A Transient Induction of Blood-Circulating Bile Acid Is a Therapeutic Marker and Target of Chemotherapy-Oriented Myelosuppression

Rapid recovery of normal blood production is essential for the completion of chemotherapy for different types of solid tumors and leukemia's. However, chemotherapeutic agents can damage bone marrow cells and cause myelosuppression, which is one of the serious side effects of the cancer treatment. It is hard to predict in which patients this will be problematic but this results in a delay in the completion of the treatment protocol. An early, reliable, marker of successful recovery of blood production during cycles of chemotherapy would thus be highly beneficial.

Under normal steady state conditions concentrations of bile acids (BA) in peripheral blood are low. However, in several liver diseases and critically ill patients circulating BA levels rise substantially. Some studies even argue that the levels of BA are correlated to clinical outcome and mortality. In contrast, we have previously reported that a specific BA, tauroursodeoxycholic acid (TUDCA), has a beneficial role as a molecular chaperone in maintenance and expansion of hematopoietic stem and progenitor cells (HSPC). More recently, we have also seen that BA in mouse PB are increased during hematopoietic stress (irradiation, LPS injections and 5-FU treatment). Circulating BA levels may thus have a more clinical relevance in hematopoiesis than previously has been recognized. At present the cause and precise role of increased BA levels during hematopoietic stress are unknown. In light of these findings we hypothesized that in the rebuild of the blood system after stress, circulating BA levels may be an indicator of recovery and they may have an unknown role in the blood recovery process.

Initially, we measured levels of BA in pediatric patients in treatment for different types of childhood cancers. These measurements showed clearly that circulating BA levels are upregulalted during recovery after chemotherapy. This was especially seen during the recovery phase from myelosuppression. Furthermore, there was a significant, positive, correlation between increased BA levels and favorable clinical outcome in these patients. Mass spectrometry analyses showed that the main component of the increased BA was glycochenodeoxycholic acid (GCDCA), glycoursodeoxycholic acid (GUDCA) and GUDCA-3S. To replicate these results in a mouse setting we used 5-FU injections and examined PB, plasma and BM cells at different time points. In the nadir (day 3 to day 6) in the mouse, BA levels were increased moderately but during BM recovery (day 6 to day 12) the levels were highly and significantly increased.

To assess if ursodeoxycholic acid (UDCA) plays a role during hematopoietic recovery, we injected TUDCA into 5-FU treated mice. PB and BM analyses revealed that TUDCA treated mice showed more rapid and better recovery. Since T/G/UDCA are known for their ability to suppress an induction of endoplasmic reticulum (ER) stress, 5-FU treated mice were also treated with an ER stress inhibitor, Salubrinal, and the mice showed similar or better degree of recovery. These findings strongly indicate that the induction of specific types of BA can serve as a supportive factor in blood recovery possibly through chaperone function and suppression of ER stress.

We also tested if the induced BA upon 5-FU treatment has a biological meaning in mice, 5-FU treated mice were injected with a chemical compound, GW4064, which suppresses BA production. However, the suppression of BA levels did not impact PB and BM profiles. This might be due to the fact that the UDCA is rarely detected in rodents even under stress and compositions of BA are largely different between human and rodents.

During critical illness glucocorticoids (GC) are known to increase substantially and the induction of circulating BA might be reflecting the GC levels. We have seen that the concentration of GC is increased at similar timing with BA induction after 5-FU treatment. In support of this, injection of corticosterone to mice also increased the level of circulating BA. Our data suggests that the BA increase upon chemotherapy is a consequence of the elevation of GC levels, possibly through the alteration of production and/or reabsorption of BA.

To conclude, BA in the circulating blood is a potential marker to assess the recovery timing of chemotherapy-treated patients. Moreover, medication of TUDCA/GUDCA may be a novel optional treatment to boost-up the recovery from myelosuppresive conditions.