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.
Genetic analyses
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.
“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?
Indeed, Sharp said at the meeting, patients who come to Cleveland Clinic for treatment of inflammatory bowel disease express their own concerns about such approaches, which could include the use of probiotics, the consumption of live microorganisms, to treat intestinal and other maladies. “Many patients are worried about manipulating their gut microbiota,” Sharp said, adding that “they see these kinds of studies through the lens of genetically modified foods. They worry that tampering with the gut microbiome could lead to irreversible effects.”Sharp also urged the microbiome research community, along with funding agencies, to start doing more public outreach to counter the often “grossly misleading” statements made by companies that sell probiotic products, including claims that probiotics can cure cancers and treat autism spectrum disorders. “Most of what people know about this area of research comes from these retailers,” Sharp said. “We should not be relying on these companies to put out the first messages about this area of research.”
This is an interesting article on what’s next for human microbiome research. It lists some of the companies getting involved (great!) and some talk about what will happen to jumpt start a whole new round of funding.
What was surprising to me was how little money was put into the multi-year programs (total $167M). Prehaps I don’t have a feel for what’s a lot of money in research.
Read International Human Microbe Program Looks Ahead – ScienceInsider.
“Jonathan Eisen [@phylogenomics], a microbiologist at University of California, Davis, is worried that microbiome research will eventually encounter the same backlash. “Without a doubt we are running into some of the same problems as the Human Genome Project,” he says. “There are many people who have oversold the human microbiome as the cause or cure of everything.” Eisen worries that although numerous connections have been discovered between the microbiome and diseases, it is usually unclear whether the microbes caused the conditions or merely exploited a new environment.“There’s sensitivity about the expected returns,” says David Relman, who studies infectious disease at Stanford University in Palo Alto, California. “We need to be grounded about what it is we’ll be able to gain at what point in time. I think the shorter-term gains may be around diagnostics, and novel ways of classifying both health and disease.”
This article has some great quotes (like above) on caution about the benefits of microbiome sequencing. I also agree with the writer, Ed Yong (@edyong209), that, yes, learning more about the human microbiome is amazing, but we need to not make outlandish claims as to what we will do with that understanding.
Ed mentioned some probiotic studies (an area I have been reading a lot about) and that hype pre-dates all the microbiome hype.
My comment: let’s learn all we can about the microbiome. Let’s see what we learn before we make as outlandish claims as we did in the 80s about knowing all about our genome.
Spot, on, Ed. Thanks for calling this out.
Read Microbiome sequencing offers hope for diagnostics : Nature News & Comment.
“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.
Quite fascinating.
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.
“The Earth Microbiome Project (EMP) is the most ambitious attempt to provide a systematic characterization of the microbial world that dominates this planet. The ecosystem services provided by microbes in every environment (including the human body) are fundamental to the survival of life on this planet and the continued economic and physical health of the human race. The pilot study of the EMP started in March 2011 and is now reaching its zenith.”
This session has four interesting talks on handling the data deluge, a field guide, why we should care, and mathematical modeling. Cool. Can’t wait for the speaker notes and the like.
Read this article…
“A large European-Asian consortium brought some order to the chaos when it reported in a Nature paper in April that humanity can be roughly divided into three “enterotypes” depending on which genus of bacteria dominates in people’s gut: Bacteroides, Ruminococcus, or Prevotella. People’s enterotype appeared to be stable over time, but it remains unclear why your gut population might be so radically different from your neighbor’s.”
Yet another report on diet and gut microbiome. If I could start all over again in grad-school, I’d study this. Human microbiological ecology is going to be big in so many areas, helping us understand the effects that our microbiome has on our health. And of course, this will go hand-in-hand with practical use of naturally occurring microbes.
Read this article…
“Nori is, by far, the most likely source of bacteria with porphyran-digesting genes. It’s the only food that humans eat that contains any porphyrans and until recently, Japanese chefs didn’t cook nori before eating it. Any bacteria that lingered on the green fronds weren’t killed before they could mingle with gut bacteria like B.plebius. Ruth Ley, who works on microbiomes, says, “People have been saying that gut microbes can pick up genes from environmental microbes but it’s never been demonstrated as beautifully as in this paper.””
Japanese gut bacteria picking up genes from marine bacteria that live on seaweed. This blew my mind, but I am not surprised. We do know that there can be rapid gene changes in humans (ADH, lactase), why shouldn’t there be rapid changes in our fellow microbiomes? Very interesting implications with respect to therapy and diets.
Read this article…
“Enterotypes aren’t quite as well-defined as, say, blood groups, but they could have similar uses as medical markers. The microbiome helps us to digest our food and it affects our susceptibility to diseases; the enterotypes could reflect these roles. Each enterotype was dominated by a specific genus of bacteria, and varied in the proportions of the other members. They produce energy in subtly different ways, they’re particularly efficient at breaking down different nutrients, and they specialise at creating different vitamins.”
This article reports on findings that there are “enterotypes”. While I have been seeing slightly different findings from others, this just goes to show that we keep finding out new things about our bacteria.
One other thing: at the end of this article is a very interesting slide show with snippets of other interesting findings related to our microbiome. Do flip through it.
[via @changeist]
Read this article…
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What does this have to do with Eastern European Jews?