Microbiome 2020 🦠

If I say “think of your body,” what do you picture? Your eyes? Your heart? Your toes? Do you think about your bacteria? Perhaps you should; current science suggests our microbes are as much “us” as our brain or fingertips. Countless microorganisms live in and on our bodies. Emerging studies into the human “microbiome” impact how we view our bodies and our health.

“Microbiome” refers to the combined genomes of the microorganisms in a particular environment. Although brought into popular usage in the early 2000’s, the term dots medical journals as far back as the 1950s.¹ “Microbiota,” often used interchangeably with “microbiome,” refers to the specific microorganisms found within a specific environment. (Confusing, I know.  Think organisms → microbiota; genomes → microbiome. Forgiveness in advance for when I screw this up).² The recent boom in microbiome interest means large studies are only now reaching conclusions. This includes “a global, crowdsourced citizen science effort” called The American Gut Project.³

Microbiome studies are legion and often confusing; here I’ll try to organize some of what I know (or think I know) about the topic. Our focus will be on the interplay between our bodies and their microbiomes. I’ll mostly skip microbial-level bio-engineering stuff not directly related to humans. It’s important and exciting, but not really pertinent to our discussion here.

Microbes, microbes everywhere

Microbes and humans are permanently intertwined (as are microbes and practically every other organism). To say this is generally good would be an understatement. It’s been a necessary part of our evolution.

Can Life exist without microbes?

Consider a popular quote by Louis Pasteur (the inventor of pasteurization – and by extension most supermarket food as we know it): “Life would not long remain possible in the absence of microbes.” Though not entirely accurate, Louis is onto something. Interesting things happen when mammals, such as mice, are born and raised in sterile environments.

Sterile, microbe-free environments simply don’t exist in nature. Research labs, though, can breed mice in 100-percent “clean” environments. Things end up all sorts of weird. “[T]hese animals possess smaller lymph nodes and a poorly developed immune system, including reductions in serum immunoglobulin and leukocytes. Germ-free animals also exhibit reduced organ sizes, including for the heart, lungs, and liver.”⁴

What about humans?

We humans don’t have to worry much about germ-free living. Our bodies are teeming with microbes, inside and out. The best current estimate counts one microbe for each cell in our body ⁵. Consider, though, that while humans have 20-30k genes, the combined genes we carry, including our microbiomes, numbers in the tens or hundreds of millions. Maybe the right ratio to consider is closer to 1:1000.⁶

This microbial intertwining begins at birth. Most mothers provide a helpful birthday gift to their children in the form of a bacterial bath through the vagina. While the microbiome indeed develops in utero, the trip through the birth canal provides a supercharged microbial kick. This “seeding” or transfer of microbes from mother to newborn may serve as a sort of disease-fighting inoculation. Vaginal microbe transfer may serve as an inoculation process that impacts newborns’ long-term health. Studies show distinct differences in the microbiome profiles of vaginal-versus-cesarean born newborns.⁷

Who are we feeding?

Those familiar with newborns know about the “rooting” instinct to search for a food source. The baby needs sustenance and nutrition to grow big and strong. Here’s something interesting, though… In addition to feeding the baby, each mother’s milk is specifically formulated to feed the microbes in their baby’s gut.

Breast milk contains something called Human Milk Oligosaccharides (HMOs) in high concentration. Here’s the thing, though: babies can’t digest HMOs. “Despite the role of milk to serve as a sole nutrient source for mammalian infants, the majority of [HMOs] in milk are not digestible by human infants. This apparent paradox raises the obvious questions about the functions of these oligosaccharides and how their diverse molecular structures affect their functions.”⁸

Researchers questioning HMOs’ function eventually landed on a bacteria called B. infantis. The HMOs feed this B. infantis bacteria. Why? The bacteria has a litany of benefits. It crowds out potentially harmful bacteria. It also produces helpful short-chain fatty acids, sialic acid, and folate.⁹ Feeding the B. infantis bacteria actually helps young children grow!

How we identify the microbes

Until fairly recently, microbes in a sample were best identified when grown in a culture. Once we have enough of said microbes, we can zoom in and take a close look. This process has drawbacks: some microbes are slow-growing and others don’t grow in culture, resulting in an incomplete picture.

Today’s researchers find more success sequencing genomes within a sample. All organisms carry the 16s rRNA gene. Sequencing this gene provides a “cheap and easy” identification marker. However, “the [16s rRNA] technique suffers from poor resolution below the bacterial genus level, making it difficult to differentiate closely related species.”¹⁰

Therefore, cutting-edge research uses Shotgun Metagenomic Sequencing (SMS). SMS “has the ability to sequence the complete collection of microbial genomes present in a microbiome sample, theoretically being able to discriminate between strains that differ by a single nucleotide.” The drawback to this increased granularity is its high cost and increased strain on computational resources.

Good and bad microbes

Popular narratives pitting “good” microbes against “bad” microbes oversimplify matters. Microbial ecosystems are massively complex. We simply don’t know how each and every microbe contributes to the delicate balance. It’s not as simple as fewer bad microbes + more good microbes = more health.

We certainly want to avoid some bacteria. Salmonella, E. coli, and Streptococci strike fearful images of nausea, vomiting and “intestinal distress.” In broad strokes, these fears prove useful. However—there’s always a “however”, right?—there’s tons of E. coli living in your large intestine right now. Only certain strains, under certain circumstances, make us toss our cookies.

It’s also worth noting how deadly viruses can be repurposed. A tweak of this gene or that turns killers into super-effective delivery agents, carrying therapies directly into affected cells.

Employing bacteria to fight cancer dates back to the late 19th century. Oncologist William B. Coley infected his cancer patients with Streptococcus pyrogenes, the culprit behind strep throat.¹¹ Talk about risky business! Some patients experienced near-miraculous remission. Others, unfortunately, incurred dangerous systemic infections. Our kitchens provide another interesting example: “You probably know Salmonella as the bacteria…in undercooked meat, waiting to wreak havoc on the human body with diarrhea, vomiting, and chills. Not necessarily something you want to ingest by choice! Salmonella, as it turns out, is toxic to cancer cells. So in this case, our enemy’s enemy just might be our friend.”¹²

Microbe influencers

Today’s social media landscape is obsessed with “influencers.” When it comes to our bodies, think of microbes as “influencers” mightier than all the Instagram and Youtube stars combined. Current research highlights some key areas of microbial-host interplay. This goes way beyond Salmonella making you sick.

But, how?

First, you should know the microbes in your gut have a direct line of communication to your brain. This direct line is the vagus nerve, spanning from your brain to your gut. It gives microbes a direct influence on human behavior. It’s part of a “direct circuit between the gut and the brain that could allow for fast sensory communication that doesn’t rely on laborious hormonal signaling. … In under 100 milliseconds, a single signal was seen to travel from the gut to the brainstem.”¹³

Stimulating the gut’s vagal nerve endings can directly influence dopamine, serotonin, and other neurotransmitters. This means gut microbes may play a pivotal role in mood and anxiety disorders. “…There is preliminary evidence for gut bacteria to have a beneficial effect on mood and anxiety, partly by affecting the activity of the vagus nerve.”¹⁴

Another study suggests the vagus nerve as a pathway by which animals may contract Parkinson’s disease. “An important and rigorous new animal study led by scientists at Johns Hopkins University has demonstrated how the misfolded proteins thought to cause Parkinson’s disease may originate in the gut, and travel up to the brain via the vagus nerve.”¹⁵

Similar theories, supported by early research, posit the gut microbiome interacts with dementia, autism and similar disorders. This doesn’t necessarily establish a causal relationship. As yet, researchers have more questions than answers relating the gut microbiome to dementia and autism spectrum disorders.¹⁶

Influencing allergies

Remember our bacterial bath during vaginal childbirth? Evidence suggests babies born by C-section may suffer due to a lack of that bacteria. A study of about a million newborns in Sweden validated earlier, smaller studies: “…Children born by C-section run a 21 percent higher risk of developing food allergies than children born [vaginally].”¹⁷

Importantly, this is still an unstable scientific ground. A 2017 study in Singapore of 1,000 births did not find a correlation between C-sections and increased allergies in children from birth to 5 years. In acknowledging this contradictory finding, the authors speculate a possible influence by the underlying conditions which lead to C-sections in the first place.¹⁸

Another study demonstrated certain microbiome compositions may protect animals from allergies. “Researchers from the University of Chicago, Argonne National Laboratory and the University of Naples Federico II in Italy discovered that when gut microbes from healthy human infants were transplanted into germ-free mice, the animals were protected from an allergic reaction when exposed to cow’s milk.” This is an amazing concept; we can theoretically use bacteria to prevent or reverse common food allergies. “This study allows us to define a causal relationship and shows that the microbiota itself can dictate whether or not you get an allergic response,” said Cathryn Nagler, the Bunning Food Allergy Professor at UChicago and senior author of the study.¹⁹

I think it’s worth noting here that this concept involves a lot of trial and error. The gut microbiome is an incredibly complex system. We also don’t have a clear view into second- or third-order effects of tampering with the gut microbiome. Cool, we’ve eradicated allergies, but what if we incubate superviruses in the process? Studies in mice look clean because of laboratory-specific, germ-free mice. The real world is messy and diverse, so experiments removed from a lab often produce different outcomes.

Influencing performance

Some researchers have turned an eye to athletes, hoping to find common microbes among elite performers. One study of a Rugby World Cup team found its players with lush microbiomes. “The scientists found that the players’ gut biomes boasted dramatic diversity—an African savanna compared with the frozen tundra of the couch-potato control group—with double the number of phyla represented. Firmicutes were higher than average, which made sense for men with a high body-mass index burning lots of energy; and the quantity of Akkermansia mucini­phila (a bacterium often found in skinny folk but not obese people) was exceptional.”²⁰

Influencing body composition

Some research demonstrates the specific impacts of one particular microbe on weight. “Christensenella minuta, can influence the phenotype—the composite of observable characteristics or traits—of the host. Germ-free mice live in sterile bubbles—and they are very skinny. When they are given a microbiome in the form of a fecal transplant from a human donor, however, they plump up within a day or two because the bacteria help them digest their food and develop a proper metabolism. We found that if C. minuta was added to the feces of an obese human donor, the recipient mice were thinner than when C. minuta was not added. Results showing C. minuta has an effect of controlling fat gain in the mouse match data that reveal lean people have a greater abundance of C. minuta in their gut than obese people.”²¹

This research was especially interesting because it suggested individual genes influence which gut bacteria thrive. This means genes may have a double effect on whether a person is likely to be skinny or not.

Influencing aging-related disease

Gut bacteria naturally shifts during middle-age. One research team hypothesized this shift could trigger processes resulting in later cognitive decline. Initial studies in lab mice produced profound results. “Our research shows that a diet supplemented with prebiotics reversed microglia activation in the middle- aged mouse brain towards young adult levels,” says Marcus Boheme, first author on the study. “Moreover, this reversing effect was observed in a key region of the brain which regulates learning and memory, the hippocampus.”²²

Managing microbiomes

Even considering the relative newness of microbiome studies, some aim to influence our microbes. Researchers have discovered a few avenues to customizing our gut microbiomes. Most are still imprecise. Compared to broad spectrum antibiotics, which hit a body like an atom bomb, microbiome mods are somewhat targeted and done in a few different ways. The simplest method is a sustained dietary change. Though simple, many microbes can’t survive the journey through the stomach to the gut, meaning dietary changes can only do so much. Fecal transfers are (obviously) more invasive, but result in higher efficacy. The other option is microbial delivery via pills designed to dissolve at just the right time.

Diet

Diet and microbes are tied together in a feedback loop. What we eat impacts our microbiome, which in turn impact impacts how we process foods. This ability to process foods likely impacts our want for certain foods. Diet changes impact our microbiome, which impacts how we process foods, which impact…et Cetera, et cetera.

Foods like yogurt have long claimed the benefits of providing good bacteria through diet. It’s not clear that this is truly useful, though I presume it’s at least a bit effective and probably won’t hurt (unless your yogurt is full of sugar).

There is, however, notable research demonstrating diet changes alter our microbiome in as little as 24 hours, albeit temporarily. Think of it like this: some bacteria are hungry for veggies, while others want dairy or simple carbs. Drinking lots of milk boosts our dairy bacteria for a short time.²³

One challenge in changing the dynamics of our microbiome through diet is, as previously mentioned, many microbes can’t survive the journey from your mouth all the way to your intestines. That’s a long way to travel for a little microbe, saying nothing of traversing a sea of stomach acids! Another consideration is how microbiota constantly evolves in an ongoing give-and-take between species. Nature works toward equilibrium. Over time, though, sustained diet changes can influence microbiome composition. Anecdotally, gut microbiomes may explain why folks on a typical American diet don’t respond well to high-fiber meals like salad, and why “healthy eaters” feel like crap after fast food.

Environment

Think about something as simple as sunlight. Research demonstrates its impact on gut microbiome diversity. Scientists compared a group who took Vitamin D supplements to another who did not. They found “UVB exposure boosted the richness and evenness of their microbiome to levels indistinguishable from the supplemented group, whose microbiome was not significantly changed.” Lead researcher Bruce Vallance from the University of British Columbia suggests, “It is likely that exposure to UVB light somehow alters the immune system in the skin initially, then more systemically, which in turn affects how favorable the intestinal environment is for the different bacteria.”²⁴

Fecal Microbiota Transplants (FMT)

Fecal transplant as a method of battling illness reportedly dates back to China in the 4th Century C.E.. For the Western World, documented FMTs go back to the 1950s. Fecal transplant is currently in clinical use for cases of Clostridium difficile (commonly called C. Diff) infection in humans.

Other potential clinical applications of FMT include: inflammatory bowel disease, irritable bowel syndrome, obesity and diabetes mellitus, multiple sclerosis and Parkinson’s disease, atopy and rheumatoid arthritis, autism, and depression.²⁵ FMT as treatment for the above are at various stages of research and not yet in clinical use. Early research, though, is indeed promising.

One study from Arizona State University—non-controlled, but nevertheless exciting—suggests FMT as a treatment for autism. “Prior to the study, 83 percent of participants had ‘severe’ autism. Now, only 17 percent are rated as severe, 39 percent as mild or moderate, and incredibly, 44 percent are below the cut-off for mild [autism spectrum disorder].” Two years later, the children are doing even better.²⁶

Another, less controversial, study shows FMT can quickly restore the compromised microbiome of cancer patients. “The study’s primary focus was on whether this process was safe and effective in restoring an individual’s gut microbiome. At this stage there is no data on specific patient outcomes, such as whether the rapid microbiome restoration actually reduced incidences of infections, but plenty of other research is certainly suggesting that this could be an important factor in future cancer treatment.”²⁷

Science isn’t always rainbows and lollipops, though. The first human trial treating obesity with FMT concluded unfavorably. The human study failed to reproduce initial successes in animal models. Even these null results help move science forward: they illustrate the incredible complexity of obesity and microbiomes.²⁸

Pharmaceuticals

Two tracks interest me regarding pharmaceutical microbe delivery: coatings and content. The first is the field of coatings. One research team tested polymer-based coatings to protect microbes on its mouth-to-gut odyssey. Another developed a microbiotic-protective gel.

“Jaklenec and colleagues developed a way to coat bacteria with polymer layers that protect them from the acids and bile salts found in the digestive tract. When the microbes reach the intestine, they attach to the intestinal lining and begin reproducing.” Bacteria delivered with this coating “survive at better rates much better than non-coated bacteria,” says lead author and Koch Institute postdoc Aaron Anselmo.²⁹

The gel-coating researchers, “mixed dilute solutions of cellulose and alginate, then added…”friendly” bacteria [and dripped] this brew into a solution of calcium chloride.” When introduced to a stomach-like environment, gel-coated probiotics survived at a much better rate. Then, when introduced to a more intestine-like neutral pH environment, “the bacteria gel swelled, releasing the probiotics.” ³⁰

The other interesting track is using bacteria to create custom pharmaceuticals. Scientists have genetically-modified bacteria that, once ingested, synthesize drugs from inside the gut. “Ultimately, genetically modified bacteria are self-propelling drug factories, making them attractive vehicles for drug delivery. In addition to their ability to secrete therapeutics, the bacteria themselves exert beneficial effects: ranging from bacteria known to be good for health (probiotics), to the selective toxicity of Salmonella towards cancer cells.”³¹

Tech companies getting into the action

As with any scientific advance, a number fringe (a label befitting even the unicorns, IMO) consumer tech companies have sprouted, touting microbiome-centered products. It’s a beautiful promise. Of course, it’s still too early to know if any of them deliver on their promises (think our yogurt above). Companies like uBiome and Viome offer to analyze your microbiome and provide suggestions for optimizing your diet. Sun Genomics uses your microbiome sample to sell personalized supplements. A company called FitBiomics, founded by Harvard researchers, is using data from elite athletes’ guts to develop a supplement for boosting workout endurance. The list goes on. For a fairly comprehensive review of microbiome startups, surf over to https://www.medicalstartups.org/top/microbiome/.

Further reading for beginners

As with any other data set, variety is key. We need a balanced diet. Don’t listen to just me. Consult the experts. Consult the detractors! A phenomenal starting point for all things microbial is I Contain Multitudes by Ed Yong. The book provided my initial, mind-blowing glimpse into the incredible universe of microbiomes. Each passing study reinforces the importance of microbes to our bodies, our minds, and our world.

1. https://www.sciencedirect.com/science/article/pii/S245223171730012X
2. https://www.fiosgenomics.com/microbiome-vs-microbiota/
3. https://newatlas.com/largest-microbiome-gut-bacteria-study/54632/
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267716/
5. ibid
6. https://www.sciencedaily.com/releases/2019/08/190814113936.htm 
7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648605/  
8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861563/  
9. https://www.darkdaily.com/university-of-california-davis-researchers-discover-infant-microbiomes-lack-b-infantis-in-developed-nations/
10. https://blog.dnagenotek.com/microbiome/sequencing-the-microbiome-are-you-getting-the-full-story  
11. https://onlinelibrary.wiley.com/doi/full/10.1111/j.1538-7836.2005.01110.x  
12. http://sitn.hms.harvard.edu/flash/2017/microbial-physicians-delivering-drugs-bacteria/  
13. https://newatlas.com/gut-brain-neural-connection-discovered/56463/  
14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859128/  
15. https://newatlas.com/parkinsons-disease-gut-brain-origins-johns-hopkins/60324/  
16. https://massivesci.com/articles/tedmed-sarkis-mazmanian-gut-brain-axis-microbiome-bacteria-autism/  
17. https://medicalxpress.com/news/2018-09-c-section-children-food-allergies-opposed.html  
18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505471/  
19. https://news.uchicago.edu/story/how-gut-bacteria-infants-could-prevent-food-allergy  
20. https://www.outsideonline.com/2274441/no-gut-no-glory  
21. https://www.scientificamerican.com/article/genes-and-microbes-influence-one-another-scientists-find/  
22. https://newatlas.com/gut-bacteria-microbiome-aging-brain-health-prebiotics/59809/  
23. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385025/  
24. https://newatlas.com/health-wellbeing/uvb-sunlight-skin-gut-microbiome-vitamin-d-autoimmune/  
25. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836576/  
26. https://newatlas.com/fecal-transplants-autism-symptoms-reduction/59278/  
27. https://newatlas.com/fecal-transplant-microbiome-cancer-trial/56536/  
28. https://newatlas.com/fecal-transplant-obesity-human-trial/59617/  
29. http://news.mit.edu/2016/delivering-beneficial-bacteria-stomach-gi-tract-0914  
30. ibid 
31. http://sitn.hms.harvard.edu/flash/2017/microbial-physicians-delivering-drugs-bacteria/