Core Concept: Prebiotics gain prominence but remain poorly defined

With the gut microbiome increasingly recognized as a major player in shaping human biology, probiotic treatments—introducing a few billion purportedly beneficial micro-organisms into human gut communities composed of trillions of microbes—are under intense investigation. Study designs and results have been a mixed bag, and the impact of probiotics remains unclear. Enter the probiotics' conceptual cousin, prebiotics.

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One's gut bacteria composition could benefit from prebiotics, but the mechanisms—not to mention the very definition—of prebiotics remain in question. Image courtesy of Shutterstock/Sebastian Kaulitzki.
Although probiotics consist of live microbes, prebiotics are microbe food: substances metabolized by microbes that are not digestible by the host. As researchers gain a more complete picture of the forces that shape microbial gut diversity, some think prebiotics could confer health benefits that probiotics have struggled to demonstrate, in part because prebiotics can nourish multiple microbial species already in place, triggering broader and potentially more robust changes in the host's microbiome and health.

Prebiotics are generally nondigestible carbohydrates that get fermented by microbes in the gut; they are found in foods that are high in fiber, although not all fibers have prebiotic properties. Despite being a couple of decades behind probiotics in research, prebiotics are potentially key ingredients in the evolving stew of gut influencers.

The goal of manipulating whole microbial populations through selective feeding raises practical challenges; as health products, both probiotics and prebiotics exist somewhere in the poorly regulated space between food and drugs. Defining what is and is not a prebiotic will have commercial consequences. Scientifically, too, an ongoing debate over the meaning of the term "prebiotics" reflects diverging views of how they may actually confer benefits. Even the duo that coined the term 20 years ago may not see eye to eye.

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FEEDING THE BEASTS
Interest in using food to modulate gut microbes to improve human health goes back more than a century. In a 1907 book called The Prolongation of Life, Russian zoologist Elie Metchnikoff, later a Nobel Prize recipient, noted that eating fermented dairy products loaded with lactic acid bacteria seemed to enhance the health of Bulgarian peasants (1). Metchnikoff and others, including those doing early work in Japan on yogurt (2), planted seeds for the field that would come to be called "functional foods." Scientific interest in probiotics was one offshoot from this concept.

The term "prebiotics" is newer, coined in a 1995 paper (3) where Glenn Gibson, now a professor of food microbiology at the University of Reading in the United Kingdom, and Marcel Roberfroid, emeritus professor of biochemistry and toxicology at the Université catholique de Louvain in Brussels, demonstrated that the fibrous oligosaccharide inulin reaches the colon intact and selectively stimulates the growth of bifidobacteria. The researchers defined prebiotics as "nondigestible food ingredients that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacterial species already resident in the colon, and thus attempt to improve host health" (3).

At the time, the idea that a food product that wasn't delivering a bolus of beneficial bacteria could nonetheless reliably change the composition of human gut microbiota was quite novel. During an early 1990s visit to the Cambridge, United Kingdom, laboratory of John Cummings, renowned for his work on dietary fiber, intestinal bacteria, and bowel function, Roberfroid announced that he had identified just such a compound: inulin. Cummings looked at him and said "Marcel, that's not possible," Roberfroid recalls.

Since that 1995 publication (3), researchers have robustly demonstrated a "prebiotic effect" from consuming certain fiber-containing foods, and animal studies have suggested that prebiotics can positively influence factors such as gut function, immune function, glucose tolerance, and metabolic regulation, as well as reduce the incidence of colon cancer.

Human studies are still in their infancy; one challenge is that the composition of gut microbes varies across individuals, so the effect of feeding them with prebiotics is highly variable too (4). Research on prebiotics' effects on obesity and inflammation is especially active (5), and one recent meta-analysis suggests that inulin consumption may play a role in weight reduction (6). Studies also suggest that combining prebiotics with probiotics—an approach called synbiotics—may potentiate the effects. And researchers are trying to ascertain how generalizable and durable prebiotic effects are across human populations of different ages, physiological states, as well as culinary and cultural traditions.

Even as these discoveries elucidate prebiotic inner workings, however, they also have led to calls for an expanded definition of what counts as a prebiotic. Gibson and Roberfroid's paper (3) stipulated that nondigestible carbohydrates—that is, oligo- and polysaccharides—as well as some peptides and lipids, serve as metabolic substrates for colonic bacteria and can thus be termed "colonic foods." Most such molecules stimulate microbial growth or metabolic activity broadly, and as such did not fit Gibson and Roberfroid's concept of "metabolic selectivity for one or a number of beneficial bacteria" (3).

However, for a variety of reasons, the requirement for a prebiotic to target specific species no longer holds, argues Laure Bindels, an assistant professor at the Université catholique de Louvain. In a review published in March 2015, Bindels et al. note that accumulating data in diverse areas, such as Crohn's disease, Clostridium difficile infection, and obesity, suggest that overall biodiversity in the microbiota is what confers benefits, and not necessarily an increase or decrease of specific populations (7). Plus, the fermentation products of one microbial species' supper can in turn feed other species. And short-chain fatty acids—widely considered the host-benefitting metabolic products of these microbes—are produced by many types of microbes, so targeting a single group, such as bifidobacteria, seems misguided. What's more, "beneficial" is a murky and outdated descriptor for a gut microbe, Bindels says. Indeed, some microbial species may act beneficially in one context but detrimentally in others. "It's not like a battle between good and evil anymore," Bindels notes.

GUTS IN A NAME
Bindels and her colleagues propose shifting the focus from bug-counting to a functional approach. A compound is a prebiotic, she stipulates, if its metabolism by gut microbes modulates the overall composition or activity of the microbial community in ways that have beneficial effects on the host. "We think that you change the ecosystem and how it functions—the way the [microbe] interacts with the host—to get benefits," she says.

These differences may seem subtle, but they are important, says Robert Hutkins, a professor of food science at the University of Nebraska, Lincoln. "It's possible that a prebiotic might not even result in a significantly measurable change in the number of a particular taxon," he says, but it certainly might change the functional properties of the community by changing the expression of various metabolic enzymes, for example.

One vocal objector to Bindels' suggested revision is Gibson. "If we deviate away from the original intentions as she seems to want, then it just opens the floodgates for lots of 'wannabe' materials to be classified as prebiotics—wrongly!" he says. "Bad for producers who have reliable products, bad for consumers who become more confused, but good for industries who have materials they want to class as prebiotics but cannot under the existing criteria."

On December 7 and 8, the International Scientific Association for Probiotics and Prebiotics debated the matter, with plans to produce a consensus paper for the field.

Hutkins acknowledges that changing the definition might well mean researchers have to rethink what qualifies as a prebiotic. He points to a recent study suggesting that riboflavin, known as vitamin B2, has prebiotic properties because it contributes to the metabolism of a gut microbe, Faecalibacterium prausnitzii (8), although the vitamin isn't itself metabolized by the bacteria. Removing the requirement for fermentation or metabolic transformation may take the concept too far from its original intent, he says. On the other hand, several carbohydrates that currently aren't on the short list of well-established and accepted prebiotics perhaps should be, he adds.

For his part, Roberfroid says the field must look beyond simply giving a thumbs-up or a thumbs-down to specific compounds. "The approach we had in 1995 is only a very small part of the story," he says. "We cannot reduce the prebiotic definition [based on] what we know about inulin." Rather, he says, the focus should be on figuring out how to apply the concept of prebiosis most effectively to feed the microbes in our guts. "Extracting specific [prebiotic] products is not the major message for me. The major message is increasing the diversity of the food we eat in order to increase the diversity of and functional benefits conferred by our microbiota."