Sneezin' All Season

Notice that not one person is covering their mouth 
and nose here. Makes for better video, 
but still…..gross.

The spring allergy season is back with a vengeance. Many of your friends and loved ones are sneezing, looking as if someone killed their dog, and stuffing facial tissues in their pockets and purses like they were fifty dollar bills. Despite the TV commercials that suggest otherwise, people don’t get that upset with other people’s sneezing, unless they neglect to cover their nose and mouth, in which case they deserve all the ridicule that can be heaped upon them. However, it makes one wonder what exactly is going on inside them that causes them to sneeze, and how does that sneeze play out biologically? Now there’s an interesting story.

A sneeze is the body’s way of trying to expel foreign material that is irritating the respiratory system, most likely the very upper respiratory system – the nasal passages. In the case of spring allergies, the offender is most likely to be grains of pollen. The rhinitis (rhino = nose, and -itis = inflammation) caused by seasonal allergens (hay fever to you and me) are small particles that stimulate an immune response for some reason. In almost all cases they are not harmful particles, as is the case with pollen grains, except that some can induce very strong allergic responses. So why do some people’s bodies try so hard to expel them?

An allergen is nothing more than a protein or carbohydrate, some sort of biomolecule, that your body recognizes as foreign and against which it mounts a specific immune response. For most people, any one specific particle may be seen as foreign, but your body doesn’t go crazy over it; it has been tolerized (learned not to respond), or the response is held in check by other parts of the immune system. But for those unlucky few (or many), pollen grains are a type of allergen that stimulates a large IgE (one type of antibody) response, along with chemicals like histamine and leukotrienes.

The reasons that some people develop an allergic rhinitis to one or more materials aren’t completely known. There is some evidence that if you are fighting off a viral infection and at the same time are first exposed to the allergen, then the heightened activity of the immune system will stimulate a response to the innocuous material. And once that happens, you’re sunk. The body has an immune memory; it builds a small army of cells that then recognize that particular allergen, and if it enters the body again, a strong response will follow and an additional memory response will be built.

Goldenrod has a bad reputation as an autumn allergen. In

truth, it is an insect pollinated plant, so it is not carried by

the wind and snorted as an allergen. Look, she’s not

sneezing. The problem is all the ragweed that grows near

the goldenrod – it’s wind-pollinated.

Therefore, some people believe that too much exposure to viruses and bacteria and other foreign materials when very young will lead to more allergies (there is a genetic component that makes some people more susceptible, but that is too big a topic for us here). On the other hand, many scientists believe that the opposite situation is just as bad or worse for developing allergies. If an environment is too clean, then children are very likely to develop food, seasonal, and perennial allergies. This is called the hygiene hypothesis, and most researchers accept it as true, even if we aren't quite sure of its mechanisms yet.

It may be that too little exposure to bacteria and viruses (which stimulate more a type of immune response called Th1) actually makes the body more likely to go overboard when an antigen stimulates a Th2 response (the type of response induced by allergens). There needs to be a balance between Th1 and Th2 that helps keep them both from over-reacting. It is also possible that when babies are very young, before they have had time to develop their own adaptive immune system (build on their own by being exposed), it is important to stimulate their innate immune system (always on guard and doesn’t require learning to react). The innate response helps build the adaptive system and works to balance the adaptive Th1 and Th2 responses.

It is no coincidence that farmers’ kids have fewer food and

environmental allergies. They are exposed to more

arabinogalactan, which scientists think this is one of the

antigens that teaches the Th1 and Th2 systems to balance

and dampens their response so body doesn’t over react to

foreign molecules and develop allergic responses

and memory response.

Finally, the hygiene hypothesis of allergy development may be mediated by a lack of early childhood allergen and germ exposure which prevents the development of a regulatory immune response. Regulatory immune cells are stimulated each time an immune response is generated; they work to tone down the response and finally turn it off. If not exposed often enough to foreign materials when young, many kids these days don’t develop the regulatory system that would keep the Th2 response to allergens in check. Think about it, hyper-clean environments with HEPA filtered air conditioners and vacuum cleaners, antibacterial soaps, surface and toys, the fact that kids just don’t play outside much anymore. These could all lead to more allergies just because their bodies haven’t learned to handle foreign molecules well.

In terms of seasonal allergic rhinitis, the allergens we are talking about most often are pollen grains. Many plants are fertilized by insects; the insect comes to a flower to drink nectar, the pollen sticks to them, and when they get to the next flower, the pollen is transferred to the stigma and the male gamete cells grow out of the pollen grain via the pollen tubules, down to the ova and fertilized the egg. However, that isn’t the only way pollen grains can be dispersed to other plants; the wind often plays a role. Wind-pollinated plants have small pollen grains, light enough that they will be spread far and wide by a gentle breeze. Unfortunately, this is rather hit or miss; they aren't going to be blown directly to another plant of the same species (as a bee would carry them to the next flower). Since the chances of a single pollen grain finding a flower are low, the plant has to make millions of times more pollen grains. That is a problem for people who suffer seasonal allergies.

Iguanas, especially marine iguanas, sneeze more than any

other animal. The sneezing is a way for the to expel certain

salts that are a byproduct of their digestive process.

There is just so much pollen in the air, the chances of coming across some each day of the season are so high as to be inevitable. Many plants take advantage of the spring increases in temperature, sunlight, and water to do their reproduction, so there is a lot of pollen around in the springtime. Other plants reproduce in the fall, so seasonal allergies come back then, although the offending pollen types will be different from spring to fall. The pollen is in the air, you breathe in the pollen, and it gets stuck in the mucus of your nasal passages. This prevents it from getting to your lungs, but your body still wants to get rid of it. So how does your body know it is there and then trigger a sneeze?

Immune cells are always on the prowl for foreign invaders, especially in/on parts of the body that contact the outside world. Your nose qualifies as such, so there are many immune cells  patrolling your nasal passages that recognize specific antigens. When an immune cell meets that one antigen (or maybe two if there is a cross reaction) that it is built to recognize, it triggers a response. In the case of allergic rhinitis, the responses are to release an antibody type called IgE. The IgE then binds to other immune cells, like eosinophils and mast cells, and then release histamine and leukotrienes, amongst other things. The histamine makes your nose and eyes itch. The chemicals make the small blood vessels leaky, so fluid comes out making your eyes water and your nose run. They stimulate more mucus production, so you get congested. Blech! In addition, the histmaine and leukotrienes do one more thing, they stimulate nerve endings in your nose to trigger a sneeze. The sneeze is meant to get those allergens out of your system as quickly and forcefully as possible.

Contrary to popular belief, your eyes won’t pop out if you

sneeze with while they are open. The blood pressure does

tend to rise fractionally behind your eyes when sneezing,

but it isn’t enough to make them bulge, let alone pop out.

The reasons that the reflex closes your eyes is to avoid

having infected mucus or saliva fly into them and to protect

them during your wild head movement when sneezing.

The nerve impulse travels to your brain, a part called the medulla, and this triggers a constriction of your intercostal chest muscles, your diaphragm, and your abdominals. You inhale, and the constriction of the palate and larynx then holds the air in your lungs as your chest and abdominal muscles start to contract. This builds up pressure, until the throat opens and the air comes rushing out at 70-100 mph. A sneeze can travel 12-20 feet and can carry 40,000 droplets of saliva and mucus. This is: 1) very good for expelling allergenic particles in the nose and throat, and 2) not something anyone wants to share with you, so cover your mouth and nose – preferably in the crook of your elbow in case you plan on opening any doors or shaking hands soon.

There is another reason why a sneeze might be in order during allergy time. A 2012 study showed that the mechanism to get rid of mucus (called the muciliary elevator) sometimes get stalled when mucus is overproduced and full of particles. The clearance mechanism uses the rhythmic beating of cilia on the nasal cells to brush the mucus toward the mouth to be coughed out or swallowed. The researchers used some nasal tissue and sent a pressure wave over the cells to mimic a sneeze. The pressure wave stimulated the cells to start clearing mucus by beating their cilia, so the scientists describe a sneeze as a rebooting of the mucus clearing mechanism. Unfortunately, people with chronic sinusitis and chronic allergies have nasal passage tissues that don’t reboot, so they just keep sneezing and sneezing without any relief. In the case of people with allergies, antihistamines and decongestants are a savior. For everyone else, just sneeze and be done with it – don’t self-medicate at the drop of a hat, people take too many drugs.

Dogfish Head 90 Minute Imperial IPA is one of the beers

that is famous for making people, those who are susceptible,

sneeze. Fermented beverages are high in histamine, and this

may be a reason for the sneezing. Or perhaps it could be an

allergy to the boiled form of alpha acids from hops;

iso-alpha acids like humulone.

More interestingly, people can sneeze for non-allergic reasons. The immune response to a cold virus produces the same chemicals and sneeze response, while pulling at your eyebrows or tweezing them stimulates the same nerve that innervates your nasal passages so you might sneeze then as well. But there are weirder reasons. Some people, called photics, sneeze in response to sudden onset of a bright light. This is a genetic trait and involves higher brain centers, like the visual cortex. Therefore, it is a reflex that extends beyond the brainstem or spinal cord – very weird. It is called, for obvious reasons, ACHOOs (Autosomal Dominant Compelling Helio-Opththalmic Outburst syndrome). Other people suffer from snatiation –sneezing when their bellies are full. This is also genetic and is inherited as an autosomal dominant trait. And some people have a tendency to sneeze after being intimate. The weirdest? Sneezing with hoppy beers – but that’s another story.

Contributed by
Mark E. Lasbury, MS, MSEd, PhD
As Many Exceptions As Rules

Zhao, K., Cowan, A., Lee, R., Goldstein, N., Droguett, K., Chen, B., Zheng, C., Villalon, M., Palmer, J., Kreindler, J., & Cohen, N. (2012). Molecular modulation of airway epithelial ciliary response to sneezing The FASEB Journal, 26 (8), 3178-3187 DOI: 10.1096/fj.11-202184

Teebi AS, & al-Saleh QA (1989). Autosomal dominant sneezing disorder provoked by fullness of stomach. Journal of medical genetics, 26 (8), 539-40 PMID: 2769729

Takubo M, Inoue T, Jiang S, Tsumuro T, Ueda Y, Yatsuzuka R, Segawa S, Watari J, & Kamei C (2006). Effects of hop extracts on nasal rubbing and sneezing in BALB/c mice. Biological & pharmaceutical bulletin, 29 (4), 689-92 PMID: 16595900

Langer, N., Beeli, G., & Jäncke, L. (2010). When the Sun Prickles Your Nose: An EEG Study Identifying Neural Bases of Photic Sneezing PLoS ONE, 5 (2) DOI: 10.1371/journal.pone.0009208

Complexities Of Allergic Disease

Last time we discussed the main players involved in the immune response to allergens, in the reaction called Type I hypersensitivity. We know that hay fever and other allergies are a result of atopy, the genetic predisposition to mount excessive IgE-mediated immune responses. Atopy is derived from a Greek word that means unusual or out-of-place. Although the immune overreaction is indeed out of place, the prevalence of allergic disease in society is not. Approximately 25% of the world’s population suffers from allergies, making it one of the most common chronic diseases. Unfortunately, this number is actually increasing, so researchers are trying to understand the factors that contribute to allergic disease.

Advances in genome sequencing and the completion of the Human Genome Project have allowed scientists to use genome-wide association studies (GWAS) in attempts to identify certain disease-causing genes. While many candidate genes have been described for hay fever, each search appears to reveal additional candidates. It has become clear that hay fever is a complex disease, driven by genetics and environmental exposures, both pre- and postnatal. Because of this complexity, atopy does not follow a Mendelian model of inheritance, like eye or hair color.

To perform GWAS, researchers collect blood or tissue samples from individuals with the disease of interest and from symptom-free control subjects. In many allergy studies, the controls are within the same family, which helps tease apart genetic differences that might actually contribute to disease. This is helpful because 300,000 to 1 million changes in the DNA are tested. These changes called single nucleotide polymorphisms (SNPs), a type of mutation that indicates a single change in the DNA base pair. If certain SNPs appear more frequently in the individuals with the disease, they are said to be associated with that disease. Additional DNA sequencing is performed to determine the exact change, and then ideally that SNP is studied in the lab to understand the consequence of the change on cellular function.

Sometimes mutations give super-human agility, strength, or intelligence. Other times they set us up to have wild and potentially unnecessary symptoms like Beast’s blue fur. Or perhaps equally annoying, the itchy watery eyes, nose, and throat from hay fever that come from a super-human response to harmless allergens.

A few notable candidate genes have been identified as associated with hay fever or with higher levels of circulating IgE antibodies, as we learned is a hallmark of atopy. Cytokines are the main signaling molecules that trigger activation of B cells to produce IgE antibodies, and not surprisingly, people with hay fever have mutations in genes that encode for cytokines or regulate their production. Also associated with hay fever are changes that enhance and stabilize the IgE receptor on mast cells and basophils, contributing to more intense symptoms. Genes responsible for airway smooth muscle contractions, contributing to cough and wheeze, are also implicated. SNPs have been identified in the genes encoding chemical mediators that cause ongoing symptoms such as leukotrienes, and in the specialized effector cells involved later in allergic inflammation response, such as eosinophils.

These are just a few examples of genes; dozens of others are being studied to learn exactly how they contribute to hay fever. Furthermore, some genes are only associated with allergies in the context of specific environments, further complicating the identification of true disease-causing genes. One clue that environmental factors influence allergies comes from studies of twins. Twin studies have shown that between monozygotic (identical) twins there is on average a 65% (range, 42-82%) chance that if one twin has allergies, the other will also have them. Between dizygotic (fraternal) twins, there is on average a 33% concordance rate (range 15-52%).

Some differences in twins are obvious, but other differences like allergies require epidemiological studies to tease apart.

The “hygiene hypothesis,” proposed by D. Strachan in 1989, became a popular basis to explore the increased incidence in allergic disease. Strachan observed that increased family size was associated with lower rate of allergies. He proposed that if allergies were prevented by early childhood infections, unhygienic contact with older siblings may protect against hay fever. Immune responses to pathogens like bacteria and viruses use a T-helper 1 (Th1) cell response. We know that Type I hypersensitivity reactions are mediated by Th2 cells’ stimulation of B cells to produce IgE antibodies. So the theory is that early childhood infections bias the immune system towards a Th1 response and suppress Th2 responses.

If Strachan’s hypothesis is correct, the Bates family should be allergen-free.

Strachan performed additional epidemiological studies to investigate the hypothesis that infections and larger family size protect against hay fever. He published a report in 2000 stating that decreases in family size do not appear to explain the increased incidence of allergies. Many additional studies looking into the protective effects of childhood infections have shown inconsistent results; some show a “protective” effect whereas others show either no association or early childhood infections correlated with development of allergies.

The “hygiene hypothesis” developed into a much broader “microflora hypothesis” which proposes that urbanization and a Western lifestyle limits our exposure to bacteria, viruses and parasites in general. Clean water, increased Cesarean sections, reduction in breastfeeding, increased antibiotic and antibacterial use, and reduced exposure to farm animals have limited our exposure to our microbial “old friends”. According to this idea, these “old friends” have evolved with us to the point where we require them for proper immune function.

 

“The Wonder Years” cast knew that we get by with a little help from our friends.

The diversity of our microbiome is decreasing, which may have detrimental effects on general health and the efficiency of our immune system. W. Parker proposed the term “biome depletion” to describe this current phenomenon. A few recommendations can be found here to increase microbial diversity in the gut.

Just like the Biodome, our biomes are not closed systems and can let in and respond to passer-byers, for better or for worse. In the case of Pauly Shore, it’s always for the worse.

If there weren’t already enough factors to consider in development of allergies, let’s peel back another layer. In addition to acquiring genes and microbiota from mothers during birthing and breastfeeding, in utero we are largely influenced by our mother’s environment through epigenetics. We’ve discussed epigenetics previously; briefly, it describes changes in the DNA and DNA-associated structural proteins that act to turn genes on or off. Epigenetic regulation either gives a green light or red light to production of specific gene products, or can act as a volume knob to finally tune gene expression. The process is plastic, allowing our genes to respond to the present environment.

Upon conception, epigenetic reprogramming occurs in the zygote, like a reset button. However, some epigenetic marks remain and are inherited by the offspring. So before and largely during pregnancy, the mother encounters various environments and the body responds using epigenetics to regulate genes at the appropriate time. These changes occur in the embryo or fetus as well, as a way to prime the baby for its eventual environment.

There is evidence that the immune system is under epigenetic regulation. At birth, atopy-prone infants tend to have diminished Th1 cell responses, thought to be influenced by the maternal environment. Additionally, maternal diet, microbial exposure, and smoking can influence epigenetic regulation of key genes involved in immune regulation and allergy development.

While there is no consensus on allergy prevention, there are many options for treatment of allergies, which will be discussed in the final allergy article in this series – coming soon!

Contributed by:  Julia van Rensburg, Ph.D.

Follow Julia on Twitter.

Dávila I, Mullol J, Ferrer M, Bartra J, del Cuvillo A, Montoro J, Jáuregui I, Sastre J, & Valero A (2009). Genetic aspects of allergic rhinitis. Journal of investigational allergology & clinical immunology, 19 Suppl 1, 25-31 PMID: 19476051

Grammatikos AP (2008). The genetic and environmental basis of atopic diseases. Annals of medicine, 40 (7), 482-95 PMID: 18608118

Strachan DP (2000). Family size, infection and atopy: the first decade of the "hygiene hypothesis". Thorax, 55 Suppl 1 PMID: 10943631

Parker W (2014). The "hygiene hypothesis" for allergic disease is a misnomer. BMJ (Clinical research ed.), 348 PMID: 25161287

Martino D, & Prescott S (2011). Epigenetics and prenatal influences on asthma and allergic airways disease. Chest, 139 (3), 640-7 PMID: 21362650

Hay Fever: Maladies, Melodies And Remedies

In addition to kicking off the barbeque, swimming and vacation seasons, spring also marks the beginning of that pesky and sometimes debilitating seasonal woe, hay fever. Much like Noel Coward’s 1924 play Hay Fever, the colloquial designation has really nothing to do with hay or fever. Clinically known as allergic rhinitis, hay fever describes the hypersensitivity to airborne allergens and the onslaught of bothersome symptoms they provoke. Approximately 20% of the world’s population suffers from seasonal or perennial hay fever. Even Paul Simon wasn’t spared from the suffocating spiral that is allergies.

 

With the blooming of spring flowers and sprouting of fresh green leaves and grasses, we are reminded that life is all around us. Quite literally, too, as windborne plant pollen is small enough to enter our eyes, nose, and mouth. Pollen, the primary cause of seasonal allergies, contains the male gametophytes of seed-bearing grasses and trees. Each pollen grain contains a generative cell, or sperm, which fertilizes the egg of the female plant, and a vegetative cell, which develops into a pollen tube and delivers the sperm to the ovule. Many trees and grasses rely on wind to spread their pollen and fertilize the female plant. So although your college roommate may have been discrete while attempting to procreate, wind-pollinated plants uphold no such personal boundaries.



Next time you smell a flower, realize you are sniffing a plant’s “naughty bits”.

So which plants are responsible for producing the powdered cheese-like substance that coats our houses, bicycles, and cars? Although thousands of plant species produce pollen that makes the Holderness family cough and gag, only a handful are responsible for their allergic wheezing and sneezing.

The exact timing of seasonal allergies can vary depending on region and climate. You can blame your early spring allergies on tree pollen, particularly that from birch trees. From March to May, many other trees including beech, ash, pine, box elder, cottonwood, oak, mulberry, elm, alder, cedar, hazel, willow, poplar, linden, olive, hornbeam, and plane contribute to early spring allergies. By June, grass pollen becomes predominant, especially timothy and ryegrass. Other grasses such as Bermuda, Johnson, Kentucky bluegrass, orchard, redtop, sweet vernal, and rye contribute to allergies. As the heat and humidity rises during July and August, your hair and electricity bill aren’t the only things that grow. Molds can thrive in grass, grains and leaves; airborne spores can cause hay fever.

The warm days and cool nights of late summer and autumn are perfect conditions for weeds, particularly ragweed, which is the primary cause of autumn-onset seasonal allergies. Ragweed can produce metric tons of pollen per square mile of plant. Other weeds that produce allergenic pollen are cocklebur, burning bush, lamb’s quarters, pigweed, plaintain, Russian thistle, sagebrush, mugwort, and sheep sorrel.

The heavy vegetation towards the end of the growing season provides a perfect breeding ground for additional outdoor mold. Mold grows in fallen autumn leaves, hay, and straw, and can be stirred up during raking or baling. In general, mold spores are considered perennial allergens because mold has the potential to grow outdoors and indoors, especially in kitchens, bathrooms, and basements throughout the entire year. However, growth conditions are optimal during different seasons, potentially resulting in a seasonal effect with mold allergies.

Even in winter, mold spores on indoor live pine trees can cause an allergic reaction. So even though the pine tree isn’t releasing pollen, it can still aggravate hay fever symptoms.

Other perennial allergens besides mold spores include dust mites, pet hair dander, and cockroach droppings. Dust mites are always present, but have been shown to increase with installation and use of central heating and insulated windows in apartment buildings. And although we may not even know cockroaches are present, the proteins in their droppings can cause hay fever. Cat dander is the most common cause of pet allergies, but thankfully The Big Bang Theory writers conveniently overlooked Sheldon’s alleged cat dander allergy so he could adopt this zazzy guy.

What is it about allergens that trigger the allergic response? Although scientists have worked to understand the molecular details of allergens and how they interact with components of our immune system, there is no clear answer as to what specifically makes something allergenic. However, within many of the most common allergens, the primary antigen has been identified. The antigen is the specific molecule that is recognized by our immune system. Antigens can be different components of a bacterial cell or viral particle; in the case of allergens, it is a protein derived from pollen, dander, mold, etc.

Pollen from birch trees is one of the largest contributors to hay fever in spring and early summer in North America The primary antigen from birch tree pollen, Betula verrucosa is called Bet v 1. The Bet v 1 antigen exists as a mixture of 14 isoforms that share ≥ 96.5% sequence identity; these isoforms possess different binding capabilities for the antibody immunoglobulin E (IgE). In fact, only 1 of the 14 isoforms, Bet v 1.0101, induces an immune response in an individual with birch tree allergy, and the two other isoforms tested, Bet v 1.0401 and Bet v 1.1001 induced no response (PMID:  20005001). Immune cells isolated from patients with no birch tree allergy did not react to any of the isoforms. The difference in the antigens is their affinity for the IgE, but precisely what makes one antigen more reactive than the other is unclear. On a basic level, the protein sequence and structure influence the binding to antibodies.


Birch pollen primary antigen Bet v 1 (wikipedia.org)

One complication with diagnosing and treating allergies is the potential for cross-reactivity between different antigens. In some parts of the world, allergic patients are double-sensitized to ragweed and mugwort, Artemisia vulgaris. The flowering season of these two plants overlaps, making it difficult to diagnose the primary sensitizer. In addition to increasing the number of allergies a patient may have, cross-reactivity also complicates prescription of the correct immunotherapy to combat the primary allergy. The primary antigen of mugwort is Art v 1 and up to 95% of people are sensitized to Art v 1. However, a minor mugwort antigen, Art v 6 shares high homology with and commonly cross-reacts with the primary ragweed antigen, Amb a 1. At least 90% of ragweed-allergen sufferers are sensitized to Amb a 1. This means that patients who are allergic to ragweed may be sensitive to mugwort and vice versa. New proteomic technologies allow for more accurate diagnoses of the primary sensitizer so that the proper immunotherapy can be prescribed. Treatment of allergies will be discussed in article 4 of this series.

With so many potential allergens bombarding us more or less year-round, it’s almost surprising that more of us don’t suffer from hay fever. As mentioned above, 1 in 5 people are afflicted and, unfortunately, that number is increasing, particularly in suburban areas of North America. Perhaps the reason allergies are not more common is because they are not hardwired into us, as is the immune response to infectious agents such as bacteria, viruses, and parasites. Hay fever is considered an atopy, a genetic predisposition to mount inappropriate immune responses to harmless environmental allergens. The immune response mounted against allergens will be described in detail in article 2 of this series.

The tendency to have seasonal allergies is hereditary, but does not follow Mendelian principles, like inheritance of eye or hair color. In addition to genes, the environment contributes to allergy susceptibility. Understanding the genetic and environmental factors involved in allergy development is complex and requires sound knowledge of the actual allergic response. A more complete discussion of genetic and environmental factors that influence allergy susceptibility will be presented in the third article of this series. We hope you’ll tune in for the remaining articles in this ongoing series.

Contributed by:  Julia van Rensburg
Follow Julia on Twitter.
 

Hirsch T, Hering M, Bürkner K, Hirsch D, Leupold W, Kerkmann ML, Kuhlisch E, & Jatzwauk L (2000). House-dust-mite allergen concentrations (Der f 1) and mold spores in apartment bedrooms before and after installation of insulated windows and central heating systems. Allergy, 55 (1), 79-83 PMID: 10696861

Leb VM, Jahn-Schmid B, Schmetterer KG, Kueng HJ, Haiderer D, Neunkirchner A, Fischer GF, Nissler K, Hartl A, Thalhamer J, Bohle B, Seed B, & Pickl WF (2008). Molecular and functional analysis of the antigen receptor of Art v 1-specific helper T lymphocytes. The Journal of allergy and clinical immunology, 121 (1), 64-71 PMID: 18037161

Jahn-Schmid B, Hauser M, Wopfner N, Briza P, Berger UE, Asero R, Ebner C, Ferreira F, & Bohle B (2012). Humoral and cellular cross-reactivity between Amb a 1, the major ragweed pollen allergen, and its mugwort homolog Art v 6. Journal of immunology (Baltimore, Md. : 1950), 188 (3), 1559-67 PMID: 22205029

Wopfner N, Bauer R, Thalhamer J, Ferreira F, & Chapman M (2008). Immunologic analysis of monoclonal and immunoglobulin E antibody epitopes on natural and recombinant Amb a 1. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 38 (1), 219-26 PMID: 18028463

Asero R, Bellotto E, Ghiani A, Aina R, Villalta D, & Citterio S (2014). Concomitant sensitization to ragweed and mugwort pollen: who is who in clinical allergy? Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology, 113 (3), 307-13 PMID: 25053399

Pull Up A Stool And Let's Talk About Your Microbiome

A medical case report recently made headlines supporting the notion that the bacteria inside our gut have something to do with the size of our gut.

Clostridium is a nasty strain of bacteria that is resistant to many antibiotics. Normally, the many other species of bacteria in the gut keep Clostridium in check, but when those friendly bacteria are wiped out during antibiotic therapy, Clostridium can thrive and produce severe inflammation (colitis) and diarrhea. This can develop into a serious illness that claims the lives of 14,000 Americans every year.

A novel way to treat this condition is through use of fecal microbiota transplant (FMT). In other words, the patient ingests the intestinal bacteria from a healthy person to replenish their own stock and get Clostridium back under control. We will leave it to your imagination as to how doctors collect the good bacteria, but let's just say you can make some decent money if you're willing and able to donate. Thankfully for patients, FMT is available in pill form.

As unappealing as it sounds, fecal transplants - which repopulate intestinal bacteria in the recipient - are proving to be very effective in treating some serious ailments. 

As reported recently, a young woman with a stable weight of ~130 pounds had to undergo FMT to fight a Clostridium infection. The good news is that she beat the infection, but the bad news is that she gained 34 pounds in 16 months, classifying her as obese with a BMI of 33. Even more alarming is that she could not lose weight despite being on a supervised liquid diet and exercise program. The donor for the FMT (her teen daughter) was overweight, but otherwise in good health, so doctors are now recommending that FMT donors be of normal weight.

In light of this news, here's a beginner's guide to the tiny creatures calling you "home"...

You are not just a person – you are an ecosystem. Your body is home to trillions of microscopic critters, including viruses, bacteria, and fungi, living on or inside you. Collectively, these communities of microbes constitute what is called your “microbiome”.

And there are more of “them” than “you” – the number of microbes inhabiting your body is larger than the number of cells making up your body! To put this in perspective, it has been estimated that your microbiome weighs about 3 pounds. Good news if you’re on a diet – when you step on the scale tonight, feel free to subtract 3 pounds of stuff that isn’t “you” per se.

A new study concerning our microbiome seems to be coming out each week, so it is time we get to know our microbial roommates.

1. Where does your microbiome come from?

We are born virtually sterile, but quickly receive an infusion of bacteria from our mom, first through the birth canal and then through the milk. Over 900 species of bacteria have been found in breast milk, and these are the pioneers that settle into your gut, which appears to stabilize by the age of 3. Of potential interest are babies born by caesarean section or those who are fed formula instead of breast milk. Babies delivered via C-section do in fact have a different microbiome and may be at higher risk for certain types of allergies and obesity (more on this below). Our microbiome continues to receive fresh new imports as we move through, inhale, and ingest our environment.

How much of you is really you? There are more microbes in your body than the number of cells making up your body. We are just now beginning to appreciate the many things they do for us.

2. Your microbiome is like your own personal “germ cloud”.

You’ve probably noticed that everyone’s home smells a little different. Sometimes this is due to cooking, pets, or the amount of trash they let accumulate, but it is also due in part to the microbiome of the inhabitants. Researchers have found that you are surrounded by a “germ cloud”, and you leave pieces of your microbiome wherever you go like a trail of breadcrumbs. It might even be possible for police to use microbiomes to track people one day like they currently use fingerprints or DNA. In other words, you have a “microbiome fingerprint” that is left behind like a germ echo wherever you go.

This “germ cloud” may also explain how dogs can track people so easily. The byproducts generated by the millions of bacteria living on your skin are aromatic (odorous), producing a scent that is released into the air as you move. Animals with a keen sense of smell can get a whiff of these aromatic compounds and follow them to the source.

Speaking of “germ clouds”, if you ever wondered if it is possible to fart out germs, some brave scientists have sniffed out the answer to this question. You can read about the results here.

3. Antibiotics substantially alter your microbiome.

We take antibiotics to get rid of pathogenic bacteria that make us sick. The problem is they are not selective, so they destroy a lot of our friendly bacteria in addition to the bad guy. We need these friendly bacteria to do all sorts of things – to name just a few:  they help us digest food, make vitamins, and build anti-inflammatory compounds.

Another important thing our microbial friends do is keep infections in check. For example, yeast infections from pathogenic fungi can arise if good bacteria are not around competing for resources. And some bacteria, like the nasty Clostridium difficile, are naturally resistant to many antibiotics. When good bacteria are killed as collateral damage in an antibiotic treatment, the growth of Clostridium can run amok. These bacteria secrete a toxin that causes diarrhea and they can lead to a life-threatening superinfection in some patients.

4. Your microbiome may protect you from allergies or obesity.

Several recent studies have correlated unusual microbiome composition with the presence of certain allergies. Dr. Hans Bisgaard has shown that infants harboring fewer species of gut bacteria have an increased risk of developing certain allergies as they grow up. More recently, Dr. Catherine Nagler has shown that certain bacterial species offer protection from peanut allergies.

Dr. Martin Blaser has found that administration of penicillin to mice soon after birth altered their gut microbiome in such a way that it made them more prone to obesity as adults. Remarkably, the tendency to grow obese is transferrable to germ-free mice – in other words, by transplanting the microbes from the penicillin treated mice to normal mice made the normal mice more susceptible to weight gain.

Studies such as these make it tantalizing to speculate that we may be able to treat certain ailments in humans by altering our microbiome with specific probiotic regimens. Maybe they could even slip these bacteria into our peanut butter instead of deadly Salmonella.

5. How do scientists study the microbiome?

Advances in DNA sequencing have allowed scientists to rapidly map the genomes for many microbial species, which provides us with a “genomic fingerprint”. We can process samples swabbed from the skin or body cavities, or process stool samples, for DNA sequencing. Usually just sequencing the 16S ribosomal RNA gene is enough to distinguish one bacteria species from another.  

It should be mentioned that some scientists are issuing cautions about over-interpreting microbiome studies. Many of the studies altering the microbiome have been performed in mice, so it remains to be determined to what extent the findings can be extrapolated to humans. Furthermore, many of the methods used to alter the microbiome in lab animals do not faithfully mimic what humans do with antibiotics. For example, in some studies the investigators give large doses of antibiotics over unusually long periods of time to see an effect in lab animals, which does not equate to the typical dosing of antibiotics in humans. Finally, many of these studies are correlative and have not yet definitively demonstrated causation. There is a big difference between correlation and causation.

6. So should I take my microbiome into my own hands?

Much more research needs to be done to assess the true impact of the microbiome versus other factors that come into play, such as host genetics, diet, and the environment. It is argued that some microbiome studies are hyped up and way overblown. Long story short:  if you or your child becomes sick with an infectious agent, it is not wise to withhold antibiotic treatment out of fear that it will cause allergies or obesity. If you are overweight, a healthier diet and plenty of exercise is going to do much more than any probiotic pill. In fact, there is little evidence that the popular probiotics on the market do anything to remedy the wide-ranging health problems some claim to treat, although there is data showing potential benefit in treating some gastrointestinal maladies, especially acute diarrhea caused by rotavirus.

Go here to learn more about the NIH human microbiome project.

Contributed by:  Bill Sullivan, Ph.D.

Follow Bill on Twitter.

Lax S, Smith DP, Hampton-Marcell J, Owens SM, Handley KM, Scott NM, Gibbons SM, Larsen P, Shogan BD, Weiss S, Metcalf JL, Ursell LK, Vázquez-Baeza Y, Van Treuren W, Hasan NA, Gibson MK, Colwell R, Dantas G, Knight R, & Gilbert JA (2014). Longitudinal analysis of microbial interaction between humans and the indoor environment. Science (New York, N.Y.), 345 (6200), 1048-52 PMID: 25170151

Bisgaard, H., Li, N., Bonnelykke, K., Chawes, B., Skov, T., Paludan-Müller, G., Stokholm, J., Smith, B., & Krogfelt, K. (2011). Reduced diversity of the intestinal microbiota during infancy is associated with increased risk of allergic disease at school age Journal of Allergy and Clinical Immunology, 128 (3), 646-65200000 DOI: 10.1016/j.jaci.2011.04.060

Cox, L., Yamanishi, S., Sohn, J., Alekseyenko, A., Leung, J., Cho, I., Kim, S., Li, H., Gao, Z., Mahana, D., Zárate Rodriguez, J., Rogers, A., Robine, N., Loke, P., & Blaser, M. (2014). Altering the Intestinal Microbiota during a Critical Developmental Window Has Lasting Metabolic Consequences Cell, 158 (4), 705-721 DOI: 10.1016/j.cell.2014.05.052

Stefka, A., Feehley, T., Tripathi, P., Qiu, J., McCoy, K., Mazmanian, S., Tjota, M., Seo, G., Cao, S., Theriault, B., Antonopoulos, D., Zhou, L., Chang, E., Fu, Y., & Nagler, C. (2014). Commensal bacteria protect against food allergen sensitization Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1412008111

Williams NT (2010). Probiotics. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists, 67 (6), 449-58 PMID: 20208051

Alang, N., & Kelly, C. (2015). Weight Gain After Fecal Microbiota Transplantation Open Forum Infectious Diseases, 2 (1) DOI: 10.1093/ofid/ofv004

6 Things You Need To Know About Your Microbiome

You are not just a person – you are an ecosystem. Your body is home to trillions of microscopic critters, including viruses, bacteria, and fungi, living on or inside you. Collectively, these communities of microbes constitute what is called your “microbiome”.

And there are more of “them” than “you” – the number of microbes inhabiting your body is larger than the number of cells making up your body! To put this in perspective, it has been estimated that your microbiome weighs about 3 pounds. Good news if you’re on a diet – when you step on the scale tonight, feel free to subtract 3 pounds of stuff that isn’t “you” per se.

A new study concerning our microbiome seems to be coming out each week, so it is time we get to know our microbial roommates.

1. Where does your microbiome come from?

We are born virtually sterile, but quickly receive an infusion of bacteria from our mom, first through the birth canal and then through the milk. Over 900 species of bacteria have been found in breast milk, and these are the pioneers that settle into your gut, which appears to stabilize by the age of 3. Of potential interest are babies born by caesarean section or those who are fed formula instead of breast milk. Babies delivered via C-section do in fact have a different microbiome and may be at higher risk for certain types of allergies and obesity (more on this below). Our microbiome continues to receive fresh new imports as we move through, inhale, and ingest our environment.

How much of you is really you? There are more microbes in your body than the number of cells making up your body. We are just now beginning to appreciate the many things they do for us.

2. Your microbiome is like your own personal “germ cloud”.

You’ve probably noticed that everyone’s home smells a little different. Sometimes this is due to cooking, pets, or the amount of trash they let accumulate, but it is also due in part to the microbiome of the inhabitants. Researchers have found that you are surrounded by a “germ cloud”, and you leave pieces of your microbiome wherever you go like a trail of breadcrumbs. It might even be possible for police to use microbiomes to track people one day like they currently use fingerprints or DNA. In other words, you have a “microbiome fingerprint” that is left behind like a germ echo wherever you go.

This “germ cloud” may also explain how dogs can track people so easily. The byproducts generated by the millions of bacteria living on your skin are aromatic (odorous), producing a scent that is released into the air as you move. Animals with a keen sense of smell can get a whiff of these aromatic compounds and follow them to the source.

Speaking of “germ clouds”, if you ever wondered if it is possible to fart out germs, some brave scientists have sniffed out the answer to this question. You can read about the results here.

3. Antibiotics substantially alter your microbiome.

We take antibiotics to get rid of pathogenic bacteria that make us sick. The problem is they are not selective, so they destroy a lot of our friendly bacteria in addition to the bad guy. We need these friendly bacteria to do all sorts of things – to name just a few:  they help us digest food, make vitamins, and build anti-inflammatory compounds.

Another important thing our microbial friends do is keep infections in check. For example, yeast infections from pathogenic fungi can arise if good bacteria are not around competing for resources. And some bacteria, like the nasty Clostridium difficile, are naturally resistant to many antibiotics. When good bacteria are killed as collateral damage in an antibiotic treatment, the growth of Clostridium can run amok. These bacteria secrete a toxin that causes diarrhea and they can lead to a life-threatening superinfection in some patients.

4. Your microbiome may protect you from allergies or obesity.

Several recent studies have correlated unusual microbiome composition with the presence of certain allergies. Dr. Hans Bisgaard has shown that infants harboring fewer species of gut bacteria have an increased risk of developing certain allergies as they grow up. More recently, Dr. Catherine Nagler has shown that certain bacterial species offer protection from peanut allergies.

Dr. Martin Blaser has found that administration of penicillin to mice soon after birth altered their gut microbiome in such a way that it made them more prone to obesity as adults. Remarkably, the tendency to grow obese is transferrable to germ-free mice – in other words, by transplanting the microbes from the penicillin treated mice to normal mice made the normal mice more susceptible to weight gain.

Studies such as these make it tantalizing to speculate that we may be able to treat certain ailments in humans by altering our microbiome with specific probiotic regimens. Maybe they could even slip these bacteria into our peanut butter instead of deadly Salmonella.

5. How do scientists study the microbiome?

Advances in DNA sequencing have allowed scientists to rapidly map the genomes for many microbial species, which provides us with a “genomic fingerprint”. We can process samples swabbed from the skin or body cavities, or process stool samples, for DNA sequencing. Usually just sequencing the 16S ribosomal RNA gene is enough to distinguish one bacteria species from another.  

It should be mentioned that some scientists are issuing cautions about over-interpreting microbiome studies. Many of the studies altering the microbiome have been performed in mice, so it remains to be determined to what extent the findings can be extrapolated to humans. Furthermore, many of the methods used to alter the microbiome in lab animals do not faithfully mimic what humans do with antibiotics. For example, in some studies the investigators give large doses of antibiotics over unusually long periods of time to see an effect in lab animals, which does not equate to the typical dosing of antibiotics in humans. Finally, many of these studies are correlative and have not yet definitively demonstrated causation. There is a big difference between correlation and causation.

6. So should I take my microbiome into my own hands?

Much more research needs to be done to assess the true impact of the microbiome versus other factors that come into play, such as host genetics, diet, and the environment. It is argued that some microbiome studies are hyped up and way overblown. Long story short:  if you or your child becomes sick with an infectious agent, it is not wise to withhold antibiotic treatment out of fear that it will cause allergies or obesity. If you are overweight, a healthier diet and plenty of exercise is going to do much more than any probiotic pill. In fact, there is little evidence that the popular probiotics on the market do anything to remedy the wide-ranging health problems some claim to treat, although there is data showing potential benefit in treating some gastrointestinal maladies, especially acute diarrhea caused by rotavirus.

Go here to learn more about the NIH human microbiome project.

Contributed by:  Bill Sullivan, Ph.D.

Follow Bill on Twitter.

Lax S, Smith DP, Hampton-Marcell J, Owens SM, Handley KM, Scott NM, Gibbons SM, Larsen P, Shogan BD, Weiss S, Metcalf JL, Ursell LK, Vázquez-Baeza Y, Van Treuren W, Hasan NA, Gibson MK, Colwell R, Dantas G, Knight R, & Gilbert JA (2014). Longitudinal analysis of microbial interaction between humans and the indoor environment. Science (New York, N.Y.), 345 (6200), 1048-52 PMID: 25170151

Bisgaard, H., Li, N., Bonnelykke, K., Chawes, B., Skov, T., Paludan-Müller, G., Stokholm, J., Smith, B., & Krogfelt, K. (2011). Reduced diversity of the intestinal microbiota during infancy is associated with increased risk of allergic disease at school age Journal of Allergy and Clinical Immunology, 128 (3), 646-65200000 DOI: 10.1016/j.jaci.2011.04.060

Cox, L., Yamanishi, S., Sohn, J., Alekseyenko, A., Leung, J., Cho, I., Kim, S., Li, H., Gao, Z., Mahana, D., Zárate Rodriguez, J., Rogers, A., Robine, N., Loke, P., & Blaser, M. (2014). Altering the Intestinal Microbiota during a Critical Developmental Window Has Lasting Metabolic Consequences Cell, 158 (4), 705-721 DOI: 10.1016/j.cell.2014.05.052

Stefka, A., Feehley, T., Tripathi, P., Qiu, J., McCoy, K., Mazmanian, S., Tjota, M., Seo, G., Cao, S., Theriault, B., Antonopoulos, D., Zhou, L., Chang, E., Fu, Y., & Nagler, C. (2014). Commensal bacteria protect against food allergen sensitization Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1412008111

Williams NT (2010). Probiotics. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists, 67 (6), 449-58 PMID: 20208051