The Microbiome: An Important Piece of the Puzzle, but Where does it Fit?
Daniel A. Leffler, MD, MS
The 1940s brought with it the first widespread use of penicillin and with it great enthusiasm that all medical ailments would shortly be conquered, but it was not to be. The 1960s brought the first effective tools to study the human genome and with them great enthusiasm that all medical ailments would shortly be conquered, but it was not to be. In 2003 we had finally mapped all of the genes in the human genome and with this great enthusiasm that all medical ailments would shortly be conquered, but it was not to be. And now, over the past few years we have begun to appreciate the great importance of the microbiome in human health and disease, and once again, we see great enthusiasm that we will soon be able to prevent, cure or otherwise mitigate all sorts of vexing issues, from celiac disease, to inflammatory bowel disease to obesity and depression. This is unlikely.
The 1940s brought with it the first widespread use of penicillin and with it great enthusiasm that all medical ailments would shortly be conquered, but it was not to be. The 1960s brought the first effective tools to study the human genome and with them great enthusiasm that all medical ailments would shortly be conquered, but it was not to be. In 2003 we had finally mapped all of the genes in the human genome and with this great enthusiasm that all medical ailments would shortly be conquered, but it was not to be. And now, over the past few years we have begun to appreciate the great importance of the microbiome in human health and disease, and once again, we see great enthusiasm that we will soon be able to prevent, cure or otherwise mitigate all sorts of vexing issues, from celiac disease, to inflammatory bowel disease to obesity and depression. This is unlikely.
The good news is that we are finally nearing a complete palate of the major factors that determine human health. These include 1) genetics, 2) epigenetics, 3) environmental exposures, 4) diet, 5) infectious disease and 6) the microbiome. In the past, when we attempted to understand disease, for instance why some people get celiac disease and others do not, we were limited to at best two or three of these factors. As we were only seeing part of the picture, outside of a few highly penetrant genetic diseases, we could never accurately predict disease onset or course. We now have reason to be optimistic that we now have all the major determinants of health and disease. Yet having all the pieces does not mean we know how to put them together. As written in a recent excellent review by Dr. Yolanda Sanz “We expect that celiac disease results from the combination of an altered human genome and microbiome in conjunction with as yet unknown epigenetic modifications, partly due to different environmental factors, which together influence mucosal gene expression and the mucus layer, prompting self- and gluten reactivity in the host.”1
The problem is that all of these factors interact and creating a level of complexity that we are only beginning to develop the scientific tools to explore. For the scientific community this means that we must focus on highly rigorous study design which goes well beyond the association studies which have been standard in microbiome research in recent years. For the patient community, unfortunately this means that the microbiome research is unlikely to provide treatment for all but a few select diseases such as clostridium difficile in the near future.
1. Cenit MC, Olivares M, Codoner-Franch P, et al. Intestinal Microbiota and Celiac Disease: Cause, Consequence or Co-Evolution? Nutrients 2015;7:6900-23.
Additional Reading
Metagenomics Reveals Dysbiosis and a Potentially Pathogenic N. flavescens Strain in Duodenum of Adult Celiac Patients.
D'Argenio V, Casaburi G, Precone V, Pagliuca C, Colicchio R, Sarnataro D, Discepolo V, Kim SM, Russo I, Del Vecchio Blanco G, Horner DS, Chiara M, Pesole G, Salvatore P, Monteleone G, Ciacci C, Caporaso GJ, Jabrì B, Salvatore F, Sacchetti L.
Am J Gastroenterol. 2016 Apr 5. doi: 10.1038/ajg.2016.95.
The microbiome as a possible target to prevent celiac disease.
Leonard MM, Fasano A.
Expert Rev Gastroenterol Hepatol. 2016 Apr 1:1-2. [Epub ahead of print]
The microbiome in celiac disease: Beyond diet-genetic interactions.
Scher JU.
Cleve Clin J Med. 2016 Mar;83(3):228-30. doi: 10.3949/ccjm.83a.15123.
Study of duodenal bacterial communities by 16s rrna gene analysis in adults with active celiac disease versus non celiac disease controls.
Nistal E, Caminero A, Herrán AR, Pérez-Andres J, Vivas S, Ruiz de Morales JM, Sáenz de Miera LE, Casqueiro J.
J Appl Microbiol. 2016 Feb 23. doi: 10.1111/jam.13111.
The problem is that all of these factors interact and creating a level of complexity that we are only beginning to develop the scientific tools to explore. For the scientific community this means that we must focus on highly rigorous study design which goes well beyond the association studies which have been standard in microbiome research in recent years. For the patient community, unfortunately this means that the microbiome research is unlikely to provide treatment for all but a few select diseases such as clostridium difficile in the near future.
1. Cenit MC, Olivares M, Codoner-Franch P, et al. Intestinal Microbiota and Celiac Disease: Cause, Consequence or Co-Evolution? Nutrients 2015;7:6900-23.
Additional Reading
Metagenomics Reveals Dysbiosis and a Potentially Pathogenic N. flavescens Strain in Duodenum of Adult Celiac Patients.
D'Argenio V, Casaburi G, Precone V, Pagliuca C, Colicchio R, Sarnataro D, Discepolo V, Kim SM, Russo I, Del Vecchio Blanco G, Horner DS, Chiara M, Pesole G, Salvatore P, Monteleone G, Ciacci C, Caporaso GJ, Jabrì B, Salvatore F, Sacchetti L.
Am J Gastroenterol. 2016 Apr 5. doi: 10.1038/ajg.2016.95.
The microbiome as a possible target to prevent celiac disease.
Leonard MM, Fasano A.
Expert Rev Gastroenterol Hepatol. 2016 Apr 1:1-2. [Epub ahead of print]
The microbiome in celiac disease: Beyond diet-genetic interactions.
Scher JU.
Cleve Clin J Med. 2016 Mar;83(3):228-30. doi: 10.3949/ccjm.83a.15123.
Study of duodenal bacterial communities by 16s rrna gene analysis in adults with active celiac disease versus non celiac disease controls.
Nistal E, Caminero A, Herrán AR, Pérez-Andres J, Vivas S, Ruiz de Morales JM, Sáenz de Miera LE, Casqueiro J.
J Appl Microbiol. 2016 Feb 23. doi: 10.1111/jam.13111.
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