Supplementary Material for: Euflammation Attenuates Central and Peripheral Inflammation and Cognitive Consequences of an Immune Challenge after Tumor Development

<p><b><i>Objective:</i></b> Repeated subthreshold bacterial exposures in rodents cause novel euflammation that attenuates neuroinflammation and sickness behaviors upon subsequent infectious challenges to the host without eliciting illness behavior. The investigation of bacterial exposure effects on brain and behavior is clinically relevant because bacterial-based antitumor treatments are used successfully, but are suboptimal due to their illness side effects. In addition, behavioral consequences (depression, cognitive impairments) to homeostatic challenges that are associated with inflammation are prevalent and reduce the quality of life in cancer patients and survivors. Therefore, this study tested the potential for euflammation to attenuate behavioral consequences of an immune challenge in tumor-bearing mice. <b><i>Methods:</i></b> Mice with and without oral tumors in their flank underwent the established peripheral euflammatory protocol or vehicle treatment, followed by an acute peripheral immune challenge (lipopolysaccharide [LPS] injection) or PBS. Cognitive function and sickness behavior were assessed after the challenge, and peripheral and central inflammatory responses were measured. <b><i>Results:</i></b> Euflammation reduced LPS-induced peripheral and central inflammation in all mice; however, neuroinflammation was less attenuated in tumor-bearing mice compared with tumor-free controls. LPS-induced lethargy and cognitive impairments were more pronounced among tumor-bearing mice and were effectively attenuated with euflammation. Cognitive changes were independent of brain-derived growth factor gene expression in the hippocampus. <b><i>Conclusion:</i></b> These results suggest that induction of euflammation may be useful in alleviating the negative side effects of bacterial-based tumor treatments and in potentially attenuating common behavioral comorbidities associated with cancer or other chronic diseases.</p>