The trendy microbes

Abstract

After dominating the earth in numbers and biomass for a good 3.5 billion years, microbes are now finally in the public consciousness. The vigorous surge in the study of microbes promises to yield novel approaches to treating diseases and maintaining health. In the middle of the deluge of scientific publications and lay articles, we pause to reflect on this trend.

Keywords: :

• microbiota
• microbiome
• termite
• fecal transplant

Step aside, orange. Microbes are the new black. Upscale cafes in New York serve microbial Mai Tais, and the in-crowd slip away for lunchtime bacterial face rubs. The literati and glitterati discuss FMT over dinner in dim-lit penthouse restaurants, and the waiter does not bat an eyelid. Sh*t is no longer a four-letter word. Gordons and Knights are in, Versaces and Ferragamos are out. Bacteroidetes and Firmicutes are already “oh-so-last-century,” the true elite now speak of Verrucomicrobia and Akkermansia. Department chairs and university trend-spotters, always a few steps behind the curve, desperately want a share of that microbiota pie. NIH study sections and panelists, always a step ahead, are starting to turn their noses at microbiota poseurs. Funding agency committees discuss computerized searches to weed out grant applications with the word “microbiota” or “microbiome,” unless they also include words like “functional analyses.” New journals, and even new columnists, have popped up to cover the trend.

Fecal transplants, a primitive therapeutic option, is now our best bet for the most severe forms of a modern disease—antibiotic-precipitated C. difficile diarrhea.¹ Perhaps feces, not the mysterious “black bile,” should be considered one of the four humors. And like those humors of yore, the body has to have this in the right proportions for good health; an imbalance can be rectified by depletion (with antibiotics) or a fresh infusion (with a transplant). Physicians and professionals, out of embarrassment, or for fear of lapsing into dormitory jokes, use the term FMT (fecal microbiota transplantation) in polite company. Beyond maladies like diarrhea and irritable bowel syndrome, the treatment has been explored for obesity and diabetes.¹ The more adventurous physicians and patients report positive effect of FMT for disorders ranging from chronic fatigue syndrome to multiple sclerosis and autism.¹ In all, the search term “microbiota” returns 189 open clinical studies for exploration and intervention.² Victorian era cure-all elixirs pale in comparison to FMT for the range of disorders they claim to tackle.

Physicians and regulators are puzzled about the formalized mode of delivery of this new and/or old treatment.³ How does one regulate something so ubiquitous, inexpensive and that, for extremely sick patients, borders on the miraculous? If the procedures are too onerous, desperate patients will fire up a video on the internet and reach for the kitchen blender. The attendant risks, however, can land a patient back in the hospital with unpredictable, possibly worse, disorders. In a rare confluence, physicians, patients, pharmaceutical companies, and regulators alike are eager to move to the next phase of this treatment: the development of colorful, odorless capsules with natural or designer bacterial formulations that are as varied and commonplace as the drugs at the local pharmacy.

A recent review heralds this new and remarkable era of microbe-based therapeutics.⁴ The authors “envision that the next generation of bacterial cell therapy systems will be autonomous microbial ‘physicians,’ integrating the capacities to diagnose human disease, make decisions on the appropriate treatment and bring it into effect, and self eliminate from the human host when the condition is alleviated.” This is not the stuff of science fiction—the review details several examples of such systems for treating infections, inflammation, diabetes, and cancer. Many of these therapeutics have yielded promising results in animal systems, but only one, a Lactococcus lactis strain producing IL-10 for the treatment of colitis, has been tested in human patients.⁴ Technical and regulatory challenges notwithstanding, the reality of bacteria-based therapeutics will be upon us very soon. Our internal pharmacopeia will upend the current standard treatments. Broad-spectrum antibiotics will bear the stigma now reserved for second-hand smoke. Narrow-spectrum antibiotics will be used to treat specific infections and, possibly, even to surgically displace select bacterial populations in the gut.

But why stop with humans? Animal microbiomes will be altered to reduce infections and treat diseases, increase biomass, and improve fitness. For instance, laminitis, a significant cause of lameness in horses and other animals often has a gut microbial etiology. A microbiota transplant may well allow that prize thoroughbred to win one more race. Targeted radical and systematic manipulation of the microbiota of farm animals has been relatively slow to catch on, but is inevitable in the coming years.

There is great interest in microbial manipulations to control arthropod vectors of human and animal diseases such as malaria and dengue. Perhaps even dust allergy, caused by the fecal material of the dust mite, could be mitigated by altering the insect’s microbiome. Disease mitigation is only one aspect of our reinvigorated interest in tinkering with microbial ecology. Termites, for example, cause extensive structural damage to buildings, crops, and forests, with the annual costs of control and repair estimated at $2 billion in the United States.⁵ Underscoring the importance of microbial symbionts to termite biology, antibiotic-mediated depletion of the microbiota resulted in delayed colony growth and reduced colony fitness.⁶ Could a phage cocktail, or an errant bacterial spore—a termite pathogen, throw a spanner into the complex microbial milieu of the hindgut, and unravel the intricate lignocellulose breakdown machinery, in effect giving the insects a lethal bout of indigestion? Such phages or spores could, in some form, be incorporated into building materials and, potentially, ward off termite attacks.

For centuries, Man and Microbe have fought relentless and brutal wars against each other. With our relatively new and nuanced view, we will forge new alliances with friendly microbes, and target the nasty ones. Human ingenuity and microbial resilience will come together to herald a brave new world. The possibilities are exciting, but true advance will require, as a timely commentary recommends, "a healthy dose of skepticism."⁷ Also, as a note of caution, we should not conflate our ability to manipulate our physical or biological world with the notion that we have power over our environment. Microbes have seen apocalypses and ice ages, dinosaurs, and dodos. For the microbes, almost old as the earth, humans are only the latest trend on the evolutionary catwalk.

Disclosure of Potential Conflicts of Interest

No potential conflict of interest was disclosed.

10.4161/gmic.36381