Cui Bono? Who Benefits From Our Microbiome? - Part II

On the face of it, one would think that the bacteria in our bodies benefit far more from their association with us than we do from our association with them.

We give them places to hide out, protected from external conflict – our GI tracts, our vaginas, our noses, our sinuses, and lots of other unexpected nooks and crannies. We only very occasionally feed them poison – antibiotics, for instance, if our microbiome gets too unruly and starts to take over in the form of earache, or stomach ache, or pneumonia.

Why have our bodies developed a tolerance for these microorganisms? Where is the benefit to us?

If we truly believe in the concept of “as above, so below” and understand that we ourselves are a reflection of everything in the cosmos, then it should come as no surprise that we are destined to live in a community, not as isolated creatures. Our solar system is part of a larger galaxy. Our earth is part of a solar system. Our cities and mountains are part of our earth. We individuals are part of society. And our microbial society is part of each one of us.

Remember the bubble boy? The child born without an immune system who lived isolated in a bubble chamber for his entire short life? He was barely able to tolerate his own microbes, and never could tolerate foreign microbes. He lived in his bubble for 12 years.

David Vetter, affectionately known as the boy in the bubble, was born with Severe Combined Immune Deficiency (SCID), one of the most severe types of primary immunodeficiency disease. At the time of his birth in 1971, a bone marrow transplant from an exact matched donor was the only cure for SCID, but there was no match available in David’s family.[i] For 12 years, David captured the world’s attention as he lived in protected environments to maintain relatively germ-free surroundings at Texas Children’s Hospital. Sadly in 1984, four months after receiving a bone marrow transfusion, David died from lymphoma—a cancer later determined to have been introduced into his system by the Epstein-Barr virus.

Together we are strong. But a house divided against itself does not stand for very long.

What are the benefits that microorganisms provide to us that so overwhelm our good judgment about our individuality that we actually allow these microorganisms space in our bodies?

Dr. Kevin Foster states: “We suggest that the health benefits of the microbiome should be understood, and studied, as an interplay between microbial competition and host control.”[ii] That still makes it sound like a battleground.

Perhaps if we thought of the relationship more like that of a teeter-totter – there needs to be balance on both sides in order to allow for dynamic interchange, growth and movement.

We should remember that we, human beings, were not the first organisms to permit such a relationship. “The relationship between mammalian hosts and microbes is just one of a myriad of evolved symbioses that date back to the dawn of multicellular life.”[iii]

One huge benefit of having a friendly microbiome is that we can enlist them in fighting off unfriendly invaders. People with healthy gut bacteria tend not to get sick as easily when they meet new bacteria – as when visiting a foreign country (think of “Montezuma’s revenge”, the colloquial term for traveler’s diarrhea experienced by Americans visiting Mexico.

Bacteria help us digest indigestible polysaccharides like those found in vegetable peels and seed coatings. Our bacteria love these compounds, and digest them into another chemical called butyrate which is taken up and used by the cells of the colon. In essence, our bacteria poop butyrate, our gut cells use it for fuel. Who would have thought?

Bacteria help us develop our tolerance to a myriad of compounds. Is it tolerance? Or is it more like mutual dependence? “We cannot assume that the host and microbiota are a single evolutionary unit acting with a common interest… Rather, the host and each individual microbial strain are distinct entities with potentially divergent selective pressures.”[iv] There are indeed some pathogens (e.g. Clostridium difficile) but mostly the pathogens appear to be exceptions – most bacterial species in our gut are helpful, or at least neutral.

How do we explain the diversity of microbe colonies in the gut? Ethnicity and race appear to have significant influence over the composition of the bacterial population. “Metagenomic carriage of metabolic pathways was stable among individuals despite variation in community structure, and ethnic/racial background proved to be one of the strongest associations of both pathways and microbes with clinical metadata…. The uniqueness of each individual’s microbial community thus appear to be stable over time (relative to the population as a whole), which may be another feature of the human microbiome specifically associated with health.”[v]

Our microbiome may even influence our food choices and preferences. The “rewarding” aspects of food ingestion depend on release of dopamine in the pre-frontal cortex – we see the food, we smell the food, we start drooling long before we ever put a bite of food in our mouths – because of the hedonic (pleasure-inducing) effect of the dopamine release in our brains. One study showed that administration of fructo-oligo-saccharides (FOS, prebiotic) could affect both the hedonic experience and the motivational aspects of food-seeking. This may be indirect evidence of the influence of food choices on the composition of the microbiome.[vi]

There are several different ways over which the host has control of the microbiome.

  • First, the host is large and one, not multiple. The host is more likely to speak with one voice.
  • The host may choose which organisms it is exposed to – Limburger cheese? Kimchi? Sauerkraut? Yogurt? Rotten meat? Rancid fat? Moldy vegetables? Penicillin?
  • Exposure may (and should naturally) occur at birth, as the baby passes through the vaginal canal, conveniently located right next to the food processing canal. Breast milk contains oligosaccharides for which we humans have no digestive mechanism as infants – but our microbiota digest them readily. Is it possible that this may explain the increasing lactose and dairy intolerance in recent generations of children?[vii] Cow’s milk contains oligosaccharides, but in much lower quantity than breast milk. Goat’s milk also contains these oligosaccharides.[viii] But if a c-section baby does not have the appropriate microbiome, that baby may very well show significant allergy to any milk with those oligosaccharides. At least if the baby can breast feed, it does get some of the mother’s helpful bacteria.
  • We think that IgA is a marker for inflammation in the gut, perhaps a marker for food sensitivity. However, IgA may in fact also promote colonization of beneficial bacteria.
  • One researcher hypothesizes that beneficial microbes are selected through their ability to adhere to the intestinal lining.

So what purpose does the microbiome serve? What good is it to us, besides cluttering up our internal landscape? If the relationship is truly symbiotic, then there must be benefits for both sides. Otherwise the relationship is between predator and prey – and the big question will be: “which is the predator and which the prey?”

  1. Certain strains of Lactobacillus are willing and able to synthesize some of the B vitamins which we humans are not able to synthesize for ourselves.[ix]
  2. “Members of the gut microbiota are able to synthesize vitamin K as well as most of the water-soluble B vitamins, such as biotin, cobalamin, folates, nicotinic acid, panthotenic acid, pyridoxine, riboflavin and thiamine”.[x] If babies were given their mothers’ microbiota at birth – either by being born through the birth canal or by having secretions wiped on their mouths at birth (in the case of c-section babies), then there would be no need to inject them with vitamin K to prevent bleeding. Our own microbiome has already taken care of this potential issue by giving our babies what they need for survival.
  3. Regarding the genus Bifidobacterium, “Several reports have highlighted the importance of bifidobacteria in regulating intestinal homeostasis, modulating local and systemic immune responses, and protecting against inflammatory diseases and infections. In addition, some bifidobacterial species are claimed to convert a number of dietary compounds into health-promoting bioactive molecules, such as conjugated linoleic acid and certain vitamins”.

We are even given to believe that our microbiome can influence our behavior. Is it possible that depression or anxiety are really a result of in-fighting in our gut between our bacteria and our brains? This has been demonstrated in mice, although perhaps not definitively in humans.[xi] One of the conclusions of this article is that “…the type of diet consumed by the host and the presence or absence of active inflammation may significantly alter the ability of probiotics to modulate host physiological function.”

There is evidence that the microbiome influences expression of a multitude of diseases in the human organisms – obesity, inflammatory bowel disease, arthritis, autism, depression, anxiety, metabolic syndrome, diabetes – to name just a few.

The population of the gut microbiome contains more than just bacteria. Other life forms – microorganisms – are also present in the gut – archeae (single cell organisms without a nucleus), viruses, phages (viruses that infect and kill bacteria), yeasts and fungi – Phages outnumber bacteria by a factor of 10:1. As bacteria outnumber our own body cells also by a factor of 10:1. Is it possible that bacteriophages operate with respect to bacteria in a similar fashion that bacteria operate with respect to us? Some helpful, some perhaps not so helpful.

One researcher suggests that “the gut microbiome can be used to predict personalized blood glucose responses to specific diets, which differ between individuals” – but in fact the results are mixed and not really predictable.[xii]

It has been “widely demonstrated that prebiotic feeding (eg, with inulin-type fructans and some polyphenols) strongly increases the presence of A. muciniphila and improves metabolic disorders associated with obesity, including decreased fat mass, insulin resistance, lower liver steatosis [fatty liver] and reinforcement of the gut barrier.”

It appears that the abundance of A muciniphila is decreased in several different diseases – obesity, type 2 diabetes, high blood pressure, high cholesterol levels and liver disease. The use of metformin dramatically increased the A muciniphila population in the animal studies. “All the studies in which animals were treated with A. muciniphila showed that the bacteria lowers body weight and fat-mass gain, hepatic steatosis, inflammation, cholesterol levels and atherosclerosis; improves insulin sensitivity and restores gut barrier function by influencing different factors (ie, mucus-layer thickness, tight-junction proteins, antimicrobial peptides and immunity)”[xiii] One of the proteins found on the outer membrane of A muciniphila has been shown to modulate the mice’s immune system and delay the onset of type 1 diabetes in diabetes-prone animals.

“…in humans the abundance of A. muciniphila was decreased in several pathological situations such as obesity, type 2 diabetes, inflammatory bowel diseases, hypertension and liver diseases… antidiabetic treatments, such as metformin administration and bariatric surgery were both found to be associated with a marked increase in the abundance of A. muciniphila…

“We observed that live A. muciniphila prevented the development of metabolic endotoxemia, an effect associated with the restoration of a normal mucus layer thickness… We observed that live A. muciniphila prevented the development of metabolic endotoxemia, an effect associated with the restoration of a normal mucus layer thickness… increased the endogenous production of specific bioactive lipids that belongs to the endocannabinoid family and are known to have anti-inflammatory activities…

“Collectively all these data reinforce the assumption that live A. muciniphila can be considered as a next-generation beneficial microbe with the exceptional particularity that this bacterium can act on numerous facets of the metabolic syndrome and cardiometabolic disorders.

“Pasteurized A. muciniphila also strongly improved glucose tolerance, hepatic insulin sensitivity, and completely blocked the diet-induced metabolic endotoxemia.”

Another experiment involving transferring the gut microbiome in a group of non-diabetic mice to another group of diabetic mice had interesting results: the incidence of diabetes was unchanged, unless A muciniphila colonies were added. “A. muciniphila transfer promoted mucus production and increased expression of antimicrobial peptide Reg3γ, outcompeted Ruminococcus torques from the microbiota, lowered serum endotoxin levels and islet toll-like receptor expression, promoted regulatory immunity and delayed diabetes development.”[xiv]

So… if Akkermansia municiphila has such a strong effect in both mice and humans to protect them against metabolic illnesses like obesity and diabetes currently at epidemic proportions in our population, why are we not using it in human beings? Are there any downsides to increasing this specific bacterial population in the gut?

The major downside appears to be the lack of widespread availability of A muciniphila as a supplement.

Can we promote the growth of this bacteria in our own GI tracts? Taking prebiotics with fructo-oligosaccharides appears to be beneficial, both in promoting the growth of that species and also in decreasing the total fat mass – at least of the mice to whom it was fed. “in mice studies, FOS supplementation significantly reduced the total fat mass accompanied by a significant reduction in serum LPS level (by over 50%) and a significant improvement in glycemic control.”[xv]

Specific foods like onion, chicory, garlic, asparagus, banana, artichoke contain fructo-oligosaccharides, and will be beneficial. Supplementation of cranberries and Concord grapes increased A muciniphila in mouse feces from 2% to over 30%. Ingestion of pomegranate extract, green tea extract, and whole California table grape showed no increase of A muciniphila in humans. All animal studies showed consistent increase of A muciniphila with metformin administration. Rhubarb, known in Chinese Medicine as Da Huang and used to treat many GI complaints including constipation and liver disease, increases the abundance of A muciniphila in mice. [xvi]

It is quite clear that the health effects on insulin resistance, glucose levels, body fat levels are dependent on the microbiome. “pretreatment of a combination of antibiotics (carbenicillin, metronidazole, neomycin and vancomycin) on HFD-fed mice before metformin treatment abolished the metformin activity (Shin et al., 2014), which strongly suggesting that the gut bacteria (i.e. A muciniphila) play an important role mediating metformin activity.”[xvii] So metformin’s effect is not due solely to the drug, but requires participation of our gut microbiome.

Administration of most antibiotics does significantly alter the composition of the gut microbiome. Interestingly, it appears that Vancomycin treatment increases the abundance

[ii] Foster, Kevin R., et al. "The evolution of the host microbiome as an ecosystem on a leash." Nature 548.7665 (2017): 43.

[iii] Ley RE, Lozupone CA, Hamady M, Knight R, Gordon JI. Worlds within worlds: evolution of the vertebrate gut microbiota. Nat Rev Microbiol. 2008; 6:776–788. [PubMed: 18794915]

[iv] ibid

[v] Huttenhower, C., Gevers, D., Knight, R., Abubucker, S., Badger, J. H., Chinwalla, A. T., ... & Giglio, M. G. (2012). Structure, function and diversity of the healthy human microbiome. nature, 486(7402), 207.

[vi] Delbès, Anne-Sophie, et al. "Prebiotics supplementation impact on the reinforcing and motivational aspect of feeding." Frontiers in endocrinology 9 (2018).

[vii] Seppo, Antti E., et al. "Human milk oligosaccharides and development of cow's milk allergy in infants." Journal of Allergy and Clinical Immunology 139.2 (2017): 708-711.

[viii] Martinez-Ferez, Antonio, et al. "Goats’ milk as a natural source of lactose-derived oligosaccharides: Isolation by membrane technology." International Dairy Journal 16.2 (2006): 173-181.

[x] ibid

[xii] Cani, Patrice D., and Willem M. de Vos. "Next-generation beneficial microbes: the case of Akkermansia muciniphila." Frontiers in microbiology 8 (2017): 1765.

[xiii] Ibid

[xvi] Sabater-Molina, M., et al. "Dietary fructooligosaccharides and potential benefits on health." Journal of physiology and biochemistry 65.3 (2009): 315-328.

[xvii] ibid