Kidney Week

Abstract: TH-PO1075

Role of Bile Acid Enzyme Cyp8b1 in Type 2 Diabetes (T2D)-Associated Kidney Disease

Session Information

• Pathology and Lab Medicine
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Pathology and Lab Medicine

• 1700 Pathology and Lab Medicine

Authors

• Sharma, Nisha, City of Hope Beckman Research Institute, Duarte, California, United States

Nisha Sharma, PhD

• Agua, Alon Roy L., City of Hope Beckman Research Institute, Duarte, California, United States

Alon Roy L. Agua, MS, PhD

• Jin, Lihua, City of Hope Beckman Research Institute, Duarte, California, United States

Lihua Jin, PhD

• Liu, Jiahui, City of Hope Beckman Research Institute, Duarte, California, United States

Jiahui Liu, PhD

• Lyu, Xintian, City of Hope Beckman Research Institute, Duarte, California, United States

Xintian Lyu, MS

• Zhang, Shili, City of Hope Beckman Research Institute, Duarte, California, United States

Shili Zhang

• Malek, Vajir, City of Hope Beckman Research Institute, Duarte, California, United States

Vajir Malek, PhD

• Natarajan, Rama, City of Hope Beckman Research Institute, Duarte, California, United States

Rama Natarajan, PhD, FASN

• Huang, Wendong, City of Hope Beckman Research Institute, Duarte, California, United States

Wendong Huang, PhD

Background

Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease, with growing evidence implicating a potential liver–gut–kidney axis in its pathogenesis. CYP8B1 is a liver-specific enzyme controlling the 12α-hydroxylated to non-12α-hydroxylated bile acid ratio. Although the bile acids and their interactions with gut microbiota are known to impact DKD, the role of CYP8B1 in DKD remains unclear. To investigate the role of CYP8B1 in DKD progression and its impact on bile acid signaling and gut microbiota alteration.

Methods

DKD was evaluated in GAN diet–induced and db/db mouse models. CYP8B1 was inhibited using knockout (KO) and knockdown (KD) approaches. Bile acid profiles were measured in serum, feces, liver, and kidney. Serum and hepatic cholesterol levels were quantified. Renal injury was assessed by the albumin-to-creatinine ratio (ACR). Histological and immunohistochemical analyses (F4/80) were performed. Kidney bile acid receptor FXR protein expression was assessed. Gut microbiota composition was accessed and analyzed.

Results

CYP8B1 suppression significantly reduced the ratio of 12α- to non-12α-hydroxylated bile acids in serum, liver, and kidney across both models. Renal function was improved, as evidenced by reduced albumin excretion and ACR (p = 0.0319). Histological analyses showed improved renal and hepatic morphology, with reduced fibrosis. Immunohistochemistry revealed approximately a 60% reduction in F4/80-positive macrophage infiltration compared with that in diabetic controls. Notably, kidney FXR protein expression was increased in CYP8B1-deficient mice relative to disease controls. Additionally, CYP8B1 inhibition significantly increased the relative abundance of Akkermansia muciniphila.

Conclusion

CYP8B1 inhibition improves DKD by modulating bile acid composition, enhancing FXR signaling, reducing inflammation, and improving gut microbiota profile. These findings identify CYP8B1 as a promising new therapeutic target within the liver-gut-kidney axis.

Acknowledgment

This study is supported by the Larry L. Hillblom Foundation (2024-D-016-FEL).

Funding

• Private Foundation Support