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
“The main difference from eukaryotes is that prokaryotic reproduction is independent of DNA acquisition and recombination. Instead, DNA is obtained from fragmented chromosomes obtained via parasexual means (that is, without reproduction). These mechanisms of DNA exchange are not restricted to gene exchange within species, and therefore traits can and do come from highly divergent organisms. For example, imagine that acacia trees could exchange DNA with lions and that the resulting new tree developed “limbs” that allowed them to attack grazing giraffes. This is in a sense what prokaryotes do all the time.”
I am fascinated by horizontal gene transfer, whereby microbes from different species share genetic information. Species, as we all learn, are defined by not being able to exchange genetic information and produce fertile offspring.
Of course, microbes flaunt this rule.
The prevalence of gene transfer, where bacteria of different species exchange genetic information, blurs the boundaries between “species”. I remember listening to Penny Chisholm talk to Ira Flatow about Parachlorococcus and redefining what we call a species of microbes, which she called “genomic variants.”
The quote above is from a review of an article in Science that examines speciation in marine bacteria. It discusses how the investigators found prevalent horizontal gene transfer. But the cool thing, as I understand it, was that many of the same genes were being captured by bacteria in the same ecological niche.
In short, the environment is selecting for horizontally transferred genes to be conserved. These genes are not transmitted through organisms in the same species, but all of the bacteria are being selected to keep these transferred genes. In short, many of the genes from a population do not have a common ancestor (as in, cells dividing and propagating genes that way).
Even cooler, an analogue has been seen in prokaryotes, in a sense. Darwin’s finches all share genetic information through the usual repeated back-crossing between species, but ” the characters defining their ecological niche appear to be maintained through selection.”
So I guess we are talking about genomic variants, but not necessarily variants with the same ancestor – the ecological niche selects for that genomic variant, which has a collection of genes from the mother cell (ancestor) and from other cells (horizontal gene transfer)
That’s so cool.
via How Bacterial Lineages Emerge.
“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?
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.
“A life-threatening germ that causes diarrhea and spreads easily from doctors’ offices to hospitals and nursing homes has climbed to historic highs nationally, federal disease trackers warned Tuesday, as they pointed to efforts in Massachusetts that have helped slow the rate of infections here.”
More on this nasty bug. It’s now getting headlines.
Read this article…
“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.
“A recent widespread outbreak of Escherichia coli O104:H4 in Germany demonstrates the dynamic nature of emerging and re-emerging food-borne pathogens, particularly STECs and related pathogenic E. coli. Rapid genome sequencing and public availability of these data from the German outbreak strain allowed us to identify an O-antigen-specific bacteriophage tail spike protein encoded in the genome. We synthesized this gene and fused it to the tail fiber gene of an R-type pyocin, a phage tail-like bacteriocin, and expressed the novel bacteriocin such that the tail fiber fusion was incorporated into the bacteriocin structure. The resulting particles have bactericidal activity specifically against E. coli strains that produce the O104 lipopolysaccharide antigen, including the outbreak strain. This O-antigen tailspike-R-type pyocin strategy provides a platform to respond rapidly to emerging pathogens upon the availability of the pathogen’s genome sequence.”
When an outbreak in pathogenic E coli broke out in Germany last summer, scientists were able to sequence the genome in a few hours on a Life Technologies Ion PGM sequencer. This speed gave the public health official insight into what they were dealing with.
This paper linked to below, was able to then take the sequence and rapidly create a strain-specifc bacteriocin-phage bacteriocide. And, based on the submission date, they did this in a few months.
This points to a promising future where we sequence the pathogen the day we discover it and rapidly create targeted bactericides. Cool. And our kids will look back and wonder why were were trying carpet-bomb bacteria with rapidly useless antibiotics. This is the post-antibiotic age.
via PLoS ONE: Genome Sequence of E. coli O104:H4 Leads to Rapid Development of a Targeted Antimicrobial Agent against This Emerging Pathogen.
“Bacterial clone-based genome sequencing frequently results in gaps, which harbour hypothetical genes of unknown function. Sorek and colleagues show that these gaps contain a vast array of genes encoding proteins that are toxic to the sequencing host (Escherichia coli), including previously uncharacterized restriction enzymes, toxin–antitoxin systems and non-coding RNAs.”
Of course, to me, this is very clever, having never thought about this. Yes, we always knew that some sequences were unclonable because of incompatibility with the cloning vector. But the cleverness is to actually look for those gaps as potential anti micribials. That’s one of those amazing “Duh”s that sometimes happen when things are right under our nose.
Only sucky thing is that the article is CLOSED ACCESS. Fail.
via Access : Bacterial genomics: A new source of antimicrobial targets : Nature Reviews Microbiology (subscription required).
“Bacteriophage could be an alternative to conventional antibiotic therapy against multidrug-resistant bacteria. However, the emergence of resistant variants after phage treatment limited its therapeutic application. Our data showed that the phage cocktail was more effective in reducing bacterial mutation frequency and in the rescue of murine bacteremia than monophage suggesting that phage cocktail established by SBS method has great therapeutic potential for multidrug-resistant bacteria infection.”
Biologic warfare at the bacterial level. In some developed countries antibiotic misuse has caused the rapid development of antibiotic-resistant bacteria. Bacteriophage therapy has therefore taken a more important role. Except, it has its issues. In this paper, they work to avoid phage resistance with a multi-phage approach.
Read this article…