Compared to images of attractive people on video screens, in glossy magazines, and even stories about them in good old-fashioned books, you are smelly. This is because you are substantially a volatile organic compound. Perhaps the best first step toward understanding your own microbiome and even doing something about it is to recognize this fact.
I’ve emphasized the importance of microbial metabolites or chemical by-products. Our microbes are busy enough making them to fulfill many a chemist’s dreams. Microbial metabolites include sugars, fatty acids, and lipid compounds as well as alcohols, ketones, aldehydes, and even smelly gases like sulfide and methane. Yes, it’s true. Humans make methane gas just like cows do.
The amount and variety of microbial metabolites is truly impressive. But given that microbes are a majority of our makeup, it’s not surprising. Those metabolites, along with our energy sources, affect our overall chemical makeup.
Some of the chemicals we make are structurally designed to build our cells, organs, tendons, muscles, and bones. However, many are smaller molecules exuded into the gases and liquids that come from our body (such as tears and urine). Other chemicals waft off our skin into the surrounding air. These are usually found in sweat and are what necessitate deodorants for many of us. These chemicals easily enter the air because of a property called high vapor pressure and are known as volatile organic compounds, or VOCs.
You may have heard of industrial VOCs, such as formaldehyde, before. However, more VOCs are produced by plants and microbes and are largely harmless. Many, though not all, VOCs carry a scent the odor receptors in our nose and olfactory glands recognize. An example of a microbial scent I am sure you are familiar with is the mildewy, musty smell found in the bathrooms, showers, and even tents of public campgrounds. This smell is caused by the chemical tribromoanisole.
People say you are “cutting the cheese” when someone farts. However, an even closer cheesy odor, at least to really smelly ones like Limburger, is actual foot odor. One of the sources of foot odor is the bacterium Brevibacterium linens. It makes the VOC called S-methyl thioester. Brevibacteria produce that chemical from the breakdown of fatty acids and certain amino acids.
The VOCs, including the smelly ones, have certain functions. Some of them can aid communication among organisms, including among microbes as well as between microbes and humans. Others help to control the balance of microbes in places like the gut. However, it is doubtful they are produced solely so we can smell them. It’s more likely we found it useful to be able to detect certain chemicals with our noses, either to avoid them or to gravitate toward them. It is hard to stop yourself from pausing to breathe in some more of that honeysuckle creeper as you pass by a front porch, or keep up your shopping cart pace as you trundle down the aisle with all the chocolate and confectionaries. Chocolate has about a thousand different VOCs.
Beyond promoting states of health, microbially produced chemicals also have commercial value. They are used as sources of perfumes and flavorings. They can even be engineered to make fragrances mimicking those from rare plants. Food scientists are trying to figure out which of those thousand VOCs in chocolate are the ones we really can’t resist. The microbially produced VOCs are more often useful in creating perfumes, whereas the non-VOC chemicals microbes produce are frequently used to create flavors that combine both aroma and taste.
The same perfume smells differently on different people. How does that happen? Our microbes churn out a major part of what gives us our own distinctive aroma. When this combines with the scent of a perfume, the odor shifts. The difference in each individual’s skin microbiome combines uniquely with each perfume, concocting a whole new personalized fragrance blend that other people can readily detect. That is why the blend of a given perfume on you is distinctive and different from the aroma of that same perfume worn by your neighbor.
Butyrate (also called butyric acid) is one of the most important microbial chemicals when it comes to signaling in the brain and the immune system. It is also a bacterial chemical you can smell. In its purest form, it smells like human vomit and is actually a major constituent of it. Once slightly modified, butyrate is used commercially to give foods a pineapple flavor and aroma. Another microbial product is propionate, and the balance of the production of butyrate versus propionate in the gut is important in certain NCDs. Under some circumstances, butyrate can be protective. For instance, the levels of butyrate-producing microbes are higher in people with healthy guts and very low in people who have IBD. Taking probiotics high in butyrate-producing bacteria helps to repair the epithelial barrier. Being able to detect levels of butyrate could be useful in balancing gut microbes and their chemical metabolites.
The ability to detect microbial metabolites as a way to evaluate your microbiome is becoming increasingly important. Being able to do so through the sense of smell has some advantages. For butyrate, humans can detect a concentration of ten parts per million. But we are rank amateurs at odor detection compared to some animals.
Some animal behaviors seem downright rude to humans. Ever watch dogs greet one another? If they are anything like our two dogs, they smell body parts, the butt in particular. Working at Cornell University’s Veterinary College, I get to observe this behavior a lot as animals come into the clinic. I used to attempt to stop my dogs from doing it whenever possible. Now I know better. If a dog is minority canine and majority microbial by cell numbers, what do you think they’re picking up?
The butt and other orifices are the open portals to the microbiome. A dog will go so far as to stick its nose in another dog’s poop. Why is it doing that? It is asking basic questions about the other animal like “Who are you?” and “How is your health?” And dogs aren’t limited to other dogs. They can pick up this information about other animals and even humans. Their nose knows.
According to Simon Gadbois and Catherine Reeve of Dalhousie University, the social network of dogs includes pee-mails and nosebooks. Dogs’ keen sense of smell makes them valuable in many ways. They can make very subtle distinctions about odors. This makes them valuable for sniffing out bombs and illegal drugs, and finding the track of lost persons, including those trapped or killed in the rubble of disaster sites.
More recently, dogs are being trained as medical service animals. A Diabetic Alert Dog can detect changes in blood chemistry signaling impending hypoglycemia in time for its owner to take action. The person is then able to get treatment and avoid a life-threatening situation. Other medical service dogs can detect colon cancer from breath or stool samples. They are picking up the specific chemical signature of the disease.
Dogs also have the capacity to make fine distinctions in cancers. They can distinguish between lung and breast cancers, detect different forms of ovarian cancers, and identify bladder cancer. The full range of talents a medical service dog could employ is not yet known. They may pick up cues beyond scent that clue them in to an owner’s impending emergency.
Now dogs are being trained to detect microbes. While we can only pick up butyrate at ten parts per million, dogs detect it at thousandfold lower concentrations. If humans are scent-detecting amateurs, dogs are professional sniffers, a trait that makes them very valuable.
One of the reasons dogs and other animals are able to detect specific microbes and their by-products is that microbes consume specific nutrients and excrete specific chemicals. All bacteria, archaea, and microbial eukaryotes have their own unique profiles of excreted chemicals, some so specialized they equate to microbial fingerprints. Biologists and chemists call these fingerprints biomarkers, which are signs that a particular microbe is present at sufficient levels to be detected. And dogs are one type of animal that can be easily trained to consciously pick up these microbial chemical signatures.
One of the first uses of dogs trained in microbial scent detection was to pick up the odor of microbial growth such as that of bacteria and mold in buildings. In 2002, researchers at the National Public Health Institute of Finland demonstrated that dogs could be trained to detect bacteria, as well as strains of mold, based on scent.
A beagle from the Netherlands named Cliff knows the human microbiome so well that he can direct doctors as to when medical treatment is needed for patients. He’s on staff at a hospital and even has his own uniform to wear to work. While other dogs can detect scents, Cliff’s scent receptors are so keen and his training so good that he can detect changes in a single type of gut microbe, Clostridium difficile, a gut pathogen. Cliff can identify which patients carry C. diff and which don’t, and he has even been able to detect impending outbreaks of C. diff up to three days before other instruments can detect it. This means he is able to warn hospital staff so they can take action to ward off a full-blown outbreak.
Even when humans aren’t present, dogs can still pick up microbial odors. Although it has not yet been proven, researchers have suggested that tracking dogs used in searching for lost children, making mountain rescues, or finding escaped prisoners by following their scent probably use the fragrant combo of our microbes, dead skin, and oils to track people over long distances. In California water-quality projects, trained dogs have been used to determine if surface and drain water sites have been contaminated by human fecal matter as part of a prioritization program for water-quality remediation. When a water supply is suspected of being contaminated with human waste, dogs can pick up the scent of the fecal microbes faster and with greater sensitivity than can other field tests. Dogs can then easily track the contamination back to its source in order to help officials correct the problem.
In case you thought dogs were alone in their microbial scent detection, giant pouched rats have been trained to detect the bacterium that causes tuberculosis. Personally, I would prefer Cliff to screen me rather than a giant pouched rat, but to each their own.
Virtually all parts of our microbiome play some role in our own odors and, to some extent, our individual smell and taste. Microbes in our gut, mouth, skin, and urogenital tract are major players in this. In the human superorganism, the emitted air and excretions from these sites can say a lot about the status of our microbiome as well as our potential health risks.
It could be said that Michael D. Levitt, MD, made his career in gas exploration. Levitt served at the Minneapolis Veterans Affairs Medical Center and as a professor in the department of medicine at the University of Minnesota Medical School. In 2006, the Annals of Improbable Research chronicled the progression of forty years of Levitt’s fart-focused papers with titles such as “Studies of a Flatulent Patient” (New England Journal of Medicine), “Flatulence” (Annual Review of Medicine), and “Only the Nose Knows” (Gastroenterology), moving on to “Evaluation of an Extremely Flatulent Patient” (American Journal of Gastroenterology). With the discovery of the human superorganism, scientists and laypeople can appreciate his observations of the gut microbiome.
Production of gas itself is not necessarily a bad thing. In fact, some gas after eating some types of food (e.g., fiber-rich food) is perfectly expected and a sign that particular microbes are metabolizing those foods. Among these microbes are the ancient archaea that evolved over a billion years. They are separate from the branch that mammals like us grew from, but they are also separate from bacteria. In many ways they are a bit of a hybrid, looking and acting like bacteria but possessing a lot of cell machinery that is more like what we have. Archaea produce gas in marshlands, they do this in cows, and they do it in our own guts.
While many gases produced are odorless, the end production of sulfur is definitely what gives gas its repulsive odor. But sulfur-containing compounds such as the sulforaphane found in broccoli, Brussels sprouts, kale, mustard greens, and cabbage also have reported anticancer qualities. The same chemical has been studied for its apparent benefits to patients with autism spectrum disorder.
The skin is a remarkable and expansive site for our microbial co-partners. Research on the skin microbiome has been slower to develop compared with that on the gut microbiome. However, recent findings indicate that skin microbiome manipulations are also going to offer a wealth of possibilities as we move toward superorganism medicine. Our skin covers us from the top of our head to the bottom of our feet and everything in between. It has many different local habitats for microbes, ranging from moist tropical rain forests to desert oil fields. Each different area has its own mix of microbes that are attuned to their preferred food sources and produce metabolites that support and modify our own body regions. You would not want the particular mix of microbes living between your toes or in your underarms to show up on your face. They wouldn’t like the outcome, and neither would you.
Human skin is a major source of body odor. That is one reason it is given so much attention in terms of personal hygiene, and a lot of money is spent on myriad personal care products that enable people to become masters of their own body odor. But you might want to think about other ways to control body odor, ways that create better outcomes for your microbiome. We may not realize it, but human sweat in its pure form is completely odorless. In fact, that was established back in the 1950s. If our sweat has an aroma, it is from the chemicals made by our skin microbiome. As I will discuss, each person’s aroma is a type of carrying card. We move around surrounded by what Jack Gilbert of Argonne National Laboratory has referred to as your personal microbial cloud. I like to think of it as the cloud of dirt that surrounds Pigpen from the comic strip Peanuts wherever he goes. We carry our own personal microbial cloud with us to work, on trips, and as we interact with one another. Other humans and animals notice our aromas, and mosquitoes zero in on them. Often mosquitoes are just a nuisance until you run into ones transmitting disease.
At summer gatherings of family or friends, some people are constantly bothered by mosquitoes, while others seem to have little trouble. Some people just seem to be mosquito magnets. These people can attract the attention of virtually all the feeding mosquitoes in the area. Foods people eat can be one factor in attracting or repelling microbes. For example, mosquitoes react to organosulfur chemicals in garlic as if they were vampires. They hate it. So garlic breath repels more than just other people.
But a major reason mosquitoes either stalk or run away from certain people is their skin microbiome. While mosquitoes can use many clues, the biggest factor in their selection of a person for feeding are the VOCs from the skin microbiome. In a study of forty-eight individuals with different skin microbiomes, researchers led by a group from Wageningen University in the Netherlands analyzed which features of the skin microbiome made humans most attractive to mosquitoes, and which features allowed us to hide in plain sight. They found that having a more diverse skin microbiome tended to protect you from the mosquitoes. Also, which specific bacteria were present in high numbers made a difference. Individuals with a high abundance of Staphylococcus bacteria were very attractive to mosquitoes, while people with higher levels of two other types of bacteria, Pseudomonas and Variovorax, were unattractive. It all comes down to the chemicals our co-partner microbes produce. Certainly, these findings may give new meaning to what constitutes truly natural mosquito repellants.
Recently, a large collaborative research group spanning the United States and Europe provided body-region-specific details of the skin microbiome. They created maps similar to those produced to depict the vegetation of the US. These maps have topography and were in effect three-dimensional. They highlighted differences between the skin microbiota in certain regions of the body (e.g., groin, tops and bottoms of feet, armpits, scalp, neck, and face) as well as differences between men and women. They also illustrated how use of personal care products can affect our skin microbiome. In addition to maps of microbial species inhabiting different areas of skin across the body, the researchers developed chemical maps of microbial metabolites showing what areas of the skin are rich in specific chemicals made by our co-partners. Many of these chemicals contribute to our body odor as they mix with our own proteins and oils on the skin. The take-home message is that each specific region of our skin has its own unique mix of microbes because the local “environment” is different. Also, each skin region is its own little perfume factory through the combination of odors emanating from hundreds of specific microbes in that skin region mixing along with our own various oils and gland secretions. The House of Chanel has nothing on us in terms of scent diversity and complexity.
To get deeper into the skin microbiome, it is useful to understand the nature of our secreting glands. There are basically two general types: sweat glands and sebaceous glands (concentrated in the scalp). Sweat glands are further subdivided in two types: eccrine (water, protein components, salt, urea, lactic acid) and apocrine (pheromones, proteins, and, importantly, more fat-loving chemicals).
The foot also has its own microbiome that differs by region. Analysis of foot odor has provided several interesting findings. It turns out that smelly feet are mainly the result of one type of bacteria, Salmonella, although some other less prominent bacteria can also produce odiferous metabolites. Salmonella inhabits the bottom side of our feet, accounting for more than 90 percent of all the bacteria present in that location. In contrast, the upper side of the foot is much more diverse and effectively “less smelly.” Some combination of features of the bottoms of our feet is likely to give the Salmonella its preferred home. Salmonella metabolizes peptides into a compound called isovaleric acid. It is abundant on the bottoms of our feet and largely absent from the tops of feet. This chemical is probably the most important in giving our well-exercised feet their distinctive acidic, cheese-like odor.
Research into the microbial origins of body odors has led to comparisons for sex, age, condition, and body location. Employing a strategy called competitive exclusion, where probiotic bacteria are used to swamp out other less desirable bacteria, proposals have been made to use replacement bacteria in specific body locations (e.g., underarms) as natural deodorants. We can make artificial sweat.
The mouth is a very complex microbial world of its own. Hundreds of species of bacteria, fungi, archaea, viruses, and protozoa interact not only with you but also with one another. In the mouth, they metabolize food and anything else that goes into your mouth, signal one another and your immune system, and organize themselves as a form of complex multicultural communities. They both respond to and help to create the local environment of your mouth. This is important not just for dental health but also for two of your senses: smell and taste. The microbiome of the mouth can influence both your own sense of smell and taste and the odors in your breath. In fact, there is a chemical signature for halitosis, and some companies produce instruments for quantifying halitosis (caused by your oral microbes). It is one way to detect when our microbes get out of balance, as happens with NCDs.
You have probably heard of the aroma or bouquet of various wines. But what is interesting is that most grape chemicals are odorless. It is only after they have been acted on by bacteria that the odor-producing chemicals are created. A recent study showed that the bacteria responsible for the production of aroma from white wine grapes are located in the human mouth. The grapes have a precursor chemical that is odorless but is turned into odor-producing chemicals by mouth bacteria. It does make one wonder whether the special “palate” of wine connoisseurs is more about their mouth bacteria than about their mammalian-based talents.
Obese individuals have apparent differences in mouth and saliva microbes that affect their interactions with foods, much as the aroma of white wine experienced by the taster is affected by the mouth microbiome. Significant differences have been reported between obese and nonobese individuals in both the composition of the mouth microbiome and in local metabolism. When it comes to white wine, the obesity-associated microbiome appears to have an impaired release of aromatic compounds.
In an interesting flip side to the story of dog detection of human microbes, humans have been used as trained judges to detect malodors associated with microbially related periodontal problems in both humans and dogs. In a London dental school study, odor detection was associated with bacteria that produced high levels of volatile sulfur and were also present at higher levels coinciding with periodontal disease.
The urogenital microbiome does not escape a discussion of scents and health. I previously brought up the vaginal microbiome relative to birth and microbiome seeding of the newborn baby, but there is so much more about the microbes in the vagina as well as those in the penis that have to do with odors, life cycle, sex, and health.
The vaginal microbiome in a healthy woman is dominated by Lactobacillus bacteria. Within the vagina there are local regional differences in microbial makeup and distribution. Changes can happen in response to age, menstrual cycle, and sexual activity. However, estrogen level appears to be a major player in many of these changes. Women with bacterial vaginosis have an altered vaginal microbiome featuring reduced amounts of Lactobacillus species and an increased presence of Gardnerella and Prevotella bacteria. Treatment for bacterial vaginosis leads to an increase of Lactobacillus species. But after several weeks there is a risk the women will revert to the disease-promoting microbe profile and possible symptom reoccurrence. We can look forward to getting to the root causes for the dysfunctional vaginal microbes, but for now we know scents from the vagina change based on (1) secretions from exocrine glands (which secrete through a duct or opening) that can be metabolized by vaginal bacteria and (2) the mix of microbes within the vagina. Not unlike with skin odors, these scents are a combination of exocrine gland secretions, sloughed-off epithelial cells, mucus, and resident microbial metabolites, which can change depending upon a variety of circumstances, including phase of the menstrual cycle. The overall changes in vaginal scents during the cycle are probably driven more by changes in the exocrine secretions and spectrum of bacterial metabolites than by changes in the bacteria themselves, since the vaginal microbiome of women is thought to remain relatively constant across the menstrual period. The exception to that is during bacterial vaginosis, when changes in the vaginal microbiome by itself seem to drive changes in scent.
Men also respond to these vaginal scent changes. An international team of researchers showed that both salivary testosterone levels and cortisol levels in men changed based on the female axilla- and vulva-derived scents linked with the phase of the menstrual cycle.
If the vagina has a microbiome, then so does the penis, albeit with less microbial complexity and in smaller numbers. While the penis is under-studied compared to the vagina, certain points have emerged. Men differ in the penis microbiome based on whether they were circumcised, their age, and their sexual activity. Their penis microbiome appears to be affected by their sexual partner’s microbiome as well. Regarding research on scents and penises, there is only a little to report about odor changes. The really obvious malodorous smells (e.g., fishiness) are usually connected to an accumulation of dead epidermal cells and microbiota changes such as the accumulation of bacteria that cause bacterial vaginosis in women. For more information on more subtle, less aquatic smells from the penis, we await additional studies.
Cliff the beagle has some new competition. There has been a technology-based effort to create an odor-detection system as powerful as Cliff’s nose called the electronic nose, or E-nose. It has the capability of analyzing the VOCs in human armpit odor. It turns out that your armpit microbes live on the gland secretions from your skin in that area, and the microbes’ odor-producing metabolites are sufficiently unique that they can be used to identify you. A dog could do it, but so can the E-nose. Imagine a time when you are at customs and immigration at an airport and they ask you to raise your arm so they can sample your armpit for identification purposes. Relax, enjoy your stay!
The E-nose has other applications, including a capacity to distinguish among Alzheimer’s disease patients, Parkinson’s disease patients, and healthy humans based on chemical analysis of their breath (exhaled air). It also can be used to detect cancer. Imagine being able to monitor NCD status as well as microbiome status all with the same piece of equipment. This capability points toward the future and what is likely to become a routine screening (as noted in the previous chapter). When it comes to physicians monitoring microbiome status and the success of probiotic administration, an E-nose seems likely to end up sitting alongside ultrasound machines in doctors’ offices sooner rather than later.
Scent detection between our scent receptors and microbial metabolites appears to go way beyond just odor detection by our brain. In fact, there is increasing recognition that it is not just about odor but rather our whole physiology. Jennifer Pluznick, now of the Johns Hopkins School of Medicine, has been studying scent receptors that show up in unusual locations of the body and seem to have more functions than just odor detection. What is particularly interesting is that some of the scent receptors interact with and are triggered by chemicals made by our microbes. In one case, at least one scent receptor seems to have major effects on blood pressure and risk of hypertension. Short-chain fatty acids made by our gut bacteria appear to use at least one of these scent receptors to help regulate blood pressure. Pluznick and her colleagues found that when mice were treated with a combination of antibiotics, their gut microbiome was destroyed, bacterial production of short-chain fatty acids that bind scent receptors was severely reduced, and blood pressure skyrocketed. Supplying the mice with just the bacterial short-chain fatty acids significantly reduced their blood pressure. That was the key to the blood pressure problem. Our microbiome appears to be able to control blood pressure using a rather unexpected strategy, production of VOCs that interact with scent receptors located in tissues not even remotely involved with smell.
Back in 1979 at Cornell, I remember teaching students about then-new research studies on how mice select their preferred mates based on urine odor. It was at least the more lighthearted part of my immunogenetics course and probably a welcome relief for students from some other topics of the day. Now it turns out it is not just mice that use those types of cues.
Humans smell one another, and that has a lot to do with attraction (even if we are not consciously aware of it). In her 2008 Psychology Today article titled “Scents and Sensibility,” Elizabeth Svoboda explains why the chemistry, spark, or electricity we feel with our future life partner has as much to do with scents as anything else. As it does with mice, some of this seems to do with our mammalian immune self-identity genes that control things like organ transplant acceptance or rejection. These genes sit in a complex known generically as the major histocompatibility complex, or MHC. The human version of the MHC is called the human leukocyte antigen complex (HLA complex, for short). It turns out that women are drawn more to scents derived from men carrying different immune-response genes than their own. (Anyone still doubt that the immune system does more than just fight infections?) They unknowingly prefer to produce offspring with men who can help to broaden their child’s immune response capabilities. That makes perfect sense and is desirable. But how does the human HLA complex or the mouse MHC equivalent affect smell-based social interactions and mate selection? Another way to ask the question: How do human immune response genes translate into odors? There are several different theories about how the HLA complex affects human scent as described in a book titled Human Scent Evidence. But this is where it gets really exciting and where the microbiome comes in.
It is known that at least some of our mammalian genes do affect the microbial partners we choose (or tolerate). Among the genes reported to affect our microbiome’s composition and diversity are the HLA genes. We don’t have to take kindly to just any old bacteria in or on our body. We have some say in choosing our microbial partners just like we do in choosing our human mates. The immune-response genes and their proteins are not known to be smelly. But they influence which smelly microbes we have in the gut and other locations. Our co-partnership with microbes is truly that. We accept them in general; then they proceed to do home renovation within our body. In effect, the smelly microbes we have are a type of surrogate for our HLA type. So when it comes to mating, loving those pungent microbes in a potential partner can probably help you conceive a more immunologically resilient child.
Armed with an increased respect for our dogs, we can anticipate encountering the electronic nose in a future doctor’s office, accompanied by our personal microbial cloud wherever we go. And with new hope for relationships that pass the smell test, we are ready to probe more deeply into self-care in the age of superorganism medicine.