Gut-kidney axis: Dysbiosis and renal disease

Table 1 Main uremic toxins and their effect on the kidney

Compound	Total plasma concentration in CKD	Lowest concentration active on cultured renal cells (μM)	Effects on cultured renal cells	Effects on kidneys in vivo
pCS	Median 50; maximum 500	100	Decreased viability, increased oxidative stress, increased inflammatory and profibrotic responses, decreased expression of nephroprotective factors	Progression of CKD, kidney fibrosis, promote epithelial-to-mesenchymal transition. Activate the renal-angiotensin system
pCG	Median 0.22; maximum 8	25	Decreased the function of proximal cell membrane transporters (MRP4)	Kidney fibrosis. Promotes epithelial-to-mesenchymal transition
IS	Median 221; maximum 1100	1000	Decreased viability, increased oxidative stress, increased inflammatory and profibrotic responses, decreased expression of nephroprotective factors	Accelerated fibrosis and CKD progression. Podocyte injury
IAA	Median 5; maximum 50	250	Reduced viability through induction of apoptosis in tubular cells	Accelerated CKD progression
TMAO	Median 25; upper quartile > 38	ND	No data	Kidney tubulointerstitial fibrosis

CKD: Chronic kidney disease; IAA: Indole-3 acetic acid; IS: Indoxyl sulfate; pCS: Para cresyl sulfate; pCG: P-cresyl-glucuronide; TMAO: Trimethylamine N-oxide.

Table 2 Significant taxa from the top 50-genus level compared between groups

	Healthy control (%)	MASLD (%)	CKD (%)	Both diseases (%)
Blautia	7.37	10.34	8.71	8.10
Collinsella	7.12	3.13	6.32	4.48
Bifidobacterium	3.44	2.68	0.85	1.24
UCG_002	1.91	0.67	1.20	1.26
Dorea	1.56	1.39	0.99	1.04
Escherichia-Shigella	1.52	2.26	4.37	4.04
Agathobacter	1.50	2.43	0.95	1.38
Ruminococcus	1.22	0.73	0.81	0.84
Romboutsia	1.15	0.25	0.68	0.41
Holdemenella	0.90	0.26	0.29	0.53
Christensenellaceae-R-7-group	0.87	0.21	0.72	0.34
Coprococcus	0.77	0.77	0.46	0.40
Erysipelotrichaceae-UCG-‘003	0.76	0.47	0.41	0.34
uncultured	0.74	0.44	0.73	0.65
Eubacterium-ruminantium-group	0.59	0.37	0.30	0.19
Clostridium_sensu_stricto-1	0.54	0.34	0.84	0.82
UCG_005	0.44	0.10	0.42	0.38
Butyricicoccus	0.44	0.70	0.54	0.41
Lachnoclostridium	0.42	1.31	0.87	0.97
Senegalimassilia	0.32	0.15	0.22	0.31
UCG_003	0.28	0.17	0.27	0.09
Ruminococcus_gnavus-group	0.18	1.59	1.86	2.68

MASLD: Metabolic dysfunction-associated steatotic liver disease; CKD: Chronic kidney disease.

Table 3 Biotic intervention studies in patients with chronic kidney disease

Study design	Study duration (weeks)	CKD stage	n	Supplementation	Uremic toxin changes	Taxa changes post-intervention
RCT, SC, DBP	18	4, 5	37	9 bacterial strains across; Bifidobacterium, Lactobacillus and Streptococcus	↓pCS; ↓IxS	↑Bifidobacterium; ↑Lachnospiraceae; ↑Faecalibacterium; ↓Clostridiales; ↓Ruminococcaceae
RCT, SC, DBP	26	5 (HD)	45	Bifidobacterium longum NQ1501, Lactobacillus acidophilus YIT2004; Enterococcus faecalis YIT0072	↓pCS	↑Bacteroidaceae; ↑Enterococcaceae; ↓Ruminococcaceae; ↓Halomonadaceae; ↓Erysipelotrichaceae; ↓Peptostreptococcaceae; ↓Clostridiales family XIII
RCT, DBP	38	5 (PD)	21	ITF	None	↓Abundance of indole-generating species
RCT, DBP	52	3, 4	56	9 strains across Bifidobacterium, Lactobacillus, Streptococcus	None	↑Bifidobacterium; ↑Blautia
RCT, SC, SB	14	3, 4	59	Β-glucan fiber	↓Free pCS; ↓IxS; ↓pCG	Shift from Bacteroides 2 enterotype to Prevotella enterotype

CKD: Chronic kidney disease; DBP: Double-blind placebo.controlled trial; HD: Hemodialysis; IXS: Indoxyl sulfate; SB: Single-blind trial; PD: Peritoneal dialysis; pCG: P-cresyl glucuronide; pCS: Para cresyl sulfate; RCT: Randomized controlled trial; SC: Single center.

Table 4 Characteristics of intestinal microbiota of patients with chronic kidney disease

Species	Genus	Family	Order	Class	Phylum	Alteration of taxa
Escherichia coli	Escherichia Shigella, Desulfobrio and Streptococcus	Enterococcaceae and Fusobecteriaceae	Enterobacteriales and Coriobacteriales	Bacteoidia Gammaprotobacteria, Fusobacteria and Actinobacteria	Proteobacteria and Fusobacteria	More abundant	66.6% studies showed lower richness compared to healthy controls. 90.9% studies showed distinct bacterial composition from healthy controls
	Roseburia, Faecalibacterium, Pyramidobacter, Prevotellaceae and Prevotella 9	Prevotellaceae, Lachnospiraceae and Lactobacillaceae	Clostridiales, Burkolderiales and Verrucomicrobiales	Betaproteobacteria and Verrucomicrobiae	Synergistetes	Less abundant

Table 5 Characteristics of the principal studies included in the Zhao et al[26] review

Ref.	Disease severity	n (case)	Hemodialysis
Wang et al[27], 2020	ESRD	223	223
Wang et al[29], 2019	CKD	128	0
Ren et al[28], 2020	CKD	110	0

ESRD: End stage renal disease; CKD: Chronic kidney disease.

Table 6 Characteristics of the studies included

Ref.	Design	Sample size	Intervention	Main results
De Mauri et al[62], 2022	Placebo-controlled, randomized study	IG = 24; CG = 23	Probiotic	In the probiotic group there was a trend in the reduction of microbiota toxins
Cosola et al[63], 2021	Randomized trial	IG = 23; CG = 24	Synbiotic	In the symbiotic group a decrease in IS in the CKD group
Ebrahim et al[64], 2022	Randomized controlled trial	IG = 23; CG = 22	Prebiotic	There was a significant reduction in uremic toxin levels, both in free IS and free pCG
Armani et al[65], 2022	Randomized controlled trial	IG = 23; CG = 23	Prebiotic	There was a significant decrease kin IL-6 levels and a trend toward pCS reduction only in the prebiotic group

CKD: Chronic kidney disease; IG: Intervention group; CG: Control group; IS: Indoxyl sulfate; pCS: Para cresyl sulfate; pCG: P-cresyl-glucuronide; IL-6: Interleukin-6.

Table 7 Studies reporting gut microbiota modulation in chronic kidney disease patients

Ref.	Type of therapy	Results
Abdelbary et al[67], 2022	Sucroferric oxyhydroxide	In HD patients, Veillonella and Ruminococcus increased, while Subdoligranulum decreased
Borges et al[68], 2017	Immobilized symbiotic LB complex L vs placebo	In 56% of patients in the treatment group, gut microbiota recovered. CRP decreased in the treatment group
Abdelbary et al[69], 2020	Dietary intervention	Patients with CKD had higher levels of Escherichia, Shigella and Klebsiella, while Blautia was decreased
Kimber et al[70], 2020	Rifaximin	Rifaximin was linked to reduced diversity and richness of microbiota
Lai et al[71], 2019	Low protein diet	Low protein diet increased Akkermanmsiaceae and Bacterpoidaceae and decreased Christensenellaceae Clostridiaceae, and Pasteurellaceae Lactobascillaceae levels
Miao et al[72], 2018	Lanthanum carbonate	Shannon index decreased following lanthanum carbonate therapy
Cruz-Mora et al[73], 2014	Symbiotic	In HD patients, symbiotic therapy increased Bifidobacterium but decreased Lactobacillus levels
Nazzal et al[74], 2017	Oral vancomycin	Following vancomycin therapy, Clostridia, Roseburia, Enterococcaceae and Bacteroides decreased
Rossi et al[16], 2016	Symbiotic	Symbiotic were linked to an increase in Bifidobacterium
Simeoni et al[75], 2019	Probiotics	Probiotics increased Lactobacillales and Bifidobacteria levels
Yacoub et al[76], 2017	Advanced glycation end products	PD patients who received a one-month advanced glycation end-products restriction had a lower abundance of Prevetella copri

CKD: Chronic kidney disease; HD: Hemodialysis; CRP: C reactive protein; PD: Peritoneal dialysis.

Table 8 Human studies reporting the use of probiotics in chronic kidney disease

Ref.	Probiotics	Study	Results
Viramontes-Hörner et al[82]	Symbiotic Lactobacillus acidophilus and Bifidobacterium lactis	Multicenter double-blind randomized trial, n = 42; HD	Safe; improve gastrointestinal symptoms
Pavan et al[83]	Symbiotic: Prebiotic + probiotic	Prospective observation placebo-controlled, n = 24 CKD	Slowing of progression of kidney disease
Natarajan et al[84]	Streptococcus thermophiles, Lactobacillus acidophilus and Bifidobacterium longum	Single center, double blind, placebo controlled trial, n = 22 HD	Improvement of quality of life. Reduction of serum indoxyl glucuronide and C reactive protein
Ranganathan et al[85]	Lactobacillus acidophilus, Streptococcus thermophilus and Bifidobacterium longum	Multicenter, prospective, randomized, double blind, n = 46 CKD	Reduction in blood urea nitrogen. Improvement in quality of life
Ranganathan et al[85]	Lactobacillus acidophilys, Streptococcus thermophiles and Bifidobacterium longum	Single center, prospective, randomized, double blind, n = 16 CKD	Reduction in blood urea nitrogen and uric and improvement in quality of life
Taki et al[86]	Bifidobacterium longum	Single center, non-randomized, placebo controlled trial, n = 27 HD	Decrease in homocysteine and triglycerides
Simenhoff et al[87]	Lactobacillus acidophilus	Single center observational trial, n = 8 HD	Reduction in dimethylamine and in nitrosodimethylamin

CKD: Chronic kidney disease; HD: Hemodialysis.