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This article was originally published in September 2022 and has since been updated for inclusion in the Spring 2024 issue of Microcosm.

Humans subconsciously interact with a multitude of microorganisms through the scents they produce; the yeasty smell of fresh dough, geosmin after it rains, acidic ferments mediated by Lactobacilli and even stinky feet. The molecules that we recognize as scents play an important, yet poorly understood, role in microbial physiology, as well as interactions with other microorganisms and larger eukaryotes. Some of these scents are unique and can act as microbial fingerprints, allowing us to identify colonizing organisms, which may offer a non-invasive glimpse into infectious diseases. Microbes are also adept at creating non-native flavors and scents that are used in the industrial production of scent and flavor compounds for food and cosmetic enhancement.

Volatile Organic Compounds

What we understand as scents and flavors are typically small aromatic molecules, known as volatile organic compounds (VOCs). These molecules have high vapor pressures, essentially boiling and turning into gas at room temperature, which is why they are considered volatile. Because of their gaseous nature, VOCs can travel far distances, making them valuable tools for communication amongst diverse organisms.

Microbial Greening of Flavor Production

Many scents and flavors that are used in food, cosmetics and medicines are inspired by natural products, often plants. Unfortunately, some of these plants are rare because they are limited to very specific environmental niches, so demand regularly exceeds supply. To overcome this, many such compounds are produced artificially, frequently from petroleum-based starting materials. While this protects some natural resources and drives down costs, there are environmental impacts, and many people are wary of artificial additives.

A solution to this involves microbial factories, using microorganisms to make compounds of interest. These microbially produced versions of flavor compounds are referred to as “like-nature,” and are not considered artificial by most legislative bodies. Flavor compounds can be produced either enzymatically or with whole cells. The compound can be produced by cells natively, or cells can be metabolically engineered to increase yield. Many compounds have a similar structure, so engineered metabolisms can be manipulated to become modular, requiring only the final reactions to be exchanged. For example, mint, citrus, patchouli and sandalwood scents are all terpenoids that can be produced through a expressed in yeast that diverges enzymatically at the final steps. The type of starting material, or feedstock, used in scent production is important for ecological and economic considerations. It is beneficial to use feedstocks that would otherwise go to waste, such as agricultural by-products, to add value to the waste product.

One particularly exciting waste feedstock is the plastic polyethylene (PET). This strategy couples enzymatic PET breakdown with engineered E. coli that can metabolize the monomers into vanillin. Vanillin is the primary molecule that we associate with the flavor of vanilla, which is one of the most expensive spices when derived from the plant. By converting PET into vanillin, producers can generate a valuable flavoring compound from trash.

Scents-ing Disease

Throughout history, infectious disease diagnosis has included the detection of characteristic scents known to be associated with certain diseases. Although, this fell out of practice for many years, it is starting to see a resurgence. For example, Pseudomonas aeruginosa colonization, which is associated with disease progression in cystic fibrosis patients, is known for its grape-like odor, which can be attributed to the VOC 2-aminoacetophenone (2-AA). Because this compound is known, investigation of a then analyzed for 2-AA using Gas Chromatography-Mass Spectrometry (GC/MS) is underway.

Some vector-borne diseases go so far as to rely on scent alteration of infected host species for their own survival. Mosquitos use smell to find their blood-meals, and improving the host’s scent increases the likelihood of mosquito visitation and disease spread. Malaria and flaviviruses, including Zika and dengue, alter the scent profile of infected hosts by increasing host (or host microbiome) production of VOCs, including and acetophenone by malaria and flaviviruses, respectively. Flaviviruses increase acetophenone production by suppressing an antimicrobial protein (RELMα) that normally inhibits some of the acetophenone-producing skin commensal bacteria. By inducing RELMα with vitamin supplementation, the VOC production is reduced and, consequently, so is mosquito host-seeking. This suggests a potential strategy for reducing community transmission of mosquito-borne flaviviruses.

Volatile Organic Compounds Mediate Interkingdom Communication

Humans are not the only organisms that sense and cultivate microbial scents. Microbially produced VOCs are important modes of interkingdom interactions, ranging from cooperative to antagonistic.

Animal Responses to VOCs

In the animal kingdom, microbes are a key component of "perfumes" used to attract a mate. For example, male greater sac-winged bats transfer secretions (and microbes) from their genitals and throats to their wing sacs in a daily . Female bats, who do not do this, have a different wing microbiome composition, so it is thought that males use their microbe-influenced scent as a form of courtship. However, no specific microbes have been tied to specific scents or mating success for male bats.

Many other animal species demonstrate similar behaviors, in which mating rituals are mediated by microbial produced scents. For example, mouse commensal microbes contribute to , which helps with species identification when choosing a mate.

Plant Responses to VOCs

Although not all VOCs are known to produce detectible odor, research shows that gas exchange resulting from microbial VOC production can have significant impacts on soil community composition, which can influence plant colonization, plant pathogenesis and dispersal. In the lab, stark defects in leaf size and survival are apparent when plants are grown under exposure to VOCs produced by . This observed reduction in growth suggests a pathogenic effect for certain VOCs. Alternatively, evidence indicates that competitive inhibition generated by VOC production may also be used to control the spread of other plant pathogens. For example, —2 pathogens that are capable of independently causing harm to plants—may use VOCs to act antagonistically against one another and effectively limit colonization of peanut plants by either microbe.

Insect Responses to VOCs

Microbial VOC production also encourages distribution of some sessile organisms by attracting pollinators. The microbial composition of nectar has a strong influence on its attractiveness to pollinators. Parasitoid wasps have been observed to preferentially visit nectar with native species (e.g., Metschnikowia gruessi, Metschnikowia reukaufii) compared to non-native yeasts (e.g., Aureobasidium pullulans, Hanseniaspora uvarum, Sporobolomyces roseus, Saccharomyces cerevisiae). Wasps that were attracted to isolated VOCs extracted from native nectar-inhabiting yeasts were also shown to live longer than those feeding on nectar fermented by non-native yeasts. This increased attraction likely helps the plant’s pollen and the yeast disperse to new places, improving fitness for both organisms.

A similar "pollination" principle is utilized in fungi. Fungi that are dispersed by hornets and fruit flies have a different scent profile than those distributed by flies and wasps that are attracted to carrion (dead, decaying flesh). The fungus Protubera nipponica produces a fruity scent and is frequently visited by the giant hornet, which after eating parts of the mushroom.

Microbially produced VOCs give us a glimpse of microbial lifestyles. Whether they are using scents to communicate or prevent the growth of organisms, VOCs are an important, yet underexplored facet of microbial physiology that will continue to inform our understanding of the microbes around us.

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