Periodontal therapy favorably modulates the oral-gut-hepatic axis in cirrhosis

Abstract

Cirrhosis is associated with a systemic proinflammatory milieu, endotoxemia, and gut dysbiosis. The oral cavity could be an additional source of inflammation. We aimed to determine the effect of periodontal therapy in cirrhosis through evaluating endotoxemia, inflammation, cognition, and quality of life (QOL). Age-matched cirrhotic and noncirrhotic subjects exhibiting chronic gingivitis and/or mild or moderate periodontitis underwent periodontal therapy with follow-up at 30 days. Saliva/stool for microbial composition and serum for Model for End-stage Liver Disease (MELD) score, endotoxin and lipopolysaccharide binding protein (LBP) and immune-inflammatory markers (IL-1β; IL-6; histatins 1, 3, 5; and lysozyme) were collected at baseline and day 30. The cognitive function and QOL were also evaluated similarly. A separate group of cirrhotic patients were followed for the same duration without periodontal therapy. Cirrhotics, especially those with hepatic encephalopathy (HE), demonstrated improved dysbiosis in stool and saliva, and improved endotoxin, LBP, and salivary and serum inflammatory mediators following periodontal therapy. These parameters, which were higher in HE at baseline, became statistically similar posttherapy. Pretherapy vs. posttherapy QOL and cognition also improved in HE patients following oral interventions. On the other hand, LBP and endotoxin increased over time in cirrhotic patients not receiving therapy, but the rest of the parameters, including microbiota remained similar over time in the no-therapy group. This proof-of-concept study demonstrates that periodontal therapy in cirrhosis, especially in those with HE, is associated with improved oral and gut dysbiosis, systemic inflammation, MELD score, and cognitive function, which was not observed in those who did not receive therapy over the same time period. NEW & NOTEWORTHY Systematic periodontal therapy in cirrhotic outpatients improved endotoxemia, as well as systemic and local inflammation, and modulated salivary and stool microbial dysbiosis over 30 days. This was associated with improved quality of life and cognition in patients with prior hepatic encephalopathy. In a cirrhotic group that was not provided periodontal therapy, there was an increase in endotoxin and lipopolysaccharide binding protein in the same duration. The oral cavity could be an important underdefined source of inflammation in cirrhosis.

Keywords: cognition; hepatic encephalopathy; inflammation; microbiota; quality of life.

Figures

Fig. 1.

Schematic of the study design.

Fig. 2.

Changes in cognition and health-related quality of life after periodontal therapy. Data are presented as median and 95% CI with individual data points. In the cirrhosis groups, the black dots are patients with HE (hepatic encephalopathy), while the others are without HE. A: change in Psychometric Hepatic Encephalopathy Score (PHES) before/after periodontal therapy shows improvement in the cirrhosis, particularly the HE group (P < 0.05, Wilcoxon matched-pairs test). A higher PHES score indicates better performance. Control values were similar pretherapy/posttherapy. B: change in EncephalApp OffTime+OnTime before and after periodontal therapy shows improvement in the cirrhosis, particularly the HE group (P < 0.05, Wilcoxon matched-pairs test). A higher OffTime+OnTime value indicates worse performance. Control values were similar before and after therapy. C: change in Sickness Impact Profile (SIP) total values before or after periodontal therapy shows improvement in the cirrhosis, particularly the HE group (P < 0.05, Wilcoxon matched-pairs test). A higher SIP total value indicates worse health-related quality of life. Control values were similar before and after therapy.

Fig. 3.

Changes in systemic inflammation after periodontal therapy. Data are presented as medians and 95% CI with individual data points. In the cirrhosis groups, the black dots are patients with HE (hepatic encephalopathy), while the others are without HE. A: change in serum endotoxin before or after periodontal therapy shows reduction in the cirrhosis group, and the HE group (P = 0.02, Wilcoxon matched-pairs test). Control values remained statistically similar. B: change in serum IL-6 before or after periodontal therapy shows reduction in the cirrhosis group, and the HE group (P = 0.42, Wilcoxon matched-pairs test). Control IL-6 levels were similar before or after therapy.

Fig. 4.

Linear discriminant function effect size (LEfSe) comparisons of microbiota family-level changes between groups and tissues. The x-axis is the log change in linear discriminant function between the groups displayed. A: changes between Cirrhosis saliva (light gray) and Control saliva (dark gray) at baseline. B: changes between Cirrhosis stool (light gray) and Control stool (dark gray) at baseline. C: changes between Cirrhosis saliva (light gray) vs. Control saliva (dark gray) at day 30. D: changes between Cirrhosis stool vs. Control stool (light gray) at day 30 only showed a decrease in taxa shown in cirrhosis and an increase in controls.

Fig. 4.

Linear discriminant function effect size (LEfSe) comparisons of microbiota family-level changes between groups and tissues. The x-axis is the log change in linear discriminant function between the groups displayed. A: changes between Cirrhosis saliva (light gray) and Control saliva (dark gray) at baseline. B: changes between Cirrhosis stool (light gray) and Control stool (dark gray) at baseline. C: changes between Cirrhosis saliva (light gray) vs. Control saliva (dark gray) at day 30. D: changes between Cirrhosis stool vs. Control stool (light gray) at day 30 only showed a decrease in taxa shown in cirrhosis and an increase in controls.

Fig. 5.

Linear discriminant function effect size (LEfSe) comparisons of microbiota family-level changes between cirrhotic patients with and without hepatic encephalopathy (HE). The x-axis is the log change in linear discriminant function between the groups displayed. HE patients are always displayed in light gray, while cirrhotic patients without HE are displayed in dark gray. A: changes between HE saliva (light gray) vs. non-HE saliva (dark gray) at baseline. B: changes between HE stool (light gray) vs. non-HE stool (dark gray) at baseline. C: changes between HE stool (light gray) vs. non-HE stool (dark gray) at day 30. D: changes between HE saliva (light gray) vs. non-HE saliva (dark gray) at day 30.

Fig. 6.

Prominent microbiota family changes before and 30 days after periodontal therapy. Individual data points for subjects pre and post are displayed, and statistics employed are Wilcoxon-matched pair rank tests for family-level relative abundance. P values for this comparison are displayed in the title of each subpart of the figure. A: cirrhosis stool changes showed significant reduction in the relative abundance of Enterobacteriaceae and Streptococcaceae and increase in Ruminococcaceae in the entire group and in hepatic encephalopathy (HE) patients specifically. Lachnospiraceae were unaffected. HE patients are marked by ○, while the remaining are patients without HE. B: cirrhosis saliva changes showed significant reduction in the relative abundance of Streptococcaceae and Pasteurellaceae in the entire group and in hepatic encephalopathy (HE) patients specifically. Lachnospiraceae were unaffected. HE patients are marked by ○, while the remaining are patients without HE. C: control stool changes showed a significant reduction in the relative abundance of Porphyromonadaceae and Enterobacteriaceae and an increase in Lachnospiraceae. No changes in Streptococcaceae were seen. D: control saliva changes did not show any significant change in Lachnospiraceae, Pasteurellaceae, Streptococcaceae, or Porphyromonadaceae. E: cirrhosis stool changes in patients who did not receive periodontal therapy. There were no statistically significant changes in the relative abundance of specific taxa of interest in the entire group and in HE. HE patients are marked by ○, while the remaining are patients without HE. F: cirrhosis saliva changes in patients who did not receive periodontal therapy. There were no statistically significant changes in the relative abundance of specific taxa of interest in the entire group and in HE. HE patients are marked by ○, while the remaining are patients without HE.

Fig. 6.

Prominent microbiota family changes before and 30 days after periodontal therapy. Individual data points for subjects pre and post are displayed, and statistics employed are Wilcoxon-matched pair rank tests for family-level relative abundance. P values for this comparison are displayed in the title of each subpart of the figure. A: cirrhosis stool changes showed significant reduction in the relative abundance of Enterobacteriaceae and Streptococcaceae and increase in Ruminococcaceae in the entire group and in hepatic encephalopathy (HE) patients specifically. Lachnospiraceae were unaffected. HE patients are marked by ○, while the remaining are patients without HE. B: cirrhosis saliva changes showed significant reduction in the relative abundance of Streptococcaceae and Pasteurellaceae in the entire group and in hepatic encephalopathy (HE) patients specifically. Lachnospiraceae were unaffected. HE patients are marked by ○, while the remaining are patients without HE. C: control stool changes showed a significant reduction in the relative abundance of Porphyromonadaceae and Enterobacteriaceae and an increase in Lachnospiraceae. No changes in Streptococcaceae were seen. D: control saliva changes did not show any significant change in Lachnospiraceae, Pasteurellaceae, Streptococcaceae, or Porphyromonadaceae. E: cirrhosis stool changes in patients who did not receive periodontal therapy. There were no statistically significant changes in the relative abundance of specific taxa of interest in the entire group and in HE. HE patients are marked by ○, while the remaining are patients without HE. F: cirrhosis saliva changes in patients who did not receive periodontal therapy. There were no statistically significant changes in the relative abundance of specific taxa of interest in the entire group and in HE. HE patients are marked by ○, while the remaining are patients without HE.