Gene Expression Dysregulation in Whole Blood of Patients with Clostridioides difficile Infection
Abstract
1. Introduction
2. Results
2.1. Patient Characteristics
2.2. Patients with Different Types of Diarrhea Have Significant Variation at the Gene Expression Level in Peripheral Blood Enriched for Innate Immunity and Neutrophil Activation
2.3. CDI Is Associated with Dysregulation of Adaptive Immunity
3. Discussion
4. Materials and Methods
4.1. Study Population
4.2. Sample Collection and Processing
4.3. Microarray Data Processing
4.4. Differential Expression Analyses
4.5. Gene Set Enrichment Analysis
4.6. Ingenuity Pathway Analysis
- Common genes: Diarrhea common genes were identified through Venn diagrams at the area of convergence from the differential expression analysis (FDR adj. p < 0.05) of each diarrhea group vs. the HC arm. To narrow down the number of common genes, filtering criteria were applied, including an absolute value of the logarithm with base 2 of fold change (|log2FC|) > 0.5 and the top 20 dysregulated genes with the highest |log2FC|.
- Unique genes: CDI unique genes were identified through Venn diagrams at the area of convergence of differential expression analysis (FDR adj. p < 0.05) of CDI cases vs. each control group (GDH, IBD, DC, and HC).
- Severity genes: Diarrhea severity genes derived from differential expression analysis (FDR adj. p < 0.05) between severe vs. non-severe diarrhea (combined CDI, GDH, IBD, and DC) as defined with the modified criteria.
4.7. Literature Search
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Clinical Variable | CDI (n = 78) | GDH (n = 37) | IBD (n = 40) | DC (n = 45) | HC (n = 51) | p-Value 1 |
---|---|---|---|---|---|---|
Age, median years (IQR) | 76 (65–83) | 73 (57–82) | 40 (28–66) | 69 (61–76) | 65 (62–72) | <0.001 |
Gender, male n (%) | 35 (45) | 14 (38) | 21 (53) | 21 (47) | 29 (57) | 0.434 |
Ethnicity, white n (%) | 77 (99) | 37 (100) | 39 (98) | 44 (98) | 50 (98) | 0.908 |
BMI, median (IQR) | 24 (21–28) | 25 (22–31) | 25 (23–28) | 27 (22–33) | 28 (23–31) | 0.054 |
Charlson comorbidity index, median (IQR) | 5 (3–6) | 4 (3–5) | 0 (0–2) | 4 (2–5) | 3 (2–3) | <0.001 |
Comorbidities, n (%) | ||||||
Diabetes | 22 (28) | 12 (32) | 2 (5) | 14 (31) | 6 (12) | 0.003 |
Hypertension | 39 (50) | 23 (62) | 7 (18) | 23 (51) | 22 (43) | 0.001 |
Hyperlipidemia 2 | 43 (55) | 19 (51) | 7 (18) | 26 (59) | 27 (53) | <0.001 |
CVD 3 | 49 (63) | 20 (54) | 8 (20) | 26 (58) | 16 (31) | <0.001 |
Respiratory disease 4 | 21 (27) | 8 (22) | 13 (33) | 17 (38) | 11 (22) | 0.357 |
CKD | 25 (32) | 8 (22) | 1 (3) | 7 (16) | 1 (2) | <0.001 |
GI disease 5 | 18 (23) | 11 (30) | 40 (100) | 16 (36) | 0 (0) | <0.001 |
Malignancy | 14 (18) | 7 (19) | 1 (3) | 9 (20) | 4 (8) | 0.058 |
Auto-immune disease | 9 (12) | 4 (11) | 40 (100) | 7 (16) | 1 (2) | <0.001 |
Immunosuppression | 2 (3) | 0 (0) | 7 (18) | 2 (4) | 1 (2) | 0.001 |
Obesity (BMI > 30) | 19 (24) | 11 (30) | 6 (15) | 15 (33) | 17 (33) | 0.192 |
Current smoker | 9 (12) | 3 (8) | 7 (18) | 10 (22) | 5 (10) | 0.198 |
Alcohol excess 6 | 5 (6) | 5 (14) | 34 (14) | 5 (11) | 11 (22) | 0.002 |
Frailty 7, n (%) | <0.001 | |||||
Mild | 21 (27) | 13 (35) | 10 (25) | 13 (29) | 12 (24) | |
Moderate | 9 (12) | 6 (16) | 1 (3) | 7 (16) | 1 (2) | |
Severe | 36 (46) | 16 (43) | 4 (10) | 4 (9) | 1 (2) | |
Carer aid, median hours/week (IQR) | 0 (0–52) | 0 (0–20) | 0 (0–0) | 0 (0–0) | 0 (0–0) | <0.001 |
Health state 8, median (IQR) | 50 (31–60) | 50 (30–70) | 60 (50–70) | 63 (41–80) | 80 (75–90) | <0.001 |
Primary diagnosis, n (%) | <0.001 | |||||
Entero-colitis | 29 (37) | 9 (24) | 40 (100) | 24 (53) | - | |
Other GI pathology | 5 (6) | 3 (8) | - | 5 (11) | - | |
Respiratory disease | 4 (5) | 1 (3) | - | 4 (9) | - | |
Cardiovascular disease | 8 (10) | 5 (14) | - | 6 (13) | - | |
Infection | 10 (13) | 8 (22) | - | 3 (7) | - | |
Other | 9 (12) | 5 (14) | - | 2 (4) | - | |
Elective admission | 6 (8) | 1 (3) | - | - | 10 (20) | |
Transfer | 7 (9) | 4 (11) | - | 1 (2) | - | |
No admission | - | 1 (3) | - | - | 41 (80) | |
Presence of entero-colitis on admission, n (%) | 29 (37) | 9 (24) | 40 (100) | 24 (53) | - | <0.001 |
Number of stool motions on worst day, median (IQR) | 5 (4–8) | 4 (2–6) | 10 (6–13) | 5 (3–8) | NA | <0.001 |
Acute illness other than entero-colitis 9, n (%) | 48 (62) | 25 (68) | 1 (2.5) | 24 (53) | 7 (18) | <0.001 |
Days from admission to clinical stool sample, median (IQR) | 3 (1–12) | 5 (2–12) | 1 (1–3) | 1 (1–3) | NA | <0.001 |
Days from admission to transcriptomic sample, median (IQR) | 7 (4–16) | 10 (7–16) | 4 (3–6) | 4 (3–6) | 4 (3–4) | <0.001 |
Days from the onset of diarrhea to transcriptomic sample, median (IQR) | 6 (4–10) | 6 (4–11) | 11 (8–19) | 4 (3–6) | NA | <0.001 |
Days from worst day to transcriptomic sample, median (IQR) | 3 (2–4) | 3 (2–4) | 2 (1–4) | 2 (2–3) | NA | 0.394 |
Days from the start of antibiotics to transcriptomic sample, median (IQR) | 6 (4–6) | 5 (2–17) | 5 (3–7) | 5 (3–6) | NA | 0.852 |
Transfusion within 5 days from transcriptomic sample, n (%) | 4 (5) | 5 (14) | 0 (0) | 3 (7) | 0 (0) | 0.025 |
Highest NEWS, median (IQR) | 2 (1–3) | 2 (1–3) | 1 (0–2) | 2 (1–4) | NA | 0.094 |
Maximum temperature median °C (IQR) | 37.3 (37–38) | 37.2 (36.9–37.6) | 37 (36.8–37.3) | 37.2 (36.9–37.8) | 36.7 (36.6–36.8) | <0.001 |
Lowest BP (mmHg), median (IQR) | 100/58 (89/52–110/65) | 95/60 (86/50–115/64) | 108/64 (100/60–120/70) | 100/60 (92/55–110/66) | 138/81 (124/73–158/89) | <0.001 |
WCC (×109/L), median (IQR) | 14.5 (10.1–18.8) | 12.1 (9.9–15.1) | 12.4 (9.5–14.8) | 11.6 (9.2–15.9) | NA | 0.100 |
CRP (mg/dL), median (IQR) | 111 (52–194) | 82 (36–144) | 52 (13–92) | 47 (23–195) | NA | 0.006 |
PLT (×109/L), median (IQR) | 253 (199–352) | 321 (247–401) | 333 (244–436) | 227 (171–314) | NA | <0.001 |
Creatinine (μmol/L), median (IQR) | 104 (70–140) | 80 (50–119) | 75 (66–96) | 86 (67–131) | NA | 0.006 |
Albumin (mg/dL), median (IQR) | 32 (28–36) | 31 (25–37) | 39 (34–41) | 38 (35–42) | NA | <0.001 |
Severe diarrhea 10, n (%) | 66 (85) | 15 (41) | 11 (28) | 23 (51) | NA | 0.004 |
Mortality, n (%) | <0.001 | |||||
28-days | 7 (9) | 0 (0) | 1 (2) | |||
90-days | 5 (6) | 2 (5) | 0 (0) | |||
1-year | 11 (14) | 7 (19) | 3 (7) | |||
Overall | 23 (29) | 9 (24) | 0 (0) | 4 (9) | 0 (0) | |
Colectomy within a year from recruitment, n (%) | 1 (1) | 0 (0) | 8 (5) | 0 (0) | 0 (0) | <0.001 |
Prior PPI use, n (%) | 49 (63) | 28 (76) | 17 (43) | 34 (76) | 12 (24) | <0.001 |
Gene Symbol | Category, Subcategory | Function | Reference |
---|---|---|---|
ACTL6A/BAF53A | Genomic stability, T-cell memory | Component of Brahma-associated factor (BAF) complexes, which participates in chromatin accessibility for pluripotency transcription factors (e.g., NANOG) by ATP-dependent nucleosome eviction. For instance, BAF regulates T cell differentiation to effector subsets and establishment of long-lived tissue memory T cells and maintains pluripotency by revoking differentiation of acute promyelocytic leukemia cells. Oncogenic activity in many cancers. | [52,53,54,55] |
ALDH9A1 | Metabolism—FAO, Redox | Least studied aldehyde dehydrogenase involved in carnitine biosynthesis, a fatty acid transporter to the mitochondria (mt) and a potent antioxidant. | [56] |
ARLNC1 | Genomic stability | Non-coding RNA that stabilizes the androgen receptor RNA in prostate cancer. | [57] |
BLCAP | Genomic stability | A tumor suppressor/apoptosis inducer which interacts with Rb1, a chromatin stabilizer, and STAT3, which mediates the transcription of many factors, including Bcl-2 family proteins, cyclins, and matrix metalloproteinases. | [58,59,60] |
CD19 | Humoral immunity | Enhances B-cell expansion and antibody secretion via interacting with B-cell receptor (BCR) and CD21 and activating PI3k/Akt signaling. Deficiency impairs humoral memory. | [61,62] |
CLDN5 | Cytoskeleton, Humoral immunity | Component of tight junctions in epithelial and endothelial cells. Downregulation in enterocytes during inflammatory colitis. Also expressed by lymphocytes and monocytes, but not granulocytes, co-localized with tight-junction scaffold proteins at the cell membrane, and mRNA and protein levels increase in relapse of multiple sclerosis. | [63,64,65] |
COQ6 | Metabolism—OXPHOS | Necessary for coenzyme Q biosynthesis, a potent antioxidant and lipid oxidation enzyme. | [66] |
COQ10A | Metabolism—OXPHOS | Required for coenzyme Q function of the mt respiratory chain. Potential marker of sepsis-induced cardiomyopathy. | [67,68] |
CYB561A3 | Metabolism—OXPHOS, Mt homeostasis | Ferrireductase necessary for mt respiration. Knockdown causes iron starvation with subsequent lysosomal and mt damage. Downregulated in HPV-induced warts and sepsis. Highly expressed in Burkitt lymphoma and involved in B cell proliferation/differentiation via cellular iron homeostasis. | [69,70,71] |
DYNLT3 | Cytoskeleton, T-cell memory | Subunit of the dynein complex, which transports organelles and cargos along the microtubule. Dynein promotes lymphocyte polarization during the immune synapse formation and asymmetric CD8+ T cell division, generating memory cells. An age-related oncogene in breast cancer. | [72,73,74] |
EI24 | Mt homeostasis | Endoplasmic reticulum (ER) protein promoting ER-mt contact for excessive calcium transfer during DNA damage, resulting in p53-mediated mt-induced apoptosis. Links ubiquitin-proteasome system (UPS) with autophagy via degradation of RING E3 ligases, including RNF41. | [75,76] |
FANCF | Genomic stability, Mt homeostasis | Subunit of the Fanconi anemia core complex (E3 ubiquitin ligase), which repairs DNA inter-strand crosslinks. Mutations have been associated with cancer. Also factor of selective autophagy (mitophagy) | [77,78,79] |
FN3KRP | Metabolism | Reverts non-enzymatic glycation of proteins, restoring their function. Increased expression has a potential protective role, promoting longevity and reducing pulmonary inflammation in smokers. | [80,81] |
GPA33 | T-cell memory | Expressed mainly by CD4+ T cells and associated with a central memory phenotype. TCR activation potentially reduces expression and marks an effector phenotype, which is required for effective humoral immunity. | [82,83] |
GPAA1 | Metabolism—FAO (inferred), Humoral immunity | Subunit of the GPIT complex, which anchors proteins lacking a transmembrane domain to the cell membrane. Heparin sulfate (HS), a glycosaminoglycan (sGAG) linked to a core protein (e.g., proteoglycan) regulating a plethora of cell functions, including lipid metabolism and autophagy, is GPI-anchored. HS strengthens IL-21 signaling in B cells, promoting differentiation towards antibody-secreting cells in germinal centers. | [51,84,85] |
LDLRAP1 | Metabolism—FAO (inferred) | Interacts with the cytoplasmic tail of the low-density lipoprotein receptor (LDLR) and drives LDL-LDLR endocytosis in polarized cells such as lymphocytes. | [86] |
LPAR5 | Humoral immunity | Negatively regulates TCR signaling and effector functions in CD8 by modifying the cytoskeleton and reprogramming metabolism. Also impairs BCR-induced calcium mobilization and antigen-dependent antibody production in B cells. | [87,88,89] |
MOCS1 | Redox | Subunit of the molybdenum co-factor which is a redox-active prosthetic in the active site of many enzymes with vital metabolic roles, including purine and sulfur amino acids catabolism in humans and anaerobic respiration in bacteria. | [90,91,92] |
MRNIP | Genomic stability | Concentrates the MRN complex on sites of DNA damage to repair double-strand breaks. | [93] |
NAA30 | Mt homeostasis | Catalytic subunit of the NatC complex, which mediates N-terminal acetylation of a big repertoire of substrates, including mitochondrial proteins, preventing their degradation. | [94,95] |
NDUFAF3 | Metabolism—OXPHOS | Participates in the assembly of Complex I of mitochondrial oxidative phosphorylation. | [96] |
NSUN7 | Genomic stability/Metabolism—glycolysis | A methyltransferase of RNA acting during metabolic stress to stabilize regulatory and other types of RNA and transcriptional co-activators for rapid responses to the need for energy (e.g., upregulation of glycolysis-related enzymes). | [97] |
OLFM4 | T-cell memory (inferred) | Glycoprotein which is strongly expressed in the GI tract and prostate. mRNA and protein increased in neutrophils of mice with C. difficile infection, promoting pathogenesis and increasing morbidity and mortality. OLFM4 was higher in serum of patients with C. difficile infection. OLFM4 downregulates the Wnt pathway in gastrointestinal malignancies. Wnt/β-catenin signals the generation of memory stem cells in CD8 subsets. | [98,99,100] |
PEX3 | Metabolism—FAO | Required for the biogenesis of the peroxisome, where very long fatty acids are oxidized and transfer proteins to organelle membranes. | [101] |
PHF5A | Humoral immunity, Genomic stability | Component of the spliceosome that regulates DNA repair during antibody class switch recombination and essential for B lymphopoiesis and Ig heavy chain production. In pancreatic cancer stem cells, the PAF1-PHF5A-DDX3 complex regulates the expression of self-renewal genes, including β-catenin. | [102,103,104] |
PIGU | Metabolism, Humoral immunity | Subunit of the GPIT complex (see GPAA1). | |
PMPCA | Mt homeostasis | Subunit of the mitochondrial processing peptidase (MPP), which cleaves almost all proteins transported from the cytosol into mitochondria to a fully mature state. | [105] |
PRICKLE1 | Cytoskeleton | A planar polarity gene which causes cytoskeleton restructuring through non-canonical Wnt signaling. | [106] |
RHOBTB2/DBC2 | Metabolism | Atypical Rho-like GTPase and substrate adaptor (BTB domain) to cullin 3 (scaffold) and RBX1/ROC1 (RING finger protein/catalytic domain of the E3 ubiquitin ligase) of the CRL3 complex, which mediates the ubiquitination and degradation of many proteins. | [107,108] |
RNF41/NRDP1 | Mt homeostasis | A RING-finger E3 ligase that promotes mitophagy via complex formation with CLEC16A and USP8. Involved in early termination of TCR signaling in CD8 cells, reducing IL-2 and IFN-γ production and TLR-mediated production of type I interferon (α/β). | [109,110,111] |
RNFT2/TMEM118 | Metabolism | Poorly characterized RING finger E3 ligase, which promotes degradation of IL-3Rα protecting from the deleterious effects of IL-3. | [112] |
RUSF1/C16orf58 | Not known | Poorly characterized protein. Interacts with TMEM9 in the BioGRID4.4 database. | |
SLC2A11 | Metabolism—glycolysis (inferred) | Transports glucose and fructose. Limited literature studies. | [113] |
SMIM20/MITRAC7 | Metabolism—OXPHOS | Stabilizes COX1 in cytochrome c of the electron transport chain. All three components of cytochrome c (COX1/2/3) are encoded in mitochondria. | [114] |
SPIB | Humoral immunity | Transcription factor regulating genes involved in the generation of memory B cells and maintenance of humoral memory (upregulates anti-apoptosis and autophagy genes). Transcription is suppressed by the Wnt pathway/SIX1 in Hodgkin lymphoma. Required for TLR7/9 mediated type I interferon (IFN-I) production in plasmacytoid dendritic cells. | [115,116,117] |
STING1/STING | T-cell memory, Humoral immunity | Detects cytosolic nucleic acids and activates IFN-I production to clear viral infections. Herpes simplex virus 1 (HSV-1) inhibits β-catenin of the canonical Wnt pathway, which activates cGAS/STING signaling. STING signaling promotes antibody production through BCR regulation and T cell memory depending on TCR signal strength. | [118,119] |
TBCB | Cytoskeleton | A tubulin chaperon that interacts with TBCE to degrade α-tubulin independent of energy. | [120] |
TMEM9 | T-cell memory | Transmembrane (organelles and cell) protein that activates the canonical Wnt pathway to promote intestinal and liver tumorigenesis and liver regeneration. | [121,122,123] |
TOP1MT | Mt homeostasis | Mitochondrial (exclusively) topoisomerase that relaxes mtDNA supercoiling. Reduced expression results in the release of mtDNA to the cytosol, which activates the cGAS/STING pathway. Genetic variants have a significant effect on the expression of proteins involved in oxidative phosphorylation with irreversible impairment of mitochondrial respiration. Overexpressed in cancer. | [124,125,126,127] |
TSPAN31 | Cytoskeleton (inferred) | A poorly studied tetraspanin activating transcription of oncogenic factors (Akt) in gastric cancer. Tetraspanins organize proteins in the cell membrane. | [128] |
TSR3 | Metabolism | An aminocarboxypropyl (acp) transferase catalyzes the last step in the biosynthesis of 1-methyl-3-(3-amino-3-carboxypropyl)-pseudouridine of the 18S rRNA. | [129] |
USP11 | Genomic stability | A deubiquitinase (ubiquitin-specific protease or USP) with a dual role in cancer which is irreplaceably involved in many important cellular functions, including DNA repair (e.g., stabilizing BRCA2), cell division (stabilizing RanBMP) and NF-κB signaling downregulation. Also facilitates differentiation to regulatory T cells. | [130,131] |
VHL | Metabolism-glycolysis, T-cell memory | Component of a ubiquitination complex involved in the degradation of hypoxia-inducible factor (HIF), which regulates gene expression and upregulates glycolytic metabolism during low oxygen conditions in memory CD8 cells. In renal cell carcinoma, it promotes STING degradation, while HIF increases due to loss of VHL, results in mtDNA leak and subsequent cGAS-STING activation. | [132,133,134] |
ZNF252P | Not known | Pseudogene with unknown function and no relevant literature studies. | |
ZNF684 | Not known | Interacts with amyloid-β, TRIM28, and another 14 interactors in the BioGRID database. No literature studies on its function. | [135,136] |
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Tsakiroglou, M.; Evans, A.; Doce-Carracedo, A.; Little, M.; Hornby, R.; Roberts, P.; Zhang, E.; Miyajima, F.; Pirmohamed, M. Gene Expression Dysregulation in Whole Blood of Patients with Clostridioides difficile Infection. Int. J. Mol. Sci. 2024, 25, 12653. https://doi.org/10.3390/ijms252312653
Tsakiroglou M, Evans A, Doce-Carracedo A, Little M, Hornby R, Roberts P, Zhang E, Miyajima F, Pirmohamed M. Gene Expression Dysregulation in Whole Blood of Patients with Clostridioides difficile Infection. International Journal of Molecular Sciences. 2024; 25(23):12653. https://doi.org/10.3390/ijms252312653
Chicago/Turabian StyleTsakiroglou, Maria, Anthony Evans, Alejandra Doce-Carracedo, Margaret Little, Rachel Hornby, Paul Roberts, Eunice Zhang, Fabio Miyajima, and Munir Pirmohamed. 2024. "Gene Expression Dysregulation in Whole Blood of Patients with Clostridioides difficile Infection" International Journal of Molecular Sciences 25, no. 23: 12653. https://doi.org/10.3390/ijms252312653
APA StyleTsakiroglou, M., Evans, A., Doce-Carracedo, A., Little, M., Hornby, R., Roberts, P., Zhang, E., Miyajima, F., & Pirmohamed, M. (2024). Gene Expression Dysregulation in Whole Blood of Patients with Clostridioides difficile Infection. International Journal of Molecular Sciences, 25(23), 12653. https://doi.org/10.3390/ijms252312653