STW5 reduces the proinflammatory signature on transcriptomic, proteomic and histological level in a rat model for gastroesophageal reflux disease

Gastroesophageal reflux disease (GERD) was the most common GI-diagnosis (8.9 million visits) in the US in 2012. Although proton pump inhibitors (PPI) represent the treatment of choice, they fail to achieve adequate symptom relief in up to 40% of patients.

In the present study, we investigated the modulation of inflammatory markers by STW5 in comparison to the PPI Omeprazole (O) in an animal model of sub-chronic GERD. Rats were pre-treated for 7 d with either STW5 (0.5 or 2 ml/kg) or O (30 mg/kg). Esophagitis was induced surgically, followed by a further 10 d treatment. On day 10, animals were sacrificed and their esophagi evaluated macroscopically and histologically. Transcriptomic profiling was performed by Agilent whole genome array (rat).

Inflamed controls showed marked esophagitis as reflected in the macro- and microscopic damage scores as well as corresponding proteomic and transcriptomic profiles. Transcripts of well-known markers of inflammation and the immune response like IL-1β (14 x), IL-6 (11 x), TNF-α (11 x), CINC-1, 2 & 3 (rat analoga to human IL-8) and transcripts so far not linked to esophagitis like CXCL1 (CXC-motif ligand; 32 x) or CCL4 (CC-motif ligand 4; 34 x) were significantly upregulated. Interestingly, transcripts of the NFκB family were only weekly (1 to 4 x) upregulated.

Both treatments improved macroscopic parameters to a similar extent as reported earlier. Proteom-profiling revealed a stronger and down-regulation of proinflammatory mediators in the STW5 groups compared to O. This was also reflected in the transcript profile. IL-1β and especially members of the C- and CXC chemokine families (CCL4, CXCL1, CXCL2, 3, 6 and 10) were strongly down regulated (10 to 33 x). Transcripts of IL-6 (4.8 to 8.3 x) and TNF-α (4.9 to 9.8 x) were down regulated by STW5 in the range of their up-regulation. They were, however, not detected on protein level. This might be related to other factors influencing protein formation or different sensitivities of the arrays. The results indicate that the chronicity of the inflammation might have led to changes in the cytokine profile with lower TNF-α and IL-6 responses compared to chemokines like CXCL1 or CCL4, so far not linked to esophagitis.

STW5 affects multiple targets on genome and proteome levels thereby reducing inflammation in the esophageal tissue. Results further substantiate the clinical data on STW5, which showed a substantial relief of concomitant reflux symptoms in patients with functional dyspepsia.