Could serum zonulin be an intestinal permeability marker in diabetes kidney disease?

Abstract

Zonulin is a protein associated with the tight junction complex opening at the intestinal epithelium, previously linked to obesity, cardiovascular diseases, type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). However, its role in CKD has not been totally elucidated. This study aimed to evaluate zonulin levels in subjects with diabetic kidney disease (DKD). This case-control study included two cases groups: 1) Advanced DKD cases: T2DM patients with estimated glomerular filtration rate (eGFR) <60ml/min/1.73m2; 2) Albuminuric T2DM cases: diabetic patients with urinary albumin excretion (UAE) >30mg/g creatinine, but with eGFR>60ml/min/1.73m2. Two control groups were also included: 1) T2DM controls: patients with T2DM without impaired kidney function; 2) Non-T2DM controls: subjects without T2DM and normal renal function. Serum levels of zonulin were measured by ELISA. Eighty-six individuals were included. Zonulin levels was different among study groups (P = 0.003). T2DM controls presented higher zonulin levels than non-T2DM controls [(131.35 (83.0–170.5) vs. 87.25 (54.7–111.8), P = 0.018] and advanced DKD cases [63.72 (45.03–106.0); P = 0.007]. Zonulin showed a positive correlation with eGFR (r = 0.222; P = 0.040), total cholesterol (r = 0.299; P = 0.034), LDL (r = 0.258; P = 0.021), and negative with albuminuria (r = -0.243; P = 0.024) and body fat (r = -0.271; P = 0.014). In the multivariate logistic regression analyses, zonulin levels were independently associated to renal outcomes [OR 0.99 (0.98–0.99, P = 0.012)] after 5-year inclusion. In conclusion, increased zonulin levels in patients with TD2M without renal disease suggest an impaired intestinal permeability. Moreover, its association with renal outcomes could indicate its use as a disease monitoring marker. However, the mechanisms behind this association should be better understood.

The role of gut dysbiosis-associated inflammation in heart failure

“…Zonulin is a family peptide produced in the intestinal and hepatic cells that regulate a protein complex named tight junctions. The literature has reported that high levels of zonulin are associated with increased intestinal permeability 20 , a condition that allows the translocation of LPS from the intestinal lumen into circulation, resulting in endotoxemia and a low-grade chronic inflammation through the activation of Toll-like receptors 21 .…”

Gut permeability, circulating bacterial fragments and measures of congestion in peritoneal dialysis

“…In the present study, we did not determine the bacterial fragments, zonulin and calprotectin levels in PD effluent, which may provide additional insights on their relation with cardiovascular disease and clinical outcome. Previous studies have reported that PD effluent endotoxin and bacterial DNA levels are prognostic indicators of PD-related peritonitis [ 43 , 44 ], but their relation to systemic inflammation or patient survival were not stated in these reports. To the best of our knowledge, the clinical significance of PDE zonulin and calprotectin levels had not been explored.…”

Zonulin as a Potential Therapeutic Target in Microbiota-Gut-Brain Axis Disorders: Encouraging Results and Emerging Questions

“…These studies suggest that the integrity of intestinal barrier may determine the severity of systemic inflammation due to the migration of immune cells from the gut into the joints [ 153 ]. In addition, a possible role of zonulin in the pathomechanism of other disorders has been suggested, including but not limited to cardiac [ 68 , 156 ], pulmonary [ 12 , 13 , 157 , 158 ], or renal diseases [ 15 , 159 , 160 , 161 ].…”