Of course, as is usual with me on the weekend, I started reading all my open tabs in my browser. And the first one I read was a paper where they crossed two pure strains of mice and correlated microbiome and genome.
Link: PLoS ONE: Murine Gut Microbiota Is Defined by Host Genetics and Modulates Variation of Metabolic Traits
“In this study, the BXD population [CS: the first generation hybrid mice] was used to detect and quantify genetic factors that may have a significant influence on the variation of gut microbiota. We have demonstrated that host-genetics is complex and involves many loci [CS: locations on the chromosomes]. These differences in microbial composition could impact susceptibility to obesity and other metabolic traits. Functional analysis of gut microbiota and characterization of the relationships with host-genotype [CS: genotype is the sum total of genes] has important implications to human health and agriculture. The gut microbial composition can be temporarily altered through dietary interventions tailored to host genotype, ultimately mitigating the effects of unfavorable alleles [CS: alleles are variations of a single gene across organisms] and inducing profiles that promote human health. Genetic variants that influence gut microbiota may also be used in selection programs of livestock to improve feed efficiency, disease resistance, and to reduce dissemination of pathogens associated with zoonotic diseases such as E.coli O157:H7 or Salmonella.”
Heavy stuff. We all knew this, but needed the simple scientific example of it. And this is foundational for this science moving forward.
So what did they do here? Lab mice are usually pure strains where each individual’s genome is identical. When you cross two strains though, the first generation of progeny are all mixed up in their genetic make up. So in this case, the scientists were able to see a whole range of variability in the genome and correlate that to the prevalence of different microbes in the gut. The idea is that regions in the genome would be associated with certain types of bacteria being maintained or lost.
Sure enough, they honed in on a region and “uncovered several candidate genes that have the potential to alter gut immunological profiles and subsequently impact gut microbial composition”. The region was rich in immune system genes. Also, these immune system genes were related to things like obesity as well, suggesting a connection with metabolism of food. Note: it’s not necessarily that there’s some auto-immune issue attacking the animal’s tissue, but could likely be that the immune system isn’t supporting the right bugs.
For those of you who know transfaunation as an option for helping resolve IBD: This might suggest that even if you do repopulate the flora of the gut, the host might not be able to maintain the flora, not just due to diet, but primarily due to immune profile.
Cool, isn’t it?
One comment that struck me, which points to the variability in frequency and intensity of IBD: “variation in gut microbiota and complex relationships with host genetics can represent unaccounted sources of differences for physiological phenotypes including susceptibility to obesity.”
But that makes sense.
What does this have to do with Eastern European Jews?
I happened to have an animated discussion last night with my wife and another couple, who are close friends (yes, we spent a lot of time talking about “poop” at a restaurant; yes, we’re total nerds). As we were leaving the restaurant, my wife reminded me that Eastern European Jews are know to have a higher rate of inflammatory bowel diseases.
That got me thinking.
And this is pure speculation: Eastern Jews are also known to have diseases that are related to genes in brain development. Folks have suggested that the living and working restrictions of Eastern Jews selected for variants of genes tied to things like increased intelligence (for much of their time in Europe, Jews were restricted to certain more white-collar, brain-centric professions). But as a consequence, while having one of these gene variants was helpful to brain development, having two copies led to severe mental development diseases.
So might IBD be a similar thing where the mixed set of genes conferred some sort of microbial or dietary advantage? And then, having the full set of IBD genes causes the full disease? For example, crowded into cities, might have Easter European Jews been more exposed to city and crowding diseases, such as cholera, typhus, or tuberculosis? What is the prevalence of these diseases in Eastern Jews? What is the lung or gut microbial resistance profile in Eastern Jews and Eastern Jews with IBD?
In short, is there a connection between gut issues (or more likely, gut microbe populations) and the evolutionary history of Eastern Jews (city living, profession and dietary restrictions, and so forth). Might the genes involved in IBD, like the the brain development genes, actually present some adaptive benefit at some level?
Kinda makes one think, doesn’t it?
Image from a mouth-watering post on knishes in NYC
“In conclusion, a time window exists that enables the artificial colonization of GF mice by a single oral dose of caecal content, which may modify the future immune phenotype of the host. Moreover, delayed microbial colonization of the gut causes permanent changes in the immune system.”
Ok. So there’s mounting evidence that rapid colonization of the gut of neonates is important to immune development. Next step is to translate that into real medical therapies. There are immune and gut diseases that afflict newborns (also, in many cases, newborns are bombarded by antibiotics at this crucial time) – what have we learned to make them healthier and also ensure that their immune system develops properly?
via PLoS ONE: Patterns of Early Gut Colonization Shape Future Immune Responses of the Host.
“Exposure to microbes during early childhood is associated with protection from immune-mediated diseases such as inflammatory bowel disease (IBD) and asthma. Here, we show that, in germ-free (GF) mice, invariant natural killer T (iNKT) cells accumulate in the colonic lamina propria and lung, resulting in increased morbidity in models of IBD and allergic asthma compared to specific pathogen-free (SPF) mice. This was associated with increased intestinal and pulmonary expression of the chemokine ligand CXCL16, which was associated with increased mucosal iNKT cells. Colonization of neonatal—but not adult—GF mice with a conventional microbiota protected the animals from mucosal iNKT accumulation and related pathology. These results indicate that age-sensitive contact with commensal microbes is critical for establishing mucosal iNKT cell tolerance to later environmental exposures.”
That’s the abtract from the paper “Gut Microbes Keep Rare Immune Cells in Line” (I think subscription is required, sorry).
There have been a good series of papers and studies into the “hygiene hypothesis” – that exposure to microbes early in life are actually important for the proper evolution of the immune system. This paper is one more example of that – these researchers were able to show what happened to the immune cells in the but of mice that never acquire bacteria, acquire bacteria only as adults, or acquire bacteria as pups.
I sometimes think of the 1850s-1990s as the Pasteurian Age – we were controlling bacteria to create a sterile world based on germ theory, aseptic techniques, public policies, and, of course, antibiotics. Alas, in the past 20 years, we’ve come to the realizations that we’ve reached (to joke a bit here) “peak antibiotics”, and that the only bugs to survive our clean homes and hospitals and antibiotics were Superbugs.
Now, in the past 5-10 years, I feel we are entering a post-Pasteurian Age, where we are gaining a deeper respect for the bacteria and fungi that share our world (and bodies) and that we are slowly thinking of how we can balance the sterile world we want and the microbe-filled world we need.
Great time to be a practical microbiologist, don’t you think?
“The results also showed that (i) consumption of an FMP containing five bacterial strains was not associated with a statistically significant change in the proportional representation of resident community members within and between individuals; (ii) the appearance and disappearance of strains comprising the FMP consortium did not exhibit familial patterns in the fecal microbiota; and (iii) B. animalis subsp. lactis CNCM I-2494 was the most prominent assayed member of the consortium represented in the microbiota during the 7-week period of FMP The results also showed that (i) consumption of an FMP containing five bacterial strains was not associated with a statistically significant change in the proportional representation of resident community members within and between individuals; (ii) the appearance and disappearance of strains comprising the FMP consortium did not exhibit familial patterns in the fecal microbiota; and (iii) B. animalis subsp. lactis CNCM I-2494 was the most prominent assayed member of the consortium represented in the microbiota during the 7-week period of FMP consumption. Analyses of the fecal gene repertoire over the course of the 16 weeks of the experiment indicated that (i) variations in the functional features of the (fecal) microbiome were less than the variations in bacterial species composition; (ii) there was no significant difference in the degree of similarity in representation of KEGG orthology group functions for a given co-twin at each time point compared to the degree of similarity that existed between co-twins, whereas individual and twin pair microbiomes were significantly more similar to one another than those from unrelated individuals; and (iii) there were no statistically significant changes in the representation of these functions when the FMP strain consortium was being consumed.”
This is a seminal paper in probiotic research. I have seen a ton of papers on this subject, but none were as thorough as this one. The one concern I had was that there was no control for the FMP (fermented milk product) matrix (I don’t know what to call it, but the fermented milk without the bacteria). I still think there might be a positive effect on the gut microbiome from that matrix.
But, these folks saw similar effects in humans who ate FMP and the mice who had only the bacteria that were found in the FMP, effectively showing what the effect of just the bacteria have on the microbiome.
Still, I’m curious to settle once and for all if there is any beneficial effect of the FMP matrix. My main thought here is that 1) we know that the lactose digesting bacteria help in the stomach (as seen in folks with lactose intolerance), but 2) only one bacterial species from the FMP really seems to make it all the way through the gut. Perhaps the matrix helps the microbiome or signals the microbiome to do something? In this study, it was suggested that the bacteria alone are activating specific microbiome metabolic pathway.
Fascinating stuff. Will need to dig into it more. And I just saw that there are some videos of the authors. Should be interesting.
via The Impact of a Consortium of Fermented Milk Strains on the Gut Microbiome of Gnotobiotic Mice and Monozygotic Twins. (subscription required, unfortunately).
What do you think of this work?
“Beyond providing the global view of the human gut microbiome, the extensive gene catalogue we have established enables future studies of association of the microbial genes with human phenotypes and, even more broadly, human living habits, taking into account the environment, including diet, from birth to old age. We anticipate that these studies will lead to a much more complete understanding of human biology than the one we presently have.”
I feel kinda cheezy for quoting the very last paragraph of this long and interesting paper. But there is so much to like about it, I didn’t know which to quote.
Basically, these folks sequenced the bacteria on fecal samples from a lot of healthy folks, and folks with IBD (inflammatory bowel disease), ulcerative colitis, obesity, and who were overweight.
They confirmed that each of these states have their own particular microbiome profile. But they also did a ton of metagenomic analysis, even establishing what the “minimal microbiome” is. And in their analysis they describe what this minimal microbiome mean to human health and physiological processes.
And the reason they are building this catalog (3.3 million microbial genes!) is that they will continue studying the subjects who donated the samples. And this is a good addition to the International Human Microbiome Consortium.
And of note, about half the authors of this work are from BGI-Shenzen, the über-sequencing institute, but the rest of the collaborators are from Europe and some from the large European sequencing centers. This reminds me of an article about BGI-Shenzen that discusses how the center is building up amazing collaborations outside of China. This is proof of what those collaborations can yield. We all gain, and it’s so much better than trying to do it alone, for the glory of China.
via A human gut microbial gene catalogue established by metagenomic sequencing : Article : Nature.
“This study demonstrates that the milk-feeding type and the HLA-DQ genotype differently influence the bacterial colonization pattern of the newborn intestine during the first 4 months of life and, therefore, could also influence the risk of developing CD in later life. Breast-feeding reduced the genotype-related differences in microbiota composition, which could partly explain the protective role attributed to breast milk in this disorder.”
Interesting study doing two things: 1) showing an effect of genotype on bacterial populations in the gut – and that they are different for those at risk for celiac disease; and, 2) showing a difference between the bacterial populations of breast-fed and formula-fed children, and a possible microbial reason why breast-feeding protects against celiac disease.
Very cool. And scary how it makes such good sense.
Read this article in PLoS ONE.
When I lived in the US in the 90s, it was hard to find live-culture yogurt in supermarkets (you could find them in natural food stores, of course). The only one I could find was Stonyfield yogurt.
When I lived in Finland, not only were there a bunch of live-culture milk products, but there was one in particular “Valio A+” that was specifically recommended for women to balance their flora.
Now back in the US, it’s hard not to find live-culture yogurt, and some are specifically marketed, yes, for women to balance their flora. Furthermore, the use of live bacterial cultures for health purposes, called probiotics, has become mainstream enough that you can find probiotic supplements for children in the supermarket.
What does this mean?
It means that folks are becoming aware of functional foods, of the importance of microorganism in their diet, and that the feeding desire to find a short cut (a pill rather than eating wholesome yogurt) is always a good business.
I’ve been seeking out all these probiotic products to get an idea of what’s out there, what the message is, and, for me, always on the look out for practical use of microbes, I’ve been trying to understand what microorganisms are in fashion.
OK, so the science behind probiotics is still in progress, so I will not go into that right now.
But, going on the premise that yogurt is the gold standard for beneficial live (with microorganisms) food, then my standard for all probiotic products used for digestive health is Stonyfield’s yogurt. Stonyfield’s has 6 bacteria (S thermophilus, L bulgaricus, L acidophilus, Bifidus, L casei, and L rhamnosus). I’d say that most of the products I have seen have one or more of these bugs. There are some proprietary sub-species and I’ve been pleased to see a few products with S salivarius or some other bacteria.
For me, the type, variety, and number of bacteria in a probiotic food or supplement is key. And I think it’s just snake oil if the product only has one bug.
Nonetheless, I think as probiotics go mainstream, buyers will be more astute as to what they are looking for. Also, I hope that new applications show up, beyond gut and vaginal flora health (I can think of a few).
What I do know, is that doctors are starting to suggest probiotics to patients on antibiotics or with digestive issues such as colitis or C diff.*
And that’s great.
Do you eat probiotic foods or take supplements? Send me pics of the ones you see or take! I could/should create a database of products and attach reviews or commentary. Hm…. not another project….
*Ego boost: A gastroenterologist aked me recently what probiotics I recommended. Ha! My first probiotic consulting gig?
As you know, I’m always looking for practical uses of microbes. One that I stumbled upon a long while back was “transfaunation”, or, seeding one person’s gut with microbes from another’s. Yes, transfering poop microbes from one to another.
Be an adult. Don’t get grossed out. I’ve read some great papers on the process how our guts get colonized after birth. Also, there are some really interesting papers on how our gut microbes (or lack thereof) are involved in various intestinal disorders. And there are some promising papers on how diet affect the bacterial ecology in the gut. [Sorry, I'll link to the papers in a larger gut related set of posts at some point in the future - you can also just search for gut and microbes in my posts.]
Here’s the basic idea. People suffering from the hardy C. diff bacteria are generally prescribed a powerful antibiotic. Problem is, the drugs don’t just kill the invaders; they also wipe out much of the beneficial bacteria in the gut. With these “good” microorganisms out of the way, any C. diff stragglers have a much easier time regrouping for a second bout of illness. If there were some way to respawn the beneficial bacteria in the intestines, such re-infections could be warded off. Some people, like Ruth, turn to expensive probiotic supplements. (At one point she was spending $350 on them every week.) But in certain cases, a patient who has lost nearly all of her good bacteria will find it nearly impossible to get them back. A fecal transplant seems to work as a sort of mega-probiotic, allowing doctors to repopulate a patient’s intestines with the appropriate microorganisms by placing a robust sample directly into her gut.
Slate had a nice article on the subject (quoted above). It’s a serious subject and for many, the only hope to get a better and healthier bacterial gut fauna (hence the term, transfaunation).
My wife’s a vet and she’s not only heard of this procedure, but performed it on animals. It’s not uncommon to jumpstart an animal’s ability to digest grass by grabbing bugs from one animal and putting it in the right place. And, did you know, some animals eat poop on purpose for this very reason – rabbits, capibaras, hamsters, elephants, termites, pandas, koalas, and hippos – to colonize their gut?
And really, folks eat yogurt to populate their gut with good bacteria. Why not poo bacteria as probiotics? I actually think, as we learn more about our gut fauna, this will be come a more accepted course of action for folks with nasty bowel infections, colitis, or inflammatory bowel diseases.
What do you think?
Image of Kristen Paulson’s Anatomy and Guts Embroidery Hoop Art on Etsy (get your own!)
“We normally think of the gut microbiota as the ‘friendly’ bacteria that carry out many beneficial functions, including protecting us from infection. But two studies now identify a different side to the gut microbiota, showing that it can actually facilitate viral infection and promote transmission.”
Another interesting review that is in a CLOSED ACCESS paper. The barrier to casual reading is too high.
Read this article…