Here’s what we’ve learned so far.
Now that startups can deliver at-home microbiome testing kits straight to your door, and with do-it-yourself fecal transplants a topic of polite conversation, we can safely say that consumer interest in the vast community of organisms that inhabit our bodies-that is to say, the microbiome-has hit mainstream status.
But rank-and-file civilians are merely catching up with the scientific community, which has been intrigued by the identity-and the implications-of the bacteria, fungi, and even viruses that make us…well, us since long before the National Institutes of Health launched the Human Microbiome Project in 2008.
And all along, research findings have had no trouble keeping investigators’ attention rapt-or keeping the dietary supplement space licking its chops at the prospect of products that can harness the microbiome’s benefits. As Joseph Petrosino, PhD, professor, Baylor College of Medicine (Houston, TX), notes, “Excitement exists because the microbiome is being shown to impact health and disease broadly, and may be readily modified to treat a specific disease state without the side effects attributed to other drug treatments.”
But it’s a long way from here to there, with plenty still to learn. Nonetheless, experts agree: No matter how long it takes to put the puzzle together, the pieces are already falling into place.
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Beyond the Belly
A sure sign that “good gut bugs” have arrived is the fact that nobody still associates their benefits solely with the gut. “While I try to avoid piling on the hype,” Petrosino says, “there are microbiome studies that show associations with diseases throughout the body-skin, oral, lung, vaginal, etc.-in addition to gut microbial associations with diseases that aren’t gut-centric.”
The gut-brain axis is one example of these associations, with central theory being that the biome in the gastrointestinal tract can influence cognitive and mental states, including asocial behavior, anxiety, and depression, as well as suicidal tendencies, autism spectrum, and even Alzheimer’s disease.
Adds Petrosino, “The field is currently moving beyond association studies-which microbes or microbial-community features are associated with health?-to attempting to identify the functions encoded by bacteria and bacterial communities that are responsible for the effects observed.” The goal: identify bacterial targets for the development of new therapeutics or even diagnostic biomarkers. “In some cases, individual organisms may have a profound therapeutic impact,” Petrosino says, “or a community of organisms may be important to maintaining or promoting a healthy outcome.”
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Ralf JÃ¤ger, FISSN, CISSN, consultant, Pharmachem Laboratories Inc. (Kearny, NJ), agrees-to an extent. “We now have a good understanding of the makeup of the human gut microbiome,” he notes. “Yet the question still remains: Can we make short- or long-term changes to the overall makeup of the gut microbiome, and do those changes result in meaningful long-term health benefits?”
Mervyn de Souza, PhD, vice president, health and wellness, NPD, innovation and commercial development, Tate & Lyle (Hoffman Estates, IL), also notes “an acknowledgment by many microbiome researchers regarding the need to focus on causality versus correlation.” While data is rife with relationships linking, say, microbiome compositions and activities and certain health or disease states, in many cases, de Souza says, “it’s not clear if a microbiome that’s associated with a disease is a contributing factor or just a consequence of that disease state.”
What is certain, he says, is that the microbiome “has an important impact on us humans-that’s been established and, for the most part, accepted.” And the complexity of its interactions with its hosts, as well as with external factors like diet and geography, is equally undeniable. But going forward, the field will need “collaboration across broad areas of expertise to drive analysis and interpretation of the massive amounts of existing and new sequencing information,” de Souza says.
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Translation to Formulation
That’s a steep hill for science to climb, and the summit’s still a hike away. Yet if researchers are impatient, dietary supplement marketers might be even more so. After all, with public curiosity about the microbiome-to say nothing of good old-fashioned probiotics-as robust as ever, companies that can formulate microbiome benefits into their products stand to win. And to hear Petrosino tell it, “the translation to products or interventions is already starting to happen.”
“We already have probiotics, prebiotics, synbiotics, immunobiotics-dead ‘probiotics’-and fermented foods like sauerkraut, kimchi, and kombucha to improve gut health,” JÃ¤ger concurs. “But if the microbiome allows us to identify a specific deficiency in the gut microbiome makeup, specific and targeted probiotics might be the best way to improve health.” Which product category will benefit most from current gut microbiome work is anyone’s guess. “But as knowledge progresses,” JÃ¤ger says, “we’ll find more ingredients that either beneficially or negatively influence the gut microbiome.”
Petrosino wagers that an advantage will accrue to products able “to distinguish themselves from the probiotics that existed before the microbiome started to be explored rigorously,” as earlier products were often “poorly formulated” or unable to deliver live organisms to the gastrointestinal sites where they’re active. And he believes that prebiotics designed “to ‘fertilize out bacterial gardens,’ as it were, will be among the first products we see emerging.”
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Bringing such development to fruition “will be a four-step process,” JÃ¤ger predicts, with the first step continuing the microbiome mapping and sequencing that’s already taught us so much.
But in addition to sequencing, de Souza advocates for mechanistic studies to reveal how microbiome metabolites, for instance, might mediate important host-microbe and microbe-microbe interactions. For example, he says there’s “solid data” on the production of short-chain fatty acids in the colon that impact mineral absorption; research his company has conducted with Connie M. Weaver, a professor in the department of nutrition science at Purdue University, has found that the microbiome, in concert with a branded form of Tate & Lyle’s soluble fiber, mediates calcium absorption and bone strength. “We could use more information on the breadth of microbiome-derived natural products, the functional roles of these metabolites and corresponding host impacts, as well as the influence of diet,” he says.
After sequencing and mechanistic work, JÃ¤ger continues, we’ll still need to identify “unique features of the microbiome for specific subgroups of the population,” while also defining what’s “normal,” and how variations on that norm can still have a meaningful-though not negative-effect.
“Third,” he says, “we have to answer the chicken-or-egg question: Is a unique microbiome the reason for superior health or disease, or is it simply a byproduct of such status”-again, teasing correlation from causation. And the last step, JÃ¤ger says, answers this question: “Can we change the microbial makeup, and does this indeed have a beneficial effect on health?”
But even then, neither academia nor industry’s task will be complete. As JÃ¤ger says, “What will it take to translate our increasing knowledge of the microbiome into dietary supplements or functional foods? Clinical trials. Microbiome research allows us to pick the best-suited strains for specific target groups-but any potential benefits need to be validated in human clinical study.”
So, hurry up and wait. But as you do, explore the following areas to see lessons we’ve learned, and longer-term questions we still have to answer.
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Methods and Models
One basic lesson we’ve learned from research on the human microbiome is that not all strains of gut microbes are the same-nor, even, are all species or subspecies. Yet because getting the isolate just right is important if you want to develop a probiotic that performs the desired functions, it’s a relief to know that laboratory technology keeps marching on.
“Technologies are improving the resolution with which we can identify bacterial strain-to-strain variance in individuals and the functions that some strains encode to benefit health,” says Petrosino. “These differences will have important ramifications in the selection of microbes used to treat disease and promote health.”
And that’s not all. “Improvements in cultures and animal-model systems are enabling us to understand what the microbes we associate with health and disease are doing in the host environment,” he adds. “Recent improvements in identifying viruses, fungi, and other members of the microbiome and their roles in health and disease will further impact this field.”
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One Size Does Not Fit All
What makes the “perfect” human microbiome? Turns out there is no such thing. Notes de Souza, even when looking at microbes from the same genera, “scientists have found significant variations in number among healthy individuals. These findings challenge the concept of an ideal ‘healthy’ microbiome.”
A more enlightened goal to pursue is what de Souza calls a healthy “functional core”-that is, a subset of metabolic and other molecular functions that the microbiome performs within a particular habitat, “but that can be provided by different organisms in different people,” he says. “Having the ability to maintain a healthy microbiome regardless of the definition, and potentially to identify, enrich, and maintain those microbe groups required to maintain a ‘functional core’ through dietary inputs as well as identification of critical probiotics would be hugely beneficial.”
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Probiotic R&D might appear to be the primary beneficiary of a well-mapped and -understood microbiome. But, says Petrosino, “Don’t underestimate prebiotics. To date, diet is one of the greatest means by which to impact the microbiome, and supplements harnessing the best part of our diet-insoluble fiber-will have a positive impact on our microbiome without having to worry about whether the strains in a particular probiotic will be accepted or sustained by the community of microbes that currently reside in the gut-that is, tolerated by the immune system.”
For his part, de Souza is “personally excited” about the opportunity to use specific soluble fibers and prebiotics to target specific beneficial members of the microbiome, or “guide populations toward more natural assemblages to mitigate disease symptoms, maintain healthy states and proactively address health imbalance without compromising our pursuit of convenience, improved health, and wellbeing.”
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Anyone who’s had a bacterial infection owes a debt to our modern catalogue of antibiotics. But “while we’ve benefitted greatly from antibiotics,” de Souza says, “what has their true impact on the current microbiome been, and have some of our best microbial allies gone extinct as collateral damage in the war against microbial pathogens?”
Perhaps an even more interesting question is whether or not we could “harness the collective power of the microbiome to maintain the balance in our favor when it comes to general health and wellbeing,” he continues. As antibiotic-resistant bugs emerge, he sees increasing knowledge of the microbiome and prebiotics as offering an “opportunity to address this issue in a smarter way that’s more sustainable, and just as effective.”
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If he could wake up one morning and answer any pressing question about the microbiome’s effects on human health, Petrosino would pose this: “What single-best measure can be taken to ensure that you set your microbiome on the right foot immediately after birth? Or is it actually even during pregnancy?”
That’s because mounting data show that the seeds of everything from mental health, obesity, and BMI to asthma and more may germinate under the influence of early microbiota/microbiome exposure and development. “And the means to establish, protect, ensure, or correct these early-life exposures so that we all set off on the right foot toward ideal health may have a great impact on quality of life, and may also have a positive impact on the cost of healthcare,” he says.
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