Table 1.
Role of gut microbiota and microbial related metabolites in the pathogenesis of CKD (Clinical studies).
| CKD model | Microbial related metabolite (s) | Main findings | Technique(s) | Study |
|---|---|---|---|---|
| 52 ESRD patients and 44 healthy controls |
Pseudouridine, l-phenylalanine, and p-hydroxyphenylacetic acid. |
1. l-phenylalanine and p-hydroxyphenylacetic acid levels are positively correlated with CRP levels in ESRD and healthy controls groups 2. In ESRD patients, pseudouridine, l-phenylalanine, and p-hydroxyphenyl acetic acid metabolites positively correlated with IL-6 levels. 3. Inflammatory markers and metabolites can be used a diagnostic and predictive marker for CKD. |
LC/MS | (40) |
|
*223 patients with ESRD and 69 healthy controls. |
PCS IS Phenylacetylglycine phenyl sulphate |
1. Alteration in gut microbiota in CKD Patients; increased the abundance of Eggerthella lenta, Flavonifractor spp, Alistipes spp, Ruminococcus spp and Fusobacterium spp, and depleted Prevotella spp, Clostridium spp, SCFA-producing species and several butyrate producers (Roseburia spp, Faecalibacterium prausnitzii and Eubacterium rectale). 2. Aberrant gut microbiota and its derived uremic toxins are associated with disease development. |
Shot gun metagenome sequencing and HPLC |
(39) |
|
*30 Caucasian CKD patients (stage 3), 121 Caucasian CKD patients (stage 5), and 80 controls |
Betaine, choline, and TMAO |
1. Advanced CKD patients (stage 5) expressed the lowest level of circulating betaine and highest levels of choline and TMAO compared with CKD patients (stage 3) and healthy controls. Serum betaine levels significantly declined with renal function drop. |
LS-MS | (41) |
| 103 CKD patients with stage 1 to 5 (Mild, moderate and ESRD) and 46 healthy controls |
PCS, IS, TAMO, and p-cresyl glucuronide |
1. CKD progression is accompanied by deterioration in kidney functions and elevation in serum uremic toxins levels. 2. The relative abundance of Alistipes and Oscillibacter is positively correlated with CKD progression, while Lachnospira, Veillonella, and Dialister negatively correlate with the disease severity. 3. Oscillibacter (involved in pyruvate metabolism) is positively associated with uremic toxins and CKD development. |
LC-MS 16S rRNA gene sequencing |
(42) |
| 141 CKD patients and 14 controls. |
PCS, IS, p-cresyl glucuronide, and Indole-3-acetic acid. |
1. Increasing the plasma level of gut-derived uremic toxins is associated with impaired kidney functions and decline in eGFR. The clearance of plasma protein-bounded metabolites is decreased with disease progression. |
HPLC | (28) |
| 77 CKD patients undergoing hemodialysis and 30 healthy |
Putrescine | 1. Hemodialysis patients with mild cognitive decline showed a significant reduction in Class Coriobacteriia and genus Tyzzerella 3, Blautia, and Lachnospira 2. Bilophila, and serum putrescine (gut-related metabolite) can be a sensitive marker for cognitive decline in hemodialysis patients. |
16S rRNA gene sequencing and GC-MS |
(43) |
| 72 patients with CKD And 20 controls |
PCS, Secondary bile acid, and ipopolysaccharide biosynthes. |
1. The early stages of CKD showed a high abundance of secondary bile acid biosynthesis microbial genes, but lipid metabolism and lipopolysaccharide biosynthesis are enriched in the advanced stages. 1. Bacteroides eggerthii can be a biomarker for the early stages of the disease. 2. CKD group showed a low abundance of Prevotella sp. 885. 3. PCS is negatively correlated with the eGFR. |
Shotgun sequencing and Metabolomics (GC-MS) |
(44) |
| 115 children and adolescents with CKD stage (1–4) |
TMAO, dimethylamine, and Trimethylamine |
1. Gut related metabolites are associated with blood pressure abnormalities and cardiovascular risk in pediatric CKD. 2. Decrease in the diversity of Phylum Cyanobacteria, genera Subdoligranulum, Faecalibacterium, Ruminococcus, and Akkermansia in CKD patients with abnormal blood pressure. 3. Plasma levels of dimethylamine, and trimethylamine are inversely associated eGFR. Accumulation of TAMO, dimethylamine, and trimethylamine are higher in advanced CKD. |
16S rRNA gene sequencing and LC–MS/MS |
(24) |
| 92 adult CKD patients (31mild, 30 moderate, and 31 advanced) and 30 healthy controls |
IS and PCS | 1. Accumulation of uremic toxins IS and PCS are positively correlated with disease progression. 2. The diversity of gut microbiota (genus-level: Escherichia_Shigella, Dialister, Lachnospiraceae_ND3007_group, Pseudobutyrivibrio, Roseburia, Paraprevotella and Ruminiclostridium, and species-level: Collinsella stercoris and Bacteroides eggerthii) are highly associated with CKD stages. |
16S rRNA gene sequencing |
(20) |
| Phase1: 10 patients with rapid decline in eGFR and 10 control patients without rapid decline Phase 2: 140 CKD and 144 healthy controls |
Indole propionic acid, IS, PCS |
1. Indole propionic acid produced from a healthy gut is highly reduced in CKD patients and patients with a decline in eGFR. 2. Indole propionic acid (renal protective metabolite) can be a biomarker for renal function. 3. IS and PCS were high in the CKD group compared with controls |
HPLC | (33) |
| 95 CKD patient with differed stages, 11 hemodialysis patients, and 18 healthy controls |
TMAO | 1. CKD patients have a high level of TMAO. Plasma TMAO is inversely correlated with eGFR. |
LC-MS/MS | (29) |
| 78 children and adolescents with CKD stage G1 to G4 |
Short chain fatty acids, propionate, and butyrate |
1. CKD children with congenital anomalies of the kidney and urinary tract (CAKUT) showed a reduction I plasma level of propionate with increase in the relative abundance of phylum Verrucomicrobia, genus Akkermansia, and species Bifidobacterium bifidum. 2. The Firmicutes to Bacteroidetes ratio didn't show significant difference between groups. CKD children with an abnormal ambulatory blood-pressure monitoring profile had higher plasma levels of propionate and butyrate. |
16S rRNA gene sequencing & GC-Flame Ionization detector |
(45) |
| Eighty patients with CKD of stages 2 to 4 |
TMAO | 1. CKD patients showed upregulation of SMAD3 and NLRP3. 2. Plasma and urine levels of TMAO are significantly high in CKD patients with elevated serum TGF-β1 and IL-1β levels. TMAO can be used as a marker for CKD progression. |
Spectrophotometer | (46) |
| 86 CKD children stage (1–3) |
Urinary TMAO | 1. Urinary TMAO is positively correlate with Bifidobacterium, Lactobacillus, Collinsella and Blautia. 2. CKD children with abnormal ambulatory blood-pressure monitoring (ABPM) profile had a lower abundance of the Prevotella genus than those with normal ABPM |
LC-MS and 16S rRNA gene sequencing |
(47) |
| 5,469 subjects of Prevention of Renal and vascular end stage disease (PREVEND study) |
TMAO | 1. TMAO was positively correlated with body mass index, age and diabetes mellitus, and negatively associated with eGFR. 2. TMAO was involved in all mortality risks. |
NMR | (48) |
| 317 community-acquired pneumonia (76 CKD patients) |
TMAO | 1. TMAO (gut-derived) is associated with various risk factors and comorbidities. 2. The level of TMAO is reduced by antibiotic treatment (modulating gut microbiota can be a good target for reducing the TMAO risks). |
LC-MS/MS | (49) |
| 488 CKD patients (stages 1–5) |
phenylacetylglutamine | 1. Phenylacetylglutamine is highly accumulated in advanced stages of CKD. 2. Elevation of serum level of phenylacetylglutamine is a risk factor for cardiovascular disease high mortality rate in CKD patients. |
LC-MS | (50) |
| 51 renal transplant recipients, 51 CKD patients, and 65 stable renal transplant recipients (unrelated cohort) |
PCS, IS, TMAO, p-cresyl glucuronide, and Phenylacetylglutamine |
1. The serum levels of gut-derived uremic toxins are significantly decreased after renal transplantation compared with CKD patients. |
UPLC-MS/MS | (51) |
| 227 CKD patients (had cardiovascular surgery for coronary artery disease) |
TMAO | 1. The advanced stage of CKD showed the highest TMAO level. 2. The elevated level of TMAO is associated with CKD development and infracted coronary arteries. |
HPLC-APCI -MS/MS |
(52) |
|
*20 CKD on HD and 60 healthy controls (Divided into 3 group 20 controls each) |
p-cresol and indole (precursors of PCS and IS) |
1. CKD is highly affected by microbial metabolism. 2. The dietary intervention significantly impacts microbial metabolism (CKD patients and healthy household controls on the same diet have a similar microbial metabolism pattern). |
GC-MS | (53) |
|
**521 stable subjects with CKD |
TAMO | 1. TAMO is associated with the progression of renal dysfunction, poor prognosis, and mortality risk in CKD patients. 2. Elevated TMAO is a risk factor for cardiovascular disease. |
LC/MS/MS | (54) |
*
The study also included in Table 2;
**
The study also included in Table 3. IS, Indoxyl sulfate; PCS, p-cresyl sulfate; TMAO, trimethylamine N-oxide; LC, liquid chromatography; GC, gas chromatography; MS, mass spectrometer; HPLC, high performance liquid chromatography; eGFR, estimated glomerular filtration rate; ESRD, end stage renal disease; SCFAs, short chain fatty acids; NMR, nuclear magnetic resonance.