies. Our study offers a new strategy to amplify TME engineering by combinational natural carbohydrate polymers and iron-based materials.

Inhibition of DRP1-dependent mitochondrial fission by Mdivi-1 alleviates atherosclerosis through the modulation of M1 polarization.

BACKGROUND: Inflammation and immune dysfunction with classically activated macrophages(M1) infiltration are important mechanisms in the progression of atherosclerosis (AS). Dynamin-related protein 1 (DRP1)-dependent mitochondrial fission is a novel target for alleviating inflammatory diseases. This study aimed to investigate the effects of DRP1 inhibitor Mdivi-1 on AS. METHODS: ApoE-/- mice were fed with a high-fat diet supplemented with or without Mdivi-1. RAW264.7 cells were stimulated by ox-LDL, pretreated with or without MCC950, Mito-TEMPO, or Mdivi-1. The burden of plaques and foam cell formation were determined using ORO staining. The blood lipid profles and inflammatory cytokines in serum were detected by commercial kits and ELISA, respectively. The mRNA expression of macrophage polarization markers, activation of NLRP3 and the phosphorylation state of DRP1 were detected. Mitochondrial reactive oxygen species (mito-ROS), mitochondrial staining, ATP level and mitochondrial membrane potential were detected by mito-SOX, MitoTracker, ATP determination kit and JC-1 staining, respectively. RESULTS: In vivo, Mdivi-1 reduced the plaque areas, M1 polarization, NLRP3 activation and DRP1 phosphorylation at Ser616. In vitro, oxidized low-density lipoprotein (ox-LDL) triggered M1 polarization, NLRP3 activation and abnormal accumulation of mito-ROS. MCC950 and Mito-TEMPO suppressed M1 polarization mediated foam cell formation. Mito-TEMPO significantly inhibited NLRP3 activation. In addition, Mdivi-1 reduced foam cells by inhibiting M1 polarization. The possible mechanisms responsible for the anti-atherosclerotic effects of Mdivi-1 on reducing M1 polarization were associated with suppressing mito-ROS/NLRP3 pathway by inhibiting DRP1 mediated mitochondrial fission. In vitro, similar results were observed by DRP1 knockdown. CONCLUSION: Inhibition of DRP1-dependent mitochondrial fission by Mdivi-1 alleviated atherogenesis via suppressing mito-ROS/NLRP3-mediated M1 polarization, indicating DRP1-dependent mitochondrial fission as a potential therapeutic target for AS.

Modified Xiaoyao San reverses lipopolysaccharide-induced depression-like behavior through suppressing microglia M1 polarization via enhancing autophagy involved in PI3K/Akt/mTOR pathway in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Modified Xiaoyao San (MXYS), a clinical empirical modified formula based on famous traditional Chinese herbal prescription Xiaoyao San, according to the "yu syndrome" theory of traditional Chinese medicine. MXYS has been shown to be an excellent effective therapy for depression patients in clinic, but the antidepressant mechanisms remain unclear. AIM OF THE STUDY: A growing body of evidence indicates the microglia autophagy and M1 polarized microglia (proinflammatory phenotype)-mediated neuroinflammation act critical roles in the pathogenesis of depression. This study aimed to investigate whether MXYS exerts antidepressant efficacy through inhibition of M1 polarized microglia-mediated neuroinflammation and modulation of autophagy involved in PI3K/Akt/mTOR pathway. MATERIALS AND METHODS: In present research, the lipopolysaccharide (LPS)-induced depressive mice and LPS-stimulated N9 microglia cell line were utilized. Behavioral tests (sucrose preference, tail suspension and open field tests) were carried out to evaluate the antidepressant effect of MXYS. The neuronal damage was measured by Nissl's staining in LPS-treated mice. The proinflammatory cytokine levels, the autophagic markers, microglia M1 polarization as well as the PI3K/Akt/mTOR pathway related proteins of MXYS treatment were analyzed by ELISA kits, Western blot and immunofluorescence staining in vivo and vitro. Finally, the influence of autophagy antagonist (3-MA) on the protective effect of MXYS-containing serum in the LPS-stimulated N9 microglia was investigated. RESULTS: Treatment of LPS-induced depressive mice with MXYS significantly reversed depression-like behaviors, accompanied by reduction of proinflammatory cytokine levels (TNF-α, IL-1ß) and amelioration of neuronal damage in prefrontal cortex. MXYS suppressed microglia M1 polarization and promoted autophagy in prefrontal cortex and LPS-stimulated N9 cells. Importantly, the remarkable inhibitory effect of the MXYS-medicated serum on microglia M1 polarization was blocked by autophagy antagonist 3-MA in LPS-stimulated N9 cells. Meanwhile, the MXYS treatment exhibited an excellent inhibition effect of PI3K/Akt/mTOR pathway in vivo and vitro. CONCLUSION: Our research suggests that the antidepressant effect of MXYS in LPS-induced depressive mice may be related to alleviate neuroinflammation through suppression of microglia M1 polarization via enhancing autophagy involved in inactivation of the PI3K/Akt/mTOR pathway.

ROS mediated pyroptosis-M1 polarization crosstalk participates in inflammation of chicken liver induced by bisphenol A and selenium deficiency.

The earth's natural environmental factors and man-made industrial pollution often lead to the co-occurrence of environmental pathogenic factors and malnutrition. Bisphenol A (BPA) is a serious environmental endocrine disruptor, and its exposure can cause liver tissue damage. Selenium (Se) deficiency is a worldwide problem that afflicts thousands of people, and Se deficiency can cause M1/M2 imbalance. In addition, the crosstalk between hepatocyte and immune cell is closely related to the occurrence of hepatitis. Therefore, this study found for the first time that the combined exposure of BPA and Se deficiency caused liver pyroptosis and M1 polarization through ROS, and the crosstalk between pyroptosis and M1 polarization aggravated liver inflammation in chicken. In this study, the BPA or/and Se deficiency chicken liver, single and co-culture model of LMH and HD11 cells were established. The results displayed that BPA or Se deficiency induced liver inflammation accompanied by pyroptosis and M1 polarization through oxidative stress, and increased expressions of chemokines (CCL4, CCL17, CCL19, and MIF) and inflammatory factors (IL-1ß and TNF-α). The vitro experiments further verified the above changes and showed that LMH pyroptosis promoted M1 polarization of HD11 cells, and vice versa. NAC counteracted pyroptosis and M1 polarization caused by BPA and low-Se, reducing the release of inflammatory factors. In brief, BPA and Se deficiency treatment can exacerbate liver inflammation by increasing oxidative stress to induce pyroptosis and M1 polarization.

Shikonin alleviates collagen-induced arthritis mice by inhibiting M1 macrophage polarization.

OBJECTIVE: To investigate the effects of shikonin (SKN) on M1 and M2 polarization of macrophages both and . METHODS: Collagen-induced arthritis (CIA) in male DBA/1 mice were treated with a dose of 4 mg/kg/day of SKN for 23 d ( = 6/group). The histopathology of inflamed joints in CIA mice was evaluated to test the anti-arthritic effect of SKN. M1/M2 polarization of macrophages induced by lipopolysaccharide (LPS) and interferon (IFN)-γ or interleukin (IL)-4 and IL-13, were used to assess the effect of SKN (0.05, 0.1, and 0.2 µM). The effect of SKN on the protein expression of nitric oxide synthase, arginase, CD68, and CD206 was evaluated using western blot analysis. RESULTS: The results of this study revealed that SKN delayed the arthritis feet symptom score, reduced the incidence rate of arthritis, and relieved the inflammation of joints in CIA mice. SKN inhibited M1 macrophage polarization but did not affect M2 macrophage polarization in the joints of CIA mice. Moreover, SKN inhibited M1 polarization induced by LPS and IFN-γ, but did not affect M2 polarization induced by IL-4 and IL-13. CONCLUSION: These findings suggest that SKN alleviated CIA through inhibiting M1 macrophage polarization and has great potential as a new drug for RA treatment.

Tubuloside B, isolated from Cistanche tubulosa, a promising agent against M1 macrophage activation via synergistically targeting Mob1 and ERK1/2.

Targeting macrophage M1 polarization is a promising strategy with fewer detrimental effects in COVID-19 curation. Phenylethanoid glycosides (PhGs) of Cistanche tubulosa are a botanical drug to possess various anti-inflammation-related functions, such as immunomodulating, hepatoprotective or neuroprotective functions, whereas their anti-inflammatory activity is rarely understood. A search into their anti-inflammatory characteristics led to the isolation of 49 PhGs along with 15 new PhGs. Their inhibitory effects against M1 polarization induced by LPS plus IFN-γ were explored in RAW264.7 macrophages. Of these PhGs, tubuloside B (Tub B) exerted substantial NO scavenging effect both in chemical- and cell-based assays, and it inhibited massive production of cytokines and chemokines. Tub B decreased ERK1/2 phosphorylation via direct binding and inhibited the MAPK signaling pathway. Tub B also directly binded to Mob1 protein, thereby increased the stability and level of Mob1 protein by inhibiting ubiquitinated degradation. Mob1 was pivotal for the anti-inflammatory activity of Tub B, and it acted independently of the canonical Hippo-YAP pathway. Moreover, ERK1/2 and Mob1 also had a synergic effect on modulating the inflammatory response. Finally, these effects of Tub B were verified in mice with LPS-induced systemic inflammatory response syndrome. Taken together, these results indicated that Tub B acted as a promising agent against M1 macrophage activation by synergistically targeting ERK1/2 and Mob1, and that it may potentially be a drug candidate to prevent/treat inflammatory diseases, especially in COVID-19.

[Effect of Xiaoyao San on OVX combined with CUS anxiety and depression model rats based on hippocampal microglia M1 polarization].

To investigate the anti-anxiety and anti-depression effect and mechanism of Xiaoyao San on rats with ovariectomy(OVX) combined with chronic unpredictable stress(CUS) model. The model of perimenopausal depression was established by OVX and CUS; the level of anxiety and depression was evaluated by open field test; the levels of interleukin-1ß(IL-1ß) and interleukin-6(IL-6) mRNA in rat hippocampus were detected by Real-time qPCR; double staining immunofluorescence was used to detect the expression of ionized calcium binding adaptor molecule-1(Iba-1) and inducible nitric oxide synthase(iNOS) in microglia of rat dentate gyrus(DG); Western blot was used to detect the protein expression of Iba-1 and iNOS of microglia in DG region of rat hippocampus. The results showed that in the model group, the number of horizontal movement, the number of vertical movement and central residence time were significantly reduced, and the grooming time was significantly prolonged(P<0.05 or P<0.01); the levels of IL-1ß and IL-6 in hippocampus increased significantly(P<0.05); the number of positive cells with co-expression of Iba-1/iNOS of microglia cells in DG region of hippocampus increased; the expression levels of Iba-1 and iNOS protein in hippocampus were significantly increased(P<0.01), suggesting that microglia in DG region of hippocampus was activated and polarized toward M1 type in rats with stress. The high dose group of Xiaoyao San significantly increased the number of horizontal movement, vertical movement and central residence time of model rats(P<0.05 or P<0.01), and significantly down-regulated the levels of inflammatory factors IL-1ß and IL-6(P<0.05). Meanwhile, it reversed the activation and quantity change of microglia in hippocampus. Although the Xiaoyao San low dose group had no significant effect on the behavioral indicators in the open field test and the levels of IL-1ß and IL-6, they all showed a trend of improvement. Low dose Xiaoyao San significantly decreased iNOS protein level(P<0.05), and high dose Xiaoyao San significantly down-regulated the protein expression of Iba-1 and iNOS in hippocampus microglia(P<0.05 or P<0.01). In conclusion, Xiaoyao San can improve anxiety and depression-like behavior in OVX combined with CUS model rats, and its mechanism is related to its anti-inflammatory effect by inhibiting M1 polarization of hippocampal microglia.

[Effect of electroacupuncture on pulmonary function and M1 polarization of alveolar macrophages in rats with chronic obstructive pulmonary disease].

OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Zusanli" (ST36) and "Feishu" (BL13) on M1 polarization of alveolar macrophages (AM) in rats with chronic obstructive pulmonary disease(COPD), so as to explore its anti-inflammatory mechanism underlying improvement of COPD. METHODS: Forty SD rats were randomly divided into normal and normal＋EA, COPD model and COPD＋EA groups (n＝10 in each group). The COPD model was established by simple fumigation. EA (4 Hz/20 Hz, 1 to 2 mA) was applied to bilateral ST36 and BL13 for 30 min, once every other day for 2 weeks. The pulmonary function including the forced vital capacity (FVC), forced expiratory volume in 0.1 and 0.3 s (FEV0.1, FEV0.3, FEV0.1/FVC, and FEV0.3/FVC) was detected by using a small animal respiratory function detector. Histopathological changes of the lung were displayed by H．E. staining. The contents of tumor necrosis factor-α (TNF-α) and induced nitric oxide synthase (iNOS) in the broncho alveolar lavage fluid (BALF) were assayed by ELISA. The expression of M1 polarization markers (CD86，iNOS), myeloid differentiation factor 88(MyD88) and nuclear factor-κB p65(NF-κB p65) in AM were detected by Western blot and quantitative real time-PCR, separately. The distribution and expression of CD86 in the lung were detected by immunohistochemistry. RESULTS: Following modeling, the levels of FVC, FEV0.1, FEV0.3, ratios of FVE0.1/FVC and FEV0.3/FVC were significantly decreased (P<0.01), while the contents of TNF-α and iNOS in the BALF, expression of CD86, iNOS, MyD88 and NF-κB p65 mRNAs and proteins in the AM, and CD86 immunoactivity in the lung were significantly increased in the model group relevant to the normal group (P<0.01). After the intervention, the decrease of the lung function and increase of the above-mentioned genes and proteins were all reversed in the COPD＋EA group (P<0.05, P<0.01). CONCLUSION: EA at ST36 and BL13 can reduce pulmonary inflammation in COPD rats, which may be related to its function in inhibiting M1 polarization of AM via down-regulating MyD88/NF-κB p65 signaling pathway.

Effect of electroacupuncture on pulmonary function and M1 polarization of alveolar macrophages in rats with chronic obstructive pulmonary disease / 针刺研究

OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Zusanli" (ST36) and "Feishu" (BL13) on M1 polarization of alveolar macrophages (AM) in rats with chronic obstructive pulmonary disease(COPD), so as to explore its anti-inflammatory mechanism underlying improvement of COPD. METHODS: Forty SD rats were randomly divided into normal and normal＋EA, COPD model and COPD＋EA groups (n＝10 in each group). The COPD model was established by simple fumigation. EA (4 Hz/20 Hz, 1 to 2 mA) was applied to bilateral ST36 and BL13 for 30 min, once every other day for 2 weeks. The pulmonary function including the forced vital capacity (FVC), forced expiratory volume in 0.1 and 0.3 s (FEV0.1, FEV0.3, FEV0.1/FVC, and FEV0.3/FVC) was detected by using a small animal respiratory function detector. Histopathological changes of the lung were displayed by H．E. staining. The contents of tumor necrosis factor-α (TNF-α) and induced nitric oxide synthase (iNOS) in the broncho alveolar lavage fluid (BALF) were assayed by ELISA. The expression of M1 polarization markers (CD86，iNOS), myeloid differentiation factor 88(MyD88) and nuclear factor-κB p65(NF-κB p65) in AM were detected by Western blot and quantitative real time-PCR, separately. The distribution and expression of CD86 in the lung were detected by immunohistochemistry. RESULTS: Following modeling, the levels of FVC, FEV0.1, FEV0.3, ratios of FVE0.1/FVC and FEV0.3/FVC were significantly decreased (P<0.01), while the contents of TNF-α and iNOS in the BALF, expression of CD86, iNOS, MyD88 and NF-κB p65 mRNAs and proteins in the AM, and CD86 immunoactivity in the lung were significantly increased in the model group relevant to the normal group (P<0.01). After the intervention, the decrease of the lung function and increase of the above-mentioned genes and proteins were all reversed in the COPD＋EA group (P<0.05, P<0.01). CONCLUSION: EA at ST36 and BL13 can reduce pulmonary inflammation in COPD rats, which may be related to its function in inhibiting M1 polarization of AM via down-regulating MyD88/NF-κB p65 signaling pathway.

Mechanisms of the prevention and inhibition of the progression and development of non-alcoholic steatohepatitis by genetic and pharmacological decoy receptor 3 supplementation.

AIMS: Treatment of non-alcoholic steatohepatitis (NASH) is difficult due to the absence of a proven treatment and its comprehensive mechanisms. In the NASH animal model, upregulated hepatic inflammation and oxidative stress, with the resultant M1 polarization of macrophages as well as imbalanced adipocytokines, all accelerate NASH progression. As a member of the tumor necrosis factor receptor superfamily, decoy receptor 3 (DcR3) not only neutralizes the death ligands, but also performs immune modulations. In this study, we aimed to investigate the possible non-decoy effects of DcR3 on diet-induced NASH mice. METHODS: Methionine- and choline-deficient (MCD) diet feeding for 9 weeks was applied to induce NASH in BALB/c mice. Decoy receptor 3 heterozygous transgenesis or pharmacological pretreatment with DcR3a for 1 month were designed as interventions. Intrahepatic inflammatory status as well as macrophage polarization, oxidative stress, and steatosis as well as lipogenic gene expression and fibrotic status were analyzed. Additionally, acute effects of DcR3a on HepG2 cells, Hep3B cells, and primary mouse hepatocytes in various MCD medium-stimulated changes were also evaluated. RESULTS: Both DcR3 genetic and pharmacologic supplement significantly reduced MCD diet-induced hepatic M1 polarization. In addition, DcR3 supplement attenuated MCD diet-increased hepatic inflammation, oxidative stress, adipocytokine imbalance, steatosis, and fibrogenesis. Moreover, acute DcR3a incubation in HepG2 cells, Hep3B cells, and mouse hepatocytes could normalize the expression of genes related to lipid oxidation along with inflammation and oxidative stress. CONCLUSION: The ability of DcR3 to attenuate hepatic steatosis and inflammation through its non-decoy effects of immune modulation and oxidative stress attenuation makes it a potential treatment for NASH.

Dietary pectin-derived acidic oligosaccharides improve the pulmonary bacterial clearance of Pseudomonas aeruginosa lung infection in mice by modulating intestinal microbiota and immunity.

BACKGROUND: A predominantly T-helper type 2 (Th2) immune response is critical in the prognosis of pulmonary Pseudomonas aeruginosa infection. But the mucosal and systemic immune responses can be influenced by the intestinal microbiota. METHODS: We assessed the effect of microbiota compositional changes induced by a diet enriched in 5% acidic oligosaccharides derived from pectin (pAOS) on the immune response and outcome of chronic pulmonary P. aeruginosa infection in mice. RESULTS: pAOS promoted Th1 polarization by increasing interferon γ release, upregulating t-bet gene expression, decreasing interleukin 4 secretion, and downregulating gata3 gene expression. pAOS also sustained the release of keratinocyte chemoattractant, recruited polynuclear leukocytes and macrophages, stimulated M1 macrophage activation and interleukin 10 release, and decreased tumor necrosis factor α release in the lung. These effects led to increased bacterial clearance after the first and second P. aeruginosa infections. pAOS modified the intestinal microbiota by stimulating the growth of species involved in immunity development, such as Bifidobacterium species, Sutturella wadsworthia, and Clostridium cluster XIVa organisms, and at the same time increased the production of butyrate and propionate. CONCLUSION: These results suggest that pAOS may have beneficial effects by limiting the number and severity of pulmonary exacerbations in patients chronically infected with P. aeruginosa, such as individuals with cystic fibrosis.