Anti‐TNFα treatment in Crohn’s disease: Impact on hepatic steatosis, gut‐derived hormones and metabolic status

Abstract

Background and Aims An association between Crohn's disease (CD) and hepatic steatosis has been reported. However, the underlying mechanisms of steatosis progression in CD are not clear. Among the most effective CD treatments are agents that inhibit Tumor‐Necrosis‐Factor (TNF) activity, yet it is unclear why anti‐TNFα agents would affect steatosis in CD. Recent studies suggest that microbiome can affect both, CD and steatosis pathogenesis. Therefore, we here analysed a potential relationship between anti‐TNF treatment and hepatic steatosis in CD, focusing on the gut‐liver axis. Methods This cross‐sectional study evaluated patients with established CD, with and without anti‐TNFα treatment, analysing serum markers of liver injury, measurement of transient elastography, controlled attenuation parameter (CAP) and MRI for fat detection. Changes in lipid and metabolic profiles were assessed by serum and stool lipidomics and metabolimics. Additionally, we analysed gut microbiota composition and mediators of bile acid (BA) signalling via stool and serum analysis. Results Patients on anti‐TNFα treatment had less hepatic steatosis as assessed by CAP and MRI. Serum FGF19 levels were significantly higher in patients on anti‐TNFα therapy and associate with reduced steatosis and increased bowel motility. Neutral lipids including triglycerides were reduced in the serum of patients on anti‐TNF treatment. Bacteria involved in BA metabolism and FGF19 regulation, including Firmicutes, showed group‐specific alterations with low levels in patients without anti‐TNFα treatment. Low abundance of Firmicutes was associated with higher triglyceride levels. Conclusions Anti‐TNFα treatment is associated with reduced steatosis, lower triglyceride levels, alterations in FXR‐signalling (eg FGF19) and microbiota composition in CD.

Therapeutic modulation of the liver immune microenvironment

“…Similar findings were observed in 390 patients with Crohn’s disease after treatment with anti-TNF agents 166 . In one study, however, patients with Crohn’s disease undergoing anti-TNF therapy exhibited less hepatic steatosis as assessed by controlled attenuation parameter and MRI paralleled by increased FGF-19 serum levels 167 …”

“…[166] In one study, however, patients with Crohn's disease undergoing anti-TNF therapy exhibited less hepatic steatosis as assessed by controlled attenuation parameter and MRI paralleled by increased FGF-19 serum levels. [167] Anti-IL-1 therapy in severe AH…”

A Potential Role for Bile Acid Signaling in Celiac Disease-Associated Fatty Liver

“…In the intestine, some bile acids are modified by various bacteria to secondary bile acids, reabsorbed from the ileum, and returned to the liver via the portal bloodstream. We and others have previously identified alterations in bile acid metabolism and gut-liver interactions as pivotal players in the pathogenesis of hepatic steatosis and its complications [10][11][12]. Similarly, alterations in bile acid homeostasis, enterohepatic bile acid pool, and gut microbiota composition have been described in CeD [13,14].…”

TNFα is a key trigger of inflammation in diet-induced non-obese MASLD in mice

“…It also has been shown that anti -TNFα treatments may reduce mucosal inflammation and restore intestinal permeability in IBD patients and may alter intestinal microbiota composition [ 51 ]. Moreover, in the study of Manka et al it was shown that the protective effects of the anti -TNFα treatment were associated with an improvement of hepatic steatosis in patients with Crohn's Disease [ 52 ]. Somewhat in contrast, in the present study, bacterial endotoxin levels suggested to be indicative of intestinal barrier dysfunction [ 53 ] were significantly higher in SFC-fed mice regardless of strain or treatment when compared with the respective controls.…”