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Identifying New Probiotics Using In Vivo Models

Probiotics pre-clinical animal trials

Dysbiotic characteristics are increasingly attributed to a range of serious, and sometimes fatal, digestive disorders affecting humans. These include inflammatory bowel diseases, chemotherapy-induced mucositis, radiation enteritis, NSAID-enteropathy and colon cancer.

We have developed animal models of these disorders as a viable tool to test and identify new probiotic species with the potential to restore homeostasis of the microbiota and improve intestinal architecture and function.

Which probiotics?

Understanding disease aetiology and pathogenesis is a critical determinant when identifying probiotics with likely therapeutic efficacy. Similarly, understanding the complex mechanisms underpinning probiotic action becomes vital when selecting probiotics for specific disorders. However, this information is often incomplete and there are examples of certain probiotics having no effect, or even deleterious clinical effects for some digestive disorders.

Therefore, pre-clinical animal model studies have the potential to streamline the selection of new probiotic candidates, further adding to safety information required for regulatory purposes. For example, the organism Streptococcus thermophilus TH-4 releases substantial amounts of folic acid that can be employed for conditions in which folic acid depletion has occurred. Intestinal mucositis induced by the chemotherapy drug methotrexate (MTX) is such a condition. Indeed this has been demonstrated in the rodent model setting.

Assessing probiotic efficacy

Traditionally, scientists have adopted a repertoire of assays and methodologies to determine therapeutic efficacy in animal model systems and hence predict the likelihood of clinical effectiveness in humans. However, these have almost universally been associated with examination of post-mortem specimens. The recent advent of non-invasive breath testing techniques allows probiotic efficacy to be determined and monitored in vivo in real time.

Non-invasive breath-tests

New breath-testing techniques enable a range of gastrointestinal functions to be determined non-invasively by the simple collection of expired breath. This is clearly an efficient and ethically acceptable means to identify new probiotic organisms. 13C-based technologies rely on the digestive degradation of 13C-labelled substrates to yield 13CO2 which can be detected in the expired breath by an Isotope Ratio Mass Spectrometer. Examples include the 13C-urea breath test to detect Helicobacter pylori infection, 13C-sucrose breath test to monitor small intestinal digestive function, 13C-octanoic acid breath test to monitor solid and liquid gastric emptying rate and 13C-lactose ureide breath test to monitor oro-caecal transit time.

Our aim is to increase application of these tests in our animal model systems in order to determine the effects of newly-identified probiotic species on a broader spectrum of physiological processes contributing to optimal digestive function. For example, the aforementioned organism S. thermophilus TH-4 has been demonstrated to partially ameliorate MTX-induced mucositis utilising the sucrose breath test in rats.

Indeed, 13C-breath-testing technologies are now being extended to include investigations into neurodegenerative diseases such as Alzheimer’s disease, autism and Huntington’s disease utilising a new 13C-methionine breath test. There is therefore a likelihood that simple breath-testing techniques could be employed to determine the therapeutic potential of new probiotics on organ functions and disorders remote from the digestive tract.

Similarly, volatile organic compounds (VOCs) in exhaled breath, for example methane and ethane, are able to form unique profiles that can be perturbed under disease conditions. VOCs can be detected by instruments such as the SIFT-MS (Selected Ion Flow Tube-Mass Spectrometer). Although in its infancy, VOC profiles in the breath of animals with induced bowel disease, could potentially be employed to monitor the impact of new probiotics on a broad range of organ systems; negating the requirement to administer 13C-labelled substrates either by oral gavage or injection.

Gordon Howarth
Gordon Howarth
began his research career in 1977 and has since published more than 130 peer-reviewed journal articles on the utilisation of in vivo models of gastrointestinal disease for the efficacy-testing of newly developed bioactive compounds.

If you’d like to read more about model systems in gastrointestinal research, here’s a relevant article: In Vitro Modelling of the Human Upper Digestive Tract.

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