Table 1.

(Patho)physiological effects of intestinally generated uremic toxins and their precursors at their side of origin.

Metabolites	Side of Origin	(Patho) Physiological Effects	Ref.
Metabolites Generated by Gut Bacteria
p-Cresol	Colon	Intestinal epithelial cells:
		↑LDH leakage	[32]
		↓ATP content
		↓TEER
		↑Paracellular transport
		Genotoxicity	[33]
		Leukocytes/Macrophages:
		↓IL-12 p40 production	[34]
		↓Respiratory burst activity	[35]
Indole	Colon	Intestinal epithelial cells:
		↑Mucin2 expression	[36,37]
		Regulation of gut homeostasis	[38]
		↓TNF-α mediated NF-κB activation	[39]
		↓IL-8 expression
		↑IL-10 expression
		↑TER
Indole-3-acetic acid	Colon	Intestinal epithelial cells:
		↑IL-22 expression	[40]
		↑Antimicrobial C-type lectin REG3G
Trimethylamine	Colon	ND
H2S	Colon	Intestinal bacteria:
		↑Antibiotic resistance	[53]
		Protection against ROS	[54]
		Protection against immune cells	[55]
		Maintenance of anaerobic conditions
		↓Butyrate oxidation	[56]
Circulating Uremic Toxins
p-Cresyl sulfate	Intestinal epithelial cells and liver	Leukocytes:
		↑Baseline ROS and ↓ROS after stimulation	[68]
		↑Rolling	[70]
		↑Plaque growth and instability	[71]
		↓IFNγ-producing Th1 cells	[73]
		↓Anti-bacterial immune response	[74]
		↓Proliferation of CD43(+) B cell progenitors	[75]
		↑Macrophage activation
		↓Antigen processing	[76]
		Premature aging of immune cells	[77]
p-Cresyl glucuronide	Intestinal epithelial cells and liver	Leukocytes:
		Synergistic to pCS: ↑ROS, impaired blood	[69]
		flow; vascular leakage	[70]
Indoxyl sulfate	Liver	Anti-inflammatory and tolerizing effect on	[80]
		DCs
		Monocytes:
		↑TNF-α→↑HUVEC CX3CL1	[81]
		↑ROS	[82]
		↑Leukocyte-endothelial cell adhesion	[82,86]
		Macrophages:
		↑TNF-α	[83]
		↑NF-κB, ROS, mitochondrial Ca2+	[84]
		overload
		↓Nrf2	[85]
Indole-3-acetic acid	Colon	Neutrophils:
		↑peroxidase activity	[87]
		↑Glucose and glutamine metabolism	[88]
		↑Oxygen consumption	[88]
		↑Structural changes and cell death	[87,89]
		↑Phagocytic activity	[91]
		Genotoxicity	[92]
Trimethylamine-oxide	Liver, kidney, and other	↑VCAM-1	[94]
		↑Monocyte-endothelial
		adhesion→↑inflammatory gene expression
		Activates PKC and p-NF-κB
H2S	Brain, vascular tissue, liver, kidney, RBC, and other	Leukocytes:
		↓Leukocyte-endothelial adhesion	[97,98]
		↓Leukocyte infiltration
		Regulation of post-translational	[100]
		modification of NF-κB pathway
		Macrophages:
		↓Pro-inflammatory cytokine production	[44]
		↓COX-2 and NO production
		↓Macrophage motitlity
		↓MPO activity	[101]
		↓Inflammation	[102]
		↓Antigen-binding	[103]
		↓Cell lysis (glomerular mesangial cells and T-lymphocytes)

LDH: lactate dehydrogenase; ATP: adenosine triphosphate; TE(E)R: transepithelial (electrical) resistance; IL: interleukin; REG3G: regenerating islet-derived 3 gamma;ND: none described; RBC: red blood cells: ROS: reactive oxygen species; DCs: dendritic cells; HUVEC: human vascular endothelial cells; VCAM: vascular cell adhesion molecule: PKC: protein kinase C; COX: cyclooxygenase; NO: nitric oxide.; MPO: myeloperoxidase. ↓: decreased; ↑: increased.