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February 28, 2020

The future of prebiotics

Erica D. Sonnenburg, PhD, authors our final article in the four-part CME series titled, "The Microbiome and Digestive Health: A Look at Prebiotics."
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This article is the final of a four-part CME series on prebiotics. This educational activity is supported by an educational grant from GlaxoSmithKline. Part 1, “Prebiotics 101,” Part 2, “Diet vs. Prebiotics,” and Part 3, “The Current State of Prebiotics” are available through AGA University.

Author
Erica D. Sonnenburg, PhD
Department of Microbiology and Immunology
Stanford University School of Medicine

Introduction

Prebiotics, as defined by the International Scientific Association for Probiotics and Prebiotics, are “a substrate that is selectively utilized by host microorganisms conferring a health benefit”. While this definition allows the inclusion of a wide variety of molecules, complex carbohydrates such as inulin, fructo-oligosaccharides (FOS), and galacto-oligosaccharides (GOS) are the most commonly known prebiotics (as previously discussed in part 3 of this series). There has been renewed excitement surrounding the potential of prebiotics to improve human health as an increasing number of diseases ranging from gastrointestinal disorders to Alzheimer’s disease have been linked to a disrupted intestinal microbiota. However, the clinical studies required to evaluate the efficacy of prebiotics as a therapeutic have been lacking. Questions that are fundamental to our understanding of prebiotics remain to be answered including: What is an optimal, effective dosage of prebiotics? Does this amount vary depending on the disease being treated or whether the goal is to maintain health in an otherwise healthy individual? Is a diversity of carbohydrate linkages and/or degree of polymerization more beneficial? Should the goal of prebiotic supplementation be the recruitment of new microbial members to the microbiota or to improve the fermentation capacity and short-chain fatty acid production of the existing community? Does a prebiotic formulation need to “match” microbiota type? If so, how do we determine the best match? While answering these questions may seem daunting, many of can be answered with properly designed human trials.

Potential health benefits of prebiotics

There is growing evidence that a diet rich in the complex carbohydrates that make up dietary fiber (the fermentable carbohydrate portion of which is referred to as microbiota-accessible carbohydrates or MACs), is beneficial to health (1). Prebiotics, which by definition promote the growth of host-associated bacteria, are a form of MACs. In a mouse model of C. difficile-associated colitis, mice fed a MAC-rich diet effectively cleared the pathogen. Clearance was also achieved using the prebiotic inulin in the absence of a MAC-rich diet, indicating that some of the benefits of MAC consumption can be accomplished using purified prebiotics (2). However, this study also demonstrated the inability of FOS to clear C. difficile indicating that in some contexts the type of prebiotic matters. In addition to infectious disease, chronic disease can also be ameliorated using prebiotic supplementation. Prebiotics have been shown to provide a benefit for weight loss, reducing systemic inflammation, and improving glucose metabolism and lipid profiles (3). However, the literature is also littered with studies reporting little to no benefit for prebiotic use, indicating that an individual’s starting microbiota may play an important role in the effectiveness of prebiotics. There is growing evidence that the state of an individual’s microbiota can be highly predictive of responses to an intervention. Starting microbiota composition can predict the postprandial blood glucose response to consumption of specific foods as well as the efficacy of an exercise regimen to prevent diabetes (4, 5). Therefore, it is reasonable to think that effective prebiotic therapy may require approaches consistent with the tenets of precision medicine.

“Precision” prebiotics

Our current ability to collect extensive datasets on an individual’s microbiota (including microbial composition, gene content and metabolite profile) and markers of health (such as real-time blood glucose monitoring and extensive host metabolite profiling) coupled with advances in machine learning will lead to precision approaches to managing health. The specific prebiotic formulation and dosage that is the most beneficial for treating or preventing a given condition may be determined by an algorithm formulated from human studies or perhaps in real time with the development of rapid measurements of an individual’s microbiota and health status. These types of data could yield directly translatable recommendations without complete understanding of the underpinning molecular mechanisms. In other words, identifying the most effective formulation and dosage of a prebiotic based on an individual’s baseline microbiota and the condition being treated does not require understanding the specific mode of action of the prebiotic therapeutic. Given the safety profile of prebiotics, there is no reason, other than the lack of meaningful investment from funding agencies, why these studies can’t start immediately.

Conclusion

The burden of non-communicable, chronic diseases continues to rise in the industrialized world and is now spreading around the globe as populations trade their traditional lifestyle for one that is associated with so-called “western” diseases. The connection between the gut microbiota and these diseases, which includes auto-immune diseases, cardiovascular disease, and diseases associated with metabolic disruptions such as type 2 diabetes, will continue to place the manipulation of the microbiota at the forefront of biomedicine. It is becoming evident that the western diet, with its reduced MAC-content, is a major contributor to these diseases. The low cost of MAC-deficient, processed foods makes it difficult to overcome the deleterious effect. In the absence of large-scale changes in the American diet, alternatives such as prebiotic supplementation could be a viable option to improve the chronic disease burden in the U.S. and abroad.

Talking points to use with your patients
  • A complex carbohydrate diet (fiber) is beneficial overall but can be challenging to adopt; individual prebiotics that can recapitulate the beneficial effect of fiber in specific disease states offers a viable alternative.
  • The majority of current studies on prebiotics have shown little clinical benefit. There are fundamental questions which need to be addressed, like the dose, duration, formulation (single or multiple, degree of polymerization) and mechanism of action to be addressed in future trials.
  • Over the next decade we will likely see an artificial intelligence-based approach to identify and develop precision prebiotics matched to an individual’s microbiome, clinical features and disease state.

To claim your CME credits for this activity, please visit AGA University.

References

1. Sonnenburg, E.D., Sonnenburg, J.L. Starving our microbial self: the deleterious consequences of a diet deficient in microbiota-accessible carbohydrates. Cell Metabolism 2014; 20(5):779-786.

2. Hryckowian A.J., Van Treuren, W., Smits, S.A. et al. Microbiota-accessible carbohydrates suppress Clostridium difficile infection in a murine model. Nature Microbiology 2018; 3(6):662-669.

3. Anderson, J.W., Baird, P., Davis, R. H. et al. Health benefits of dietary fiber. Nutrition Reviews 2009; 67(4):188-205.

4. Zeevi, D., Korem, T., Zmora, N. et al. Personalized Nutrition by Prediction of Glycemic Responses. Cell 2015; 163(5):1079-1094.

5. Liu, Y., Wang, Y., Ni, Y. et al. Gut Microbiome Fermentation Determines the Efficacy of Exercise for Diabetes Prevention. Cell Metabolism. 2019;31(1):77-91.e5.

Conflict of interest disclosures

Dr. Sonnenburg has no conflicts of interest to disclose.

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