Can human embryonic stem cells model human nutrition?

Human embryonic stem cell colony

Scientists at Harvard University have proposed a new model for studying nutrition, human embryonic stem cells. Human embryonic stem cells are unique in their ability to turn into all the cell types in the body, including the various tissue types in the human gut.

Drs. Doug Melton and Danny Ben-Zvi propose in an essay in Cell that human embryonic stem cell derived tissues populated by gut microbiota may be an ideal system for studying the physiology of digestion and nutrition. The authors state that the mechanisms of human nutrition are largely unknown and that it is difficult to model how nutrition affects human health on a biological front. By developing systems of stem cell derived tissues, it may be possible to model the gut in the petri dish or even on a chip. Significant engineering advances have been made to model biological systems on a chip.  These chips are devices with specific cell types in chambers that are connected through microfluidic channels to better model the tissues and organs in the human body and how they interact with one another.

Chips could be developed that are made of up cells of the various organs that make up our gastrointestinal tract.  These organoids could then be populated by bacteria that make up the microbiota. Food could be passed through the chip and scientists could watch bacteria break down food that is passing through it and see how the microbiota adapts to changes in diet. Various conditions could be tested such as what bacterial strains are best at digesting complex carbohydrates? The authors state that many combinations of bacterial strains should be tested to find what bacteria conduct these tasks most efficiently. To do this in mice would require thousands of animals and this may be too restrictive to conduct such experiments. This however could be done using chips with stem cell derived tissues that make up our GI tract and connected through microfluidic channels to stem cell derived liver and pancreas cells that are important for nutrition and digestion.

Significant biological and engineering challenges still exist before this is a reality, including the ability for specific strains of bacteria to thrive in such an environment.  However, if some challenges can be overcome, the authors propose that the complexity of nutrition and digestion could be better dissected using systems of stem cell derived tissues in the dish.  This work would complement existing research using model organisms and epidemiological and other human studies to better address the questions that we ask every day about what food we should eat and the effects this has on the human body. 

Deciphering individual bacterial strains in the gut is important to understanding the microbiome

Phylogenetic trees go beyond just genus and species, but also to strains.

When scientists determine the bacterial population of one’s microbiome using genetic sequencing they are forced to make determinations of the populations’ phylogeny.  Some scientists will determine the abundance of each genus, like all the bacteria that belong to the Clostridium genus, while others will narrow their scope to specific species, like all the bacteria that belong to the Clostridium difficile versus Clostridium scindens species.  These distinctions can be immensely important.  For example, C difficile can cause colitis, but C. scindens can prevent colitis, so measuring the amount of Clostridium in the gut does not paint as clear a picture as measuring the amount of C. difficile (potentially harmful) and C. scindens (potentially helpful).  There is, however, a deeper level of differentiation within species: the strain (e.g. C. difficile A90 vs. C. difficile AA1).  These strains are very similar genetically, especially in the genomic regions most important to determining phylogeny, there are however, potentially important genetic differences. 

Scientists have long realized and understood that by characterizing the species population of the microbiome they were neglecting possible important strain-specific effects.  There have even been specific examples within the microbiome that differences in strains are important, like strains within the Staphylococcus aureus that differ in their antibiotic resistance (e.g. MRSA).  Just how important these strain-specific differences are is unknown, but there is mounting evidence they need to be taken into account.  Last week in the journal Cell, researchers from the University of Washington published results that showed strain-specific differences can be vast and immense, and that this is even more so true in the microbiome where genetic mutations and genetic transfers happen at a high rate.

The researchers used metagenomics data from patients with IBD from a previously published data set.  They took this data, compared it with previously published species’ genomes, and did a lot of fancy bioinformatics to measure strain-specific genetic differences within species.  I don’t mean to neglect the bioinformatics aspect of the paper, which is critically important their results, but the details of their ‘pipeline’ are beyond the scope of this short blog.  In any event, they learned that there were many examples of different strains that coded for as much as 20% more copies of specific genes.  As it turns out, these differences were prevalent in genes that coded for important functions, like transport, signaling, biosynthesis, motility, secretion, and virulence.  These are important processes in the gut environment, and each may have important impacts on the host.

Before this paper, the level of genomic resolution and bioinformatics needed to make strain specific determinations was difficult, and beyond the expertise of most labs.  Now that these researchers have published their methods, this type of strain analysis can be incorporated into many more experiments.  It does have its drawbacks, as full genomes are needed for each species that is analyzed, and inserted/deleted genes are not analyzed, but overall it is a very important paper.  As we move forward in microbiome research, this type of analysis that incorporates specific strains will become critical in associating diseases and phenotypes with the microbiome.