Periodontitis salivary microbiota exacerbates colitis-induced anxiety-like behavior via gut microbiota.

The gut-brain axis is a bidirectional communication system between the gut and central nervous system. Many host-related factors can affect gut microbiota, including oral bacteria, making the brain a vulnerable target via the gut-brain axis. Saliva contains a large number of oral bacteria, and periodontitis, a common oral disease, can change the composition of salivary microbiota. However, the role and mechanism of periodontitis salivary microbiota (PSM) on the gut-brain axis remain unclear. Herein, we investigated the nature and mechanisms of this relationship using the mice with dextran sulfate sodium salt (DSS)-induced anxiety-like behavior. Compared with healthy salivary microbiota, PSM worsened anxiety-like behavior; it significantly reduced the number of normal neurons and activated microglia in DSS mice. Antibiotic treatment eliminated the effect of PSM on anxiety-like behavior, and transplantation of fecal microbiota from PSM-gavaged mice exacerbated anxiety-like behavior. These observations indicated that the anxiety-exacerbating effect of PSM was dependent on the gut microbiota. Moreover, the PSM effect on anxiety-like behavior was not present in non-DSS mice, indicating that DSS treatment was a prerequisite for PSM to exacerbate anxiety. Mechanistically, PSM altered the histidine metabolism in both gut and brain metabolomics. Supplementation of histidine-related metabolites had a similar anxiety-exacerbating effect as that of PSM, suggesting that histidine metabolism may be a critical pathway in this process. Our results demonstrate that PSM can exacerbate colitis-induced anxiety-like behavior by directly affecting the host gut microbiota, emphasizing the importance of oral diseases in the gut-brain axis.

A fluorescent controllable supramolecular crosslinked polymer constructed by complementary metal coordination interaction.

In this work, two different monomers M1 and M2 were designed and synthesized. M1 + M2 + Zn(OTf)2 could self-assemble to form a supramolecular crosslinked polymer (SCP) based on complementary terpyridine-based metal coordination interaction. The self-assembly of M1 + M2 + Zn(OTf)2 was studied by various techniques, such as 1H NMR, 2D COSY NMR, 2D NOESY NMR, UV-Vis analysis, fluorescence analysis, viscosity measurement, and TEM. The experimental result indicated that the molecular weight of the SCP depended on the initial monomer concentration. The SCP could further turn into supramolecular polymer gel at high concentrations, and the reversible gel-sol transformation could be realized by heating/cooling. Moreover, the fluorescence quenching/enhancement of the SCP could be adjusted by adding base/acid.

Meta-analysis of PD-(L)1 inhibitor plus chemotherapy versus chemotherapy as first-line treatment in extensive-stage small-cell lung cancer.

BACKGROUND: Immunotherapy targeting programmed death 1(PD-1) and its ligand (PD-L1) has been successful in extensive-stage small cell lung cancer (ES-SCLC). However, first-line PD-(L)1 inhibitor combined with chemotherapy (immunochemotherapy) versus chemotherapy has not been well studied. METHODS: Randomized controlled trials had been searched from PubMed, Embase, and the Cochrane Library until December 29, 2022. Randomized effect consistency models were applied for estimating the pooled hazard ratios (HRs) and odds ratios (ORs). Study outcomes included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), 6-month and 1-year disease progression rate, 1-year and 2-year mortality rate, and Grade ≥3 adverse events (AEs). RESULTS: Six eligible trials with 2600 ES-SCLC patients were included. Compared with chemotherapy, immunochemotherapy significantly improved ORR (OR 1.32, 95% CI 1.07-1.63; p = 0.01), PFS (HR 0.68, 95% CI 0.58-0.78; p < 0.001), and OS (HR 0.72, 96% CI 0.66-0.78, p < 0.001) without increasing Grade ≥3 AEs (p = 0.07). Compared with patients with chemotherapy, the 6-month disease progression rate was reduced by 0.39 (p = 0.01) and the 1-year disease progression rate was reduced by 0.75 (p < 0.001), the 1-year mortality rate was reduced by 0.33 (p < 0.001) and the 2-year mortality rate was reduced by 0.50 (p < 0.001) respectively in patients with immunochemotherapy. However, patients with brain metastases failed to prolong PFS and OS from immunochemotherapy (p > 0.05). CONCLUSION: Compared with chemotherapy, PD-(L)1 inhibitor plus chemotherapy as first-line treatment could improve the efficacy and prognosis of ES-SCLC patients without more serious side effects. However, more research is needed to validate these results.

Knockdown of Bach1 protects periodontal bone regeneration from inflammatory damage.

Periodontal bone regeneration is a major challenge in the treatment of periodontitis. However, the regenerative vitality of periodontal ligament cells (PDLCs) declines in the environment of periodontitis and accompanying oxidative stress. This study aimed to investigate the functional mechanisms of Bach1, a transcriptional suppressor involved in oxidative stress response, and its regulation of PDLC osteogenesis under inflammatory conditions. We observed a significant elevation in Bach1 expression in periodontal tissues with periodontitis and PDLCs under inflammatory conditions. Knockdown of Bach1 alleviated the inflammation-induced oxidative stress level and partly offset the inhibitory effect of inflammatory conditions on osteogenesis, as well as the expression of osteogenic genes BMP6, OPG and RUNX2. Similarly, knockdown of Bach1 protects PDLCs from inflammatory damage to periodontal bone regeneration in vivo. Furthermore, we found that Bach1 could bind to the histone methyltransferase EZH2, and the binding increased under inflammatory conditions. Bach1 enhanced the ability of EZH2 to catalyse H3K27me3 on the promoter region of RUNX2 and BMP6, thus repressing the expression of osteoblastic genes. In conclusion, our study revealed that knockdown of Bach1 effectively rescued the osteogenesis and oxidative stress of PDLCs with inflammation. Bach1 could be a promising target for enhancing periodontal tissue regeneration under periodontitis conditions.

Periodontitis salivary microbiota exacerbates nonalcoholic fatty liver disease in high-fat diet-induced obese mice.

Periodontitis may aggravate the development of nonalcoholic fatty liver disease (NAFLD); however, the precise mechanism is unknown. In this study, salivary microbiota collected from patients with periodontitis was transferred intragastrically to obese mice induced by high-fat diet. Microbiomics and metabolomics analysis were performed to assess the influence of periodontitis salivary microbiota on gut microbiome and liver metabolism. Periodontitis salivary microbiota altered gut microbiota composition and exacerbated intestinal barrier dysfunction in obese mice. Subsequently, the bacterial lipopolysaccharide transported to liver may activate the toll-like receptor 4 signaling and cause the release of pro-inflammatory factors. Moreover, the tryptophan-kynurenine-AhR signal axis was upregulated in liver, which may be related to aggravated hepatic steatosis and glucolipid metabolism dysregulation during NAFLD development. This study indicated that in the context of obesity, periodontitis salivary microbiota may aggravate the pathological progression of NAFLD, in which the tryptophan-AhR pathway may play a key role.

Prognostic value of esophageal cancer immune prognostic index in advanced esophageal squamous cell carcinoma patients with anti-programmed cell death-1 therapy.

BACKGROUND: This study aimed to determine whether the immune prognostic index (ECIPI), based on hemoglobin (Hb) and neutrophil-to-lymphocyte ratio (NLR), could predict the prognosis in patients with advanced esophageal squamous cell carcinoma (ESCC) receiving programmed cell death-1 (PD-1) inhibitor treatment. METHODS: Advanced ESCC patients who had been treated with PD-1 inhibitors from Jan 2016 to Oct 2021 were included. Kaplan-Meier method and Cox proportional hazards regression were used to analyze progression-free survival (PFS) and overall survival (OS). The overall response rate (ORR) was the percentage of complete and partial responses. Univariate and multivariate analyses were used for estimating hazard ratio (HR) and 95% confidence interval (CI). Patients were grouped by ECIPI (good: Hb > 105 g/L and NLR ≤ 4.3; intermediate: Hb ≤ 105 g/L and NLR ≤ 4.3, or Hb > 105 g/L and NLR < 4.3; poor: Hb ≤ 105 g/L and NLR > 4.3). Variables for the multivariate model were selected if the p-value was below 0.05 in the univariate analysis. All statistical comparisons were two-way, and a p-value below 0.05 was set as statistical significance. RESULTS: Totally, of 123 ESCC patients with stage III or IV were included in the study. Efficacy evaluation showed that patients with pretreatment ECIPI good had the best ORR compared with those with ECIPI intermediate and ECIPI poor (53% vs. 22% vs. 8%, p < 0.01). Multivariate analysis showed that ECIPI was an independent influential factor for PFS (p = 0.004) and OS (p < 0.001). Kaplan-Meier curves demonstrated that patients with ECIPI good had the longest PFS (median: 11.6 vs. 3.5 vs. 1.7 months, p < 0.0001) and OS (median: 23.6 vs. 16.7 vs. 4.0 months, p < 0.0001) compared with those with ECIPI intermediate and ECIPI poor. Subgroup analysis indicated that ECIPI good was associated with improved PFS and OS in patients with ECOG 0-1, PD-1 inhibitor plus chemotherapy, first-line treatment, and smoke (all p < 0.05). CONCLUSIONS: Pretreatment ECIPI was associated with the prognosis in advanced ESCC patients with anti-PD-1 therapy, suggesting that ECIPI may be a useful tool to identify patients likely sensitive to PD-1 inhibitors.

Periodontitis-related salivary microbiota aggravates Alzheimer's disease via gut-brain axis crosstalk.

The oral cavity is the initial chamber of digestive tract; the saliva swallowed daily contains an estimated 1.5 × 1012 oral bacteria. Increasing evidence indicates that periodontal pathogens and subsequent inflammatory responses to them contribute to the pathogenesis of Alzheimer's disease (AD). The intestine and central nervous system jointly engage in crosstalk; microbiota-mediated immunity significantly impacts AD via the gut-brain axis. However, the exact mechanism linking periodontitis to AD remains unclear. In this study, we explored the influence of periodontitis-related salivary microbiota on AD based on the gut-brain crosstalk in APPswe/PS1ΔE9 (PAP) transgenic mice. Saliva samples were collected from patients with periodontitis and healthy individuals. The salivary microbiota was gavaged into PAP mice for two months. Continuous gavage of periodontitis-related salivary microbiota in PAP mice impaired cognitive function and increased ß-amyloid accumulation and neuroinflammation. Moreover, these AD-related pathologies were consistent with gut microbial dysbiosis, intestinal pro-inflammatory responses, intestinal barrier impairment, and subsequent exacerbation of systemic inflammation, suggesting that the periodontitis-related salivary microbiota may aggravate AD pathogenesis through crosstalk of the gut-brain axis. In this study, we demonstrated that periodontitis might participate in the pathogenesis of AD by swallowing salivary microbiota, verifying the role of periodontitis in AD progression and providing a novel perspective on the etiology and intervention strategies of AD.

Pretreatment Neutrophil-to-Lymphocyte Ratio as a Prognostic Biomarker in Unresectable or Metastatic Esophageal Cancer Patients With Anti-PD-1 Therapy.

Background: The neutrophil-to-lymphocyte ratio (NLR) is an inflammatory index calculated by the absolute neutrophil count dividing the absolute lymphocyte count, and its prognostic role in esophageal cancer (EC) patients with anti-PD-1 therapy remains unclear. Methods: A total of 140 unresectable or metastatic EC patients receiving PD-1 inhibitor treatment were included from Jan 2016 to Mar 2020. Kaplan-Meier method and log-rank test were used for comparing overall survival (OS) and progression-free survival (PFS) between groups. Multivariate Cox analysis was performed to assess the prognostic value of NLR. Results: The cutoff value of NLR was set at 5, and the median follow-up time was 20.0 months. Patients with pretreatment NLR <5 had higher ORR (46.7% vs. 12.1%; p < 0.001) and DCR (85.0% vs. 69.7%; p = 0.047) than those with NLR ≥5. Kaplan-Meier curves showed that pretreatment NLR <5 was associated with longer PFS (median: 10.0 vs. 3.5 months, p < 0.0001) and OS (median: 22.3 vs. 4.9 months, p < 0.0001). Multivariate analysis demonstrated that pretreatment NLR ≥5 independently and significantly increased the risk of disease progression (hazard ratio (HR), 1.77 (95% confidence interval (CI), 1.12-2.82); p = 0.015) and death (HR, 4.01 (95% CI, 2.28-7.06); p < 0.001). Subgroup analysis showed that pretreatment NLR ≥5 was associated with poor efficacy and survival in most subsets. Conclusions: Our findings showed that pretreatment NLR was independently and significantly associated with the efficacy and prognosis of EC patients treated with PD-1 inhibitors. NLR could serve as a convenient and useful prognostic biomarker for EC patients with anti-PD-1 therapy.

First-line PD-1/PD-L1 inhibitors plus chemotherapy versus bevacizumab plus chemotherapy for advanced non-squamous non-small cell lung cancer: A Bayesian network meta-analysis of randomized controlled trials.

Chemotherapy in combination with immune checkpoint inhibitor (ICI) or bevacizumab has demonstrated a superior effect for non-squamous non-small cell lung cancer (NS-NSCLC). There are still few randomized controlled trials (RCTs) investigating the differences between ICI plus chemotherapy (ICI-chemotherapy) and bevacizumab plus chemotherapy (Bev-chemotherapy) in first-line treatment of NS-NSCLC. We identified RCTs in databases and conference abstracts presented at international conferences by Sep 1, 2021. Bayesian network meta-analysis was performed using randomized effect consistency model to estimate hazard ratio (HR) and odds ratio (OR). The outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and grade ≥ 3 treatment-related adverse events (TRAEs). Fifteen RCTs (17 articles) of 6561 advanced NS-NSCLC patients receiving ICI-chemotherapy, Bev-chemotherapy, or chemotherapy at first-line were eligible for analysis. NMA results showed that first-line ICI-chemotherapy prolonged OS (HR 0.79, 0.66-0.94) in patients with advanced NS-NSCLC compared with Bev-chemotherapy, while no differences were in PFS, ORR, and grade ≥ 3 TRAEs (p > 0.05). Ranking plots suggested that ICI-chemotherapy had the most probability to offer the best OS (probability 0.993), PFS (probability 0.658), and ORR (probability 0.565), and Bev-chemotherapy had the most risks of grade ≥ 3 TRAEs (probability 0.833). Therefore, our findings showed that first-line ICI-chemotherapy was associated with better OS than Bev-chemotherapy in patients with advanced NS-NSCLC, and more clinical trials are warranted to confirm these results.

Prognostic Value of the Pretreatment Lung Immune Prognostic Index in Advanced Small Cell Lung Cancer Patients Treated With First-Line PD-1/PD-L1 Inhibitors Plus Chemotherapy.

BACKGROUND: Lung immune prognostic index (LIPI) refers to a biomarker combining derived neutrophil-to-lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH). Its prognostic effect on advanced small cell lung cancer (SCLC) patients receiving programmed cell death 1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors plus chemotherapy as first-line treatment remains unclear. Our research investigated the relationship between pretreatment LIPI and the prognosis of patients receiving first-line PD-1/PD-L1 inhibitors plus chemotherapy. METHODS: Advanced SCLC patients receiving PD-1/PD-L1 inhibitors plus chemotherapy as first-line treatment from Jan 2015 to Oct 2020 were included. Based on the values of dNLR and LDH, the study population was divided into two groups: LIPI good and LIPI intermediate/poor. The Kaplan-Meier method was used to compute the median survival time and the log-rank test was used to compare the two groups. Univariate and multivariate analyses were used to examine the correlation between the pretreatment LIPI and clinical outcomes. RESULTS: One hundred patients were included in this study, of which, 64% were LIPI good (dNLR < 4.0 and LDH < 283 U/L), 11% were LIPI poor (dNLR ≥ 4.0 and LDH ≥ 283 U/L), and the remaining 25% were LIPI intermediate. The LIPI good group had better progression-free survival (PFS) (median: 8.4 vs 4.7 months, p = 0.02) and overall survival (OS) (median: 23.8 vs 13.3 months, p = 0.0006) than the LIPI intermediate/poor group. Multivariate analysis showed that pretreatment LIPI intermediate/poor was an independent risk factor for OS (HR: 2.34; 95%CI, 1.13, 4.86; p = 0.02). Subgroup analysis showed that pretreatment LIPI good was associated with better PFS and OS in males, extensive disease (ED), PD-1 inhibitor treatment, smokers, and liver metastasis (p < 0.05). CONCLUSIONS: Pretreatment LIPI could serve as a prognostic biomarker for advanced SCLC patients receiving first-line PD-1/PD-L1 inhibitors plus chemotherapy.