Changes of Th17/Treg ratio and tongue coating microbiota in autoimmune liver disease patients with type D personality

doi:10.21203/rs.3.rs-3330770/v1

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Research Article

Changes of Th17/Treg ratio and tongue coating microbiota in autoimmune liver disease patients with type D personality

https://doi.org/10.21203/rs.3.rs-3330770/v1

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Background

Autoimmune liver disease (AILD) is an important immune-mediated liver disorder that may gradually progress to severe liver fibrosis without timely medical intervention. Previous studies have indicated that patients with type D personality are unlikely to seek consultation and adhere to medications, and are more prone to depression, clinicians should actively identify AILD patients with type D personality. This study aimed to determine the changes of Th17/Treg ratio and tongue coating microbiota in AILD patients with type D personality.

Methods Twenty-four

AILD patients were investigated and divided into two groups based on the standardized psychological DS14 questionnaire. Flow cytometry was used to analyze the ratio of Th17 to Treg cells, tongue coating samples were collected for 16S rRNA gene sequencing, and then data analysis and statistical analysis were performed.

Results

AILD patients with type D personality had a significantly higher Th17/Treg ratio than those with non-type D personality. There were no massive contrasts in microbial diversity between type D personality group and non-type D personality group according to the alpha diversity analysis. However, microbial composition of the two groups varied according to Nonmetric multidimensional scaling and Venn diagram analysis. Linear discriminant analysis effect size analysis showed that Melissococcus and Lachnoanaerobaculum were dominant in type D personality group, while short-chain fatty acid-related bacteria (Clostridium and Blautia) and Actinobacillus were enriched in non-type D personality group.

Conclusion

Type D personality may be a related risk factor for AILD, while the composition of tongue microbiota may be useful in aiding the diagnosis of the severity of AILD patients.

Th17

Treg

Tongue coating microbiota

Autoimmune liver disease

Type D personality

Autoimmune liver disease (AILD), a group of immune-mediated liver injuries, encompasses several major patterns: autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis and various overlap syndromes of any two of the above diseases at the same time [1]. Clinical features of AILD frequently include the existence of autoantibodies, aberrant cytokine levels and/or the presence of T and B cell autoreactivity. Although AILD is a rare disease, it has a significant impact on health and economic cost to society with increasing incidence and prevalence[2, 3]. In addition, AILD is not yet curable and liver transplantation is the only available treatment option in certain circumstances.

The initial section of the digestive tract is the tongue, which is a crucial component of the oral cavity. Tongue diagnosis is a vital part of disease diagnosis in traditional Chinese medicine and is frequently employed in clinical practice. The tongue coating, a noticeable layer of moss attached to the back of the tongue, is the primary coverage of tongue and can reflect the health status of humans[4]. Tongue coating is made up of saliva, desquamated epithelial cells, metabolites and microorganisms. Among these components, tongue coating microbiota is an important factor affecting the formation of the tongue coating and colonized by a complex microbial community. A large number of microorganisms colonized in the gastrointestinal tract, such as oral cavity, stomach, small intestine, and other areas. The effects of oral and gut bacteria have been highlighted in autoimmune encephalomyelitis, rheumatoid arthritis, systemic lupus erythematosus, AILD and other autoimmune illnesses [5]. As the epithelium of the tongue dorsum and digestive tract develop from the same endoderm in the process of embryogenesis, their functions are intimately associated. Some studies found that more oral microbiota could appear in the stool with the systemic illnesses[6]. Tongue-coating microbiota is an important component of the oral microbiota and has the ability to enter the digestive tract and influence the gut microbiota fluctuations[7].

Type D personality is a broad personality type characterized by a combination of social inhibition and negative affectivity[8]. Social inhibition refers to the tendency not to share emotions and behaviors in social interactions with others. Negative affectivity means the propensity to experience negative emotions, such as depression, sadness, stress, anxiety and irritability. As type D personality was linked to poor views regarding physical and emotional health status and poor self-administration of the illness, it is a vulnerability factor that affects people with various diseases, such as coronary heart disease, fibromyalgia and tumors[9–13].

It is well known that chronic stress is associated with disruption of immune homeostasis and upregulated the proportion of Th17 cells to Tregs in the liver[14]. Previous studies have shown that the Treg population is significantly decreased and an imbalance in the Th17/Treg ratio may facilitate immune dysfunction in AILD patients [15]. Given that type D personality may lead to chronic stress and is independently associated with significant immune activation[16, 17], we first attempted to evaluate the Th17/Treg ratio in a group of AILD patients with type D and non-type D personality. Additionally, accumulated evidence suggests that gut microbiota is closely associated with the development of Th17 and Treg cells and tongue-coating microbiota affects the fluctuation of intestinal flora[18]. We then described the features of the tongue coating microbiota of AILD patients with type D personality using 16S rRNA analysis. Although the structure of the tongue coating microbiota in AILD patients has not been extensively studied, it has great potential. In summary, this study intended to investigate the effect of type D personality on Th17/Treg balance and tongue coating microbiota in AILD patients.

Study population

Twenty-four patients who were diagnosed with AILD (7 cases of autoimmune hepatitis, 14 cases of primary biliary cholangitis and 3 cases of autoimmune hepatitis-primary biliary cholangitis overlap syndrome) between November 2020 and June 2021 in the Second Hospital of Nanjing, People's Republic of China constituted the study population. The diagnostic criteria were based on the European Association for the Study of the Liver Clinical Practice Guidelines[19–21]. All participants were enrolled from endocrine outpatients without using probiotics, antibiotics or any other medications influencing tongue coating microbiota within one month. Our research procedures were approved by the ethical commission of the Second Hospital of Nanjing (Approval No. 2023-LY-kt051) and written informed consent was provided to each participant.

DS14 questionnaire

Type D personality was recognized utilizing the 14-item Chinese version type D scale (DS14). DS-14 was developed by Denollet and has two 7-item subscales measuring social inhibition and negative affectivity [22]. Each item (items 1 and 3 are reverse-scored) is evaluated on a 5-point rating scale ranging from 0 ( false) to 4( true), as described in Fig. 1. Participants were classified as having a type D personality by scoring at least 10 points on both the social inhibition and negative affectivity subscales. The DS14 is a brief, psychometrically sound measurement tool with high internal consistency and good test-retest reliability.

Flow cytometric analysis

For helper T lymphocytes intracellular staining, the cells isolated from blood were pre-stimulated with 250×PMA and 250×BFA at 37°C for 4 h. Cells were then stained with CD3-PerCP-Cy5.5 and CD4-FITC for 0.5 h followed by fixation and permeabilization and subsequently exposed to IL-17A-PE antibodies for 1 h. For Treg staining, the cells were cultured with CD4-FITC and CD25-PE for 0.5 h followed by fixation and permeabilization and staining with Foxp3-APC antibodies for 1 h. Flow cytometric measurements were performed on BD Canto II and analyzed with FlowJo 10 software (TreeStar, Ashland, OR).

Tongue coating collection and DNA isolation

We collected tongue coating samples using a protocol that had been tried out during a pilot phase of this research. In order to get rid of the food particles form the mouth, all participants were asked to gargle with mineral water twice before sampling and stick out their tongue as far as they could. A fresh disposable toothbrush was used to scrape back and forth from the middle of the tongue dorsum at least 5 times. Place the fresh disposable toothbrush in a centrifuge tube with 10 ml sterile water. Then, the centrifugal tubes were centrifuged at 3,000 r/min for 10 min. Finally, the sediments were collected in 1.5 ml EP tubes and stored in a -80°C freezer. DNA was separated utilizing the QIAamp DNA Mini Kit (Qiagen, Germany) as indicated by the manufacturer's guidelines and stored at -20°C before further examination.

PCR amplification and sequencing

PCR amplification was carried out with the general primers that target the V3-V4 region of the bacterial 16S rRNA gene. The 338F 5'-ACTCCTACGGGAGGCAGCA-

3' and 806R 5'-GGACTACHVGGGTWTCTAAT-3' were the forward primer and reverse primer, respectively. The following was the procedure for amplification: Step 1: 30 seconds at 98°C; Step 2 consists of 25 cycles: 30 seconds at 98°C, 30 seconds at 50°C, 30 seconds at 72°C, and a final extension of 5 minutes at 72°C. Each PCR was performed in triplicate with a reaction volume of 20 µl of mix, which consisted of 4 µl of 5× High GC Buffer, 4 µl of 5× Reaction Buffer, 2 µl of 10 mM dNTPs, 1 µl of forward primer (10 µM), 1 µl of reverse primer (10 µM), 0.25 µl of high-fidelity DNA polymerase polymerase, 1 µl of template DNA and 6.75 µl of ddH₂O. The PCR products were identified and purified before sequencing with an Illumina MiSeq sequencing system (Illumina, San Diego, CA). Raw sequencing data have been submitted to the Sequence Read Archive (SRA) database under the accession number PRJNA955440.

Data analysis

With a few minor modifications, microbiota bioinformatics was carried out using QIIME2 2019.4 in accordance with the official tutorials. In summary, using the demux plugin, sequence data were demultiplexed and then primers were cut with the cutadapt plugin after raw. Utilizing the DADA2 module, sequences were then quality- sifted, denoised, merged, and chimera-removed before having the diversity of the sequences estimated. The feature-classifier plugin's classify-sklearn nave Bayes taxonomy classifier was used to classify amplicon sequence variants(ASVs) using the SILVA Release 132 data.

Statistical analysis

Analysis using statistics and bioinformatics software tools QIIME2 and R were largely used to analyze sequence data (v3.2.0). The ASV table in QIIME2 was used to construct and visualize ASV-level alpha diversity indicators. Using Jaccard metrics, UniFrac distance metrics and Bray-Curtis metrics, beta diversity analysis was used to test the structural differences of microbial communities in samples and was then depicted using nonmetric multidimensional scaling (NMDS). A Venn diagram was created using the R package "VennDiagram" to describe the shared and unique ASVs in the sample or population. Linear discriminant analysis effect size (LEfSe) was utilized with the default parameters to identify species with rich differences between populations. The R package "muma" was used to introduce orthogonal partial least squares discriminant analysis as a supervised model to reveal the variance in microbiota between groups. The statistical analysis was performed using GraphPad Prism 8 software and a P value less than 0.05 was considered statistically significant.

The occurrence of type D personality in 24 AILD patients

Data were collected using a 14-item Chinese version Type D scale (DS14). As displayed in Table 1, 9 (37.5%) AILD patients were classified as having a type D personality. The average scores of negative affectivity and social inhibition in patients with type D personality were 16.4 ± 5.4 and 14.7 ± 3.8, respectively. Both average scores of social inhibition and negative affectivity were significantly higher in the type D personality group than those in the non-type D personality group (p < 0.001).

Table 1

The occurrence of type D personality in 24 AILD patients
	n (%)	negative affectivity	social inhibition
Type-D personality	9 (37.5%)	16.4 ± 5.4	14.7 ± 3.8
Non- type D personality	15(62.5%)	7.1 ± 5.8	6.7 ± 3.0
P-value		0.0007***	< 0.0001***
***P < 0.001 indicate statistically significant differences when comparing the average scores of negative affectivity and social inhibition between type D personality group and non-type D personality group

Proportions of Th17 and Treg cells in AILD patients with type D personality

The development of autoimmune diseases is usually closely related to the proportion of Th17 and Treg cells. We examined Th17 and Treg cells percentages in the peripheral blood of AILD patients with type D personality. Although there was no significant difference between the Th17 and Treg proportions, we found that patients with type D personality showed a significantly higher Th17/Treg ratio(P < 0.001)(Fig. 2).

Alpha and beta diversity analysis of tongue coating microbiota

We used the Chao1 index, Simpson index, Shannon index, Pielou index, Observed species index, Faith’s phylogenetic diversity index and Good’s coverage index as characteristics to assess the diversity of the tongue coating microbiota in both groups. No appreciable differences in microbial diversity were found between the two groups (Fig. 3A). NMDS analysis was used to compare the similarity of bacterial communities and showed significant differences between the two groups (Fig. 3B; NMDS, pressure = 0.174) in bacterial communities. The distinct species composition between the two groups was depicted using Venn diagrams. As shown in Fig. 3C, 2021 bacterial features were common in all samples and each group had its own unique microbial communities. A total of 6130 and 9625 unique features were endemic to the type D personality group and non-type D personality group, respectively.

The relative abundances of tongue coating microbial taxa at the phylum and genus levels

The top 5 phyla of both groups included Fusobacteria, Actinobacteria, Bacteroidetes, Proteobacteria and Firmicutes (Fig. 4A). The abundance of Bacteroidetes was higher and the abundance of the Proteobacteria was lower in the type D personality group(P < 0.05)(Fig. 4B). The main bacteria were basically consistent between the two groups, but different relative abundances were observed (Fig. 4C).

LEfSe reveals the imbalance of the tongue microbiota differs between groups

With LAD scores greater than 3, different bacterial species from each group were identified using LEfSe analysis(Fig. 5). At the class level, higher abundances of Bacteroidia and Epsilonproteobacteria were found in the type D personality group and non-type D personality group, respectively. At the order level, Bacteroidales were upregulated and Campylobacterales were downregulated in the type D personality group. Upon further segmentation to the genus level, the differentially enriched taxa in AILD patients with type D personality were Melissococcus and Lachnoanaerobaculum, whereas the differentially enriched taxa in AILD patients with non-type D personality were mainly from Clostridium, Blautia and Actinobacillus.

AILD is a potentially life-threatening autoimmune condition and caused by immune attack on hepatocytes or cholangiocytes [23]. If prompt medical attention is not received, AILD will develop into severe liver fibrosis. Currently, AILD has no curative treatment option. To control hepatic or biliary inflammation, patients with AILD need to take life-long immunosuppression or bile acids.

Tregs play an important role in maintaining immune homeostasis by actively inhibiting autoreactive lymphocytes and Treg injury is associated with the occurrence and persistence of AILD[24]. Th17 cells, which primarily produce IL-17 and IL-22, were initially associated with host resistance to infection and were involved in tissue damage in AILD[25]. The functional abnormalities of the Th17/Treg balance has been shown to be associated with liver damage. Recently there has been increasing evidence that personality traits may contribute to poor treatment adherence in people with chronic diseases[26]. Type D personality, the "distressed" personality trait, is an important index of adverse clinical outcomes and may increase the burden of illness[27, 28]. In the current study, we found that patients with type D personality showed a significantly higher Th17/Treg ratio (Fig. 2) and type D personality may be a related risk factor that affects the Th17/Treg balance in AILD patients.

Microorganisms living in the human body can improve immune function, maintain the local ecological balance in organs, break down nutrients and provide energy for the host through participating in the generation and metabolism of proteins, lipids and vitamins[29–31]. Numerous investigations have indicated that the human microbiome is involved in many diseases and aspects of human health and previous researches have demonstrated a link between dysbiosis and the development of AILD. Tongue coating microbiota is an easily detectable colonizing microorganism with high sampling stability, moderate renewal rate and disease sensitivity. These qualities increase the likelihood that tongue-coating microbiota will be a useful research subject. Additionally, tongue-coating microbiota might reflect the status of the gastrointestinal ecosystems and is closely associated with many diseases. Considering that the microbiota influences the development of Th17 cells and Tregs, we attempted to examine the tongue coating microbiota in AILD patients with type D and non-type D personality in our research. No massive contrasts were observed in microbial diversity between the two groups based on the ASV-level alpha diversity indicators (Fig. 3A). However, NMDS distinguished the microbiota on tongue coating between type D personality group and non-type D personality group and microbial composition of the two groups was different (Fig. 3B). As depicted in Fig. 4A, Fusobacteria, Actinobacteria, Bacteroidetes, Proteobacteria and Firmicutes as the main parts of the tongue coating microbiome, were the most common phyla found in our study and steadily reappeared in previous researches [32–34], demonstrating the stable residence of these microbes in the tongue coating. LEfSe analysis at the genus level revealed that AILD patients with non-type D personality had a greater relative abundance of Clostridium, Blautial and Actinobacillus (Fig. 5). Clostridium and Blautia have probiotic characteristics and can produce short-chain fatty acids (SCFAs)[35, 36]. SCFAs are regulatory compounds with the potential to maintain human health by affecting the development, prevention, and treatment of various diseases, as well as cognition and emotional state via the gut-brain axis[37]. Of note, SCFAs can stimulate the production of neuroactive molecules including histamine, serotonin, 5-aminovaleric acid, γ-aminobutyric acid and affect nervous system disorders such as mood and cognition[38–40]. Moreover, accumulating evidence suggests that SCFAs can reduce inflammation and promote the development and function of Tregs, thereby affecting the Th17/Treg immune balance[41].

Our study found differences in the Th17/Treg ratio and tongue coating microbiota between AILD patients with type D personality and those with non-type D personality. However, the number of subjects is a limitation of our research and further investigation with more samples is required to further validate our findings. Second, the mechanism of the relationship between the tongue coating microbiota and Th17/Treg ratio is not clear, and further studies are still needed.

In the present study, we found that the ratio of Th17/Treg was significantly higher in AILD patients with type D personality than those with non-type D personality. We also found significant changes in tongue coating microbiota of AILD patients with type D personality. Considering that the ratio of Th17/Treg has been reported to be an important factor influencing the symptoms of AILD, we conclude that type D personality may be a related risk factor for AILD, while the composition of tongue microbiota may be useful in aiding the diagnosis of the severity of AILD patients.

AILD: Autoimmune liver disease; Treg: Foxp3+CD4+CD25+ regulatory T cell; Th17: Interleukin-17 producing T help cell; DS14:Type D Personality Scale; PMA: Phorbol 12-myristate 13-acetate; BFA: Brefeldin A; SRA: Sequence read archive; ASVs: Amplicon sequence variants; NMDS: Nonmetric multidimensional scaling LEfSe: Linear discriminant analysis effect Size; SCFAs: Short-chain fatty acids.

Ethics approval and consent to participate: The research procedures were approved by the ethical commission of the Second Hospital of Nanjing (Approval No. 2023-LY-kt051) and written informed consent was provided to each participant.

Consent for publication: Not applicable.

Availability of data and materials: Raw sequencing data have been submitted to the Sequence Read Archive (SRA) database under the accession number PRJNA955440.

Competing interests: The authors declare that they have no competing interests.

Funding: This study was supported by the key medical science and technology development project of Nanjing Health Science and Technology Development Fund(No. ZKX22039), Nature Foundation Project of Nanjing University of Chinese Medicine(No. XZR2020069), The Obstetrics and gynecology disease Biobank, Jiangsu Biobank of Clinical Resources (No. BM2015004) and Jiangsu Province Major Disease Biological Resource Sample Library Open Project of Obstetrics and Gynecology Disease Subbank (Biological Sample Bank of Nanjing Gulou Hospital) (No. TC2021B021).

Authors' contributions: HYZ and YYF imagined the original idea for this review and critically modified the work. JYS and ZHL performed the experiments and prepared the manuscript. ZXW collected the samples. YW carried out the statistical evaluations. All authors have reviewed and consented to submit the final manuscript.

Acknowledgements: We thank Yuanbao Biotech. Co., Ltd (Nanjing, China) for support and help in the analysis of 16s rRNA-seq data. At the same time, thanks to others who contributed to the experiment but were not listed as authors.

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No competing interests reported.

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Changes of Th17/Treg ratio and tongue coating microbiota in autoimmune liver disease patients with type D personality

Status:

Version 1

Abstract

Background

Methods Twenty-four

Results

Conclusion

Figures

Background

Methods

Study population

DS14 questionnaire

Flow cytometric analysis

Tongue coating collection and DNA isolation

PCR amplification and sequencing

Data analysis

Statistical analysis

Results

The occurrence of type D personality in 24 AILD patients

Proportions of Th17 and Treg cells in AILD patients with type D personality

Alpha and beta diversity analysis of tongue coating microbiota

The relative abundances of tongue coating microbial taxa at the phylum and genus levels

LEfSe reveals the imbalance of the tongue microbiota differs between groups

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1