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. 2024 May 31;12(6):1227.
doi: 10.3390/biomedicines12061227.

Association of Circulating Markers of Microbial Translocation and Hepatic Inflammation with Liver Injury in Patients with Type 2 Diabetes

Leila Gobejishvili  1   2   3 , Vatsalya Vatsalya  2 , Diana V Avila  3 , Yana B Feygin  4 , Craig J McClain  2   3   5 , Sriprakash Mokshagundam  5   6 , Shirish Barve  2   3
Affiliations

Association of Circulating Markers of Microbial Translocation and Hepatic Inflammation with Liver Injury in Patients with Type 2 Diabetes

Leila Gobejishvili et al. Biomedicines. .

Abstract

Background: Virtually the entire spectrum of liver disease is observed in association with type 2 diabetes mellitus (T2DM); indeed, T2DM is now the most common cause of liver disease in the U.S. We conducted a pilot study to investigate the relevance of increased microbial translocation and systemic inflammation in the development of liver injury in patients with T2DM.

Methods: Patients with T2DM (n = 17) and non-diabetic controls (NDC; n = 11) aged 25-80 yrs. participated in this study. Serum levels of endotoxin, calprotectin, soluble CD14 and CD163, and several inflammatory cytokines were measured. In addition to standard liver injury markers, ALT and AST, novel serum markers of liver injury, keratin 18 (K-18) M30 (apoptosis-associated caspase-cleaved keratin 18), and M65 (soluble keratin 18) were evaluated. Statistical analyses were performed using the Mann-Whitney test to assess differences between study groups. Pearson's correlation analysis was performed to determine the strength of association between two variables using GraphPad Prism 9.5.0 software.

Results: Patients with T2DM had significantly higher levels of sCD14 in comparison to NDC, suggesting an increase in gut permeability, microbial translocation, and monocyte/macrophage activation. Importantly, relevant to the ensuing inflammatory responses, the increase in sCD14 in patients with T2DM was accompanied by a significant increase in sCD163, a marker of hepatic Kupffer cell activation and inflammation. Further, a positive correlation was observed between sCD163 and endotoxin and sCD14 in T2DM patients but not in NDC. In association with these changes, keratin 18 (K-18)-based serum markers (M65 and M30) that reflect hepatocyte death were significantly higher in the T2DM group indicating ongoing liver injury. Notably, both M65 and M30 levels correlated with sCD14 and sCD163, suggesting that immune cell activation and hepatic inflammation may be linked to the development of liver injury in T2DM.

Conclusions: These findings suggest that the pathogenic changes in the gut-liver axis, marked by increased microbial translocation, may be a major component in the etiology of hepatocyte inflammation and injury in patients with T2DM. However, larger longitudinal studies, including histological evidence, are needed to confirm these observations.

Keywords: T2DM; endotoxemia; liver injury; sCD14; sCD163.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Serum markers of gut microbial translocation. (A) Endotoxin levels, (B) Calprotectin, (C) Soluble CD14 levels, (D) Soluble sCD163. Data are presented as individual values with mean ± SD. Mann–Whitney test. ** p < 0.01, *** p < 0.001, ns—non-significant.
Figure 2
Figure 2
Elevated serum soluble CD163 levels correlate with endotoxin and sCD14 levels in patients with T2DM. (A) Pearson correlation analysis between endotoxin and sCD163 levels in NDC and T2DM groups, (B) Pearson correlation analysis of sCD14 and sCD163 levels in NDC and T2DM groups. P and r values are indicated.
Figure 3
Figure 3
Serum levels of cytokine, chemokine, and hormones in patients with T2DM and non-diabetic controls. (A) IL-6, IL-8, TNF, MCP-1, and PAI-1 levels, (B) Leptin, adiponectin, resistin, and insulin levels. Data are presented as individual values with mean ± SD, ns -non-significant.
Figure 4
Figure 4
Serum levels of liver injury markers M65 and M30. Data are presented as individual values with mean ± SD, * p < 0.05, ns—non-significant.
Figure 5
Figure 5
The liver injury marker, M65, correlates with sCD14 and sCD163 in patients with T2DM. (A) Pearson correlation analysis of serum sCD14 and M65 levels in NDC and T2DM groups, (B) Pearson correlation analysis of serum sCD163 and M65 levels in NDC and T2DM groups. P and r values are indicated.
Figure 6
Figure 6
The liver injury marker, M30, correlates with sCD14 and sCD163 in patients with T2DM. (A) Pearson correlation analysis of serum sCD14 and M30 levels in NDC and T2DM groups, (B) Pearson correlation analysis of serum sCD163 and M30 levels in NDC and T2DM groups. P and r values are indicated.
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Grants and funding

This study was supported by grants from the National Institutes of Health: P20GM113226 (Craig J McClain), P50AA024337 (Craig J McClain), grant funding from the Kentucky Diabetes Research Board (KDRB) (Shirish Barve) and Intramural Basic Grant, University of Louisville School of Medicine (Leila Gobejishvili).