Non-Invasive Tests in Animal Models and Humans: A New Paradigm for Assessing Efficacy of Biologics Including Prebiotics and Probiotics

Abstract

Newer biological agents that are designed to have multiple effects on a host require better ways to determine both their safety and toxicity. Indeed ecologically potent factors such as agents that can alter the gut milieu and change host responses are now being realized as a viable alternative to more focused pharmaceuticals. Even in the pharmaceutical arena there is a growing awareness of the preventative and therapeutic potential of alternative agents. Probiotics and prebiotics amongst other agents fall into this category and can have both direct and indirect effects on the pathogenesis and progress of disease. This review details some of the new approaches using non-invasive tests to enable firstly a better definition of a stressed through to a damaged gastrointestinal mucosa. They constitute ways to apply dynamic function testing in animal models and humans to provide reference points to which other measurements can be related e.g. altered circulating cytokines, altered gene expression. As such this phenotypic scaffold, alone and combined with newer molecular parameters, will improve our understanding of the interaction of luminal factors within the alimentary tract and the impact that these have on physiologically challenged mucosa and in disease both at the gastrointestinal level and also in remote organs. Practically, the dynamic function tests, primarily breath tests, can now be used as diagnostic and prognostic indicators of the efficacy of new biologics such as probiotics and prebiotics that in part elicit their effects by altering the ecology of particular regions of the intestine.

Assessment of Prebiotics and Probiotics

“…altered circulating cytokines, altered gene expression). As such, this phenotypic scaffold, alone and combined with newer molecular parameters, will improve our understanding of the interaction of luminal factors within the alimentary tract and the impact that these have on physiologically challenged mucosa and in disease both at the gastrointestinal level and in remote organs [54].…”

Histone deacetylase inhibitors: clinical implications for hematological malignancies

“…Class IV of HDACs has only one member (Butler and Kozikowski 2008), HDAC 11, which shares similarities to both class I and class II HDACs.…”

“…The active site of HDACs consists of a cylindrical pocket, covered by hydrophobic and aromatic amino acids, where the lysine residue fits when deacetylation takes place; a zinc ion is located near the bottom of the cylindrical pocket, which is coordinated by amino acids and a single water molecule (Butler and Kozikowski 2008). During deacetylation, the water molecule acts as the nucleophile attacking the carbonyl, assisted by the zinc ion (Fig.…”

A simple and inexpensive enteric-coated capsule for delivery of acid-labile macromolecules to the small intestine

“…We therefore have developed a simple and inexpensive enteric-stable capsule with an ability to deliver milligram amount payloads to the small intestine of pigs. Non-invasive functional breath tests have been used previously in animal models (Anderson et al, 2002;Pelton et al, 2004;Butler, 2008;Terry et al, 2012) with more applications/examples in humans (Ishii et al, 2001;Festi et al, 2005;Tooley et al, 2006;de Lacy Costello et al, 2013;Pizzoferrato et al, 2013). In our studies, we chose 13 C sodium acetate ( 13 C-acetate) for a surrogate biomarker of "payload" in the GI tract of pigs as it is relatively inexpensive and its metabolism in the duodenum to 13 CO 2 can be non-invasively measured and quantified from exhaled breath, enabling determination of gastric emptying rates (Braden et al, 1995;Barbosa et al, 2005).…”