As our understanding of the intestinal microbiota’s structure, function, regulation, and wide-ranging influence on human health grows, several important roadblocks to therapeutic targeting remain. First is the descriptive nature of most studies to date, which in many cases have documented steady-state phenotypes without investigating cause–effect relationships. Substantive progress is underway in this direction, with a number of investigators beginning to mechanistically address causal relationships using mouse models and direct manipulation or transfer of microbial populations. For example, fecal microbial transplant from patients with inflammatory bowel disease was shown to accelerate or exacerbate intestinal inflammation in genetically-susceptible mice,
1
and mouse models of metabolic syndrome—a collection of symptoms associated with obesity, diabetes, and heart disease—support a role for altered epithelial–microbial interaction in development and progression of this state, at least in rodents.- Nagao-Kitamoto H.
- Shreiner A.B.
- Gillilland 3rd, M.G.
- Kitamoto S.
- Ishii C.
- Hirayama A.
- Kuffa P.
- El-Zaatari M.
- Grasberger H.
- Seekatz A.M.
- Higgins P.D.
- Young V.B.
- Fukuda S.
- Kao J.Y.
- Kamada N.
Functional characterization of inflammatory bowel disease-associated gut dysbiosis in gnotobiotic mice.
Cell Mol Gastroenterol Hepatol. 2016; 2: 468-481
2
The next major roadblock in translation of discovery, then, is validating the human clinical relevance of mouse models. To somewhat cheekily paraphrase Judah Folkman’s comment in cancer—if you have metabolic syndrome or colitis and you are a mouse, we can probably target your microbiome therapeutically. However, because it is not yet clear how faithfully and completely the mouse + microbiota holo-organism maps this same partnership in humans, validation and confirmation of rodent results in human clinical specimens is essential.
In this issue of Cellular and Molecular Gastroenterology and Hepatology, Chassaing et al
3
address the human relevance of mouse models of metabolic syndrome. In their article, they provide evidence from patient samples that bacterial encroachment—a shrinking of the “bug-free” zone adjacent to the colonic epithelium—is a feature of human metabolic syndrome. Encroachment has been associated with human inflammatory bowel disease and was demonstrated in mouse models of both colitis and metabolic syndrome,4
but the current study represents the first clear demonstration of the same phenomenon in obese human patients with diabetes. The authors report that in a cohort of 42 individuals ranging from 31 to 74 years of age, the epithelial–bacterial distance (the average width of the sterile mucus layer) was inversely correlated with body mass index, fasting glucose, and hemoglobin A1C levels.Interestingly, in these human patients the primary predictor of encroachment was dysglycemia. Unlike in mouse models in which body mass index and dysglycemia are essentially linked, here it was possible to separate these parameters in the analysis. Examining only obese patients with normal blood glucose versus healthy control subjects eradicated the difference in bacterial distance, uncoupling the effects of obesity and failed glucose regulation. This may be an important step in untangling the mechanisms driving metabolic syndrome and its associated low-grade inflammation, and underscores the power of comparing mouse and human results to shed light on mechanism. Together with an increased number of CD19+ cells (likely B cells) in the mucosa of diabetic patients, these data suggest that bacterial encroachment is contributing to the low-grade inflammation often observed in patients with metabolic syndrome.
Returning to a mouse model, the authors furthermore suggested that this effect is not simply the result of available glucose in the intestine driving bacterial proliferation, because acute streptozotocin-induced dysglycemia failed to cause encroachment (ie, high glucose levels alone are not sufficient). Although this could in principle be a timing issue with the model and does not rule out a permissive role for localized glucose availability, it certainly suggests a more complex metabolic circuit as the primary driver.
Looking ahead, a key question derived from this work will be whether the altered microbiome and narrowed sterile layer above the epithelium are the initiators of low-grade intestinal inflammation in metabolic syndrome, or alternatively consequences of chronic metabolic changes that then contribute to continuing disorder. Bacterial encroachment may provide a direct mechanism for some of the proinflammatory effects of dietary emulsifiers, which the authors have previously shown drive encroachment and colitis.
5
Examination of these and related questions in coordinated mouse models and patient samples will be necessary to define both mechanism and clinical relevance.References
- Functional characterization of inflammatory bowel disease-associated gut dysbiosis in gnotobiotic mice.Cell Mol Gastroenterol Hepatol. 2016; 2: 468-481
- Hepatocyte toll-like receptor 5 promotes bacterial clearance and protects mice against high-fat diet-induced liver disease.Cell Mol Gastroenterol Hepatol. 2016; 2: 584-604
- Colonic microbiota encroachment correlates with dysglycemia in humans.Cell Mol Gastroenterol Hepatol. 2017; 4: 205-221
- Intestinal epithelial cell toll-like receptor 5 regulates the intestinal microbiota to prevent low-grade inflammation and metabolic syndrome in mice.Gastroenterology. 2014; 147: 1363-1377.e17
- Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome.Nature. 2015; 519: 92-96
Article info
Publication history
Published online: June 14, 2017
Footnotes
Conflicts of interest The author discloses no conflicts.
Funding This work was funded by National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases award R01DK095004.
Identification
Copyright
© 2017 The Author. Published by Elsevier Inc. on behalf of the AGA Institute.
User license
Creative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0) | How you can reuse 
Elsevier's open access license policy
Creative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0)
Permitted
For non-commercial purposes:
- Read, print & download
- Redistribute or republish the final article
- Text & data mine
- Translate the article (private use only, not for distribution)
- Reuse portions or extracts from the article in other works
Not Permitted
- Sell or re-use for commercial purposes
- Distribute translations or adaptations of the article
Elsevier's open access license policy
ScienceDirect
Access this article on ScienceDirectLinked Article
- Colonic Microbiota Encroachment Correlates With Dysglycemia in HumansCellular and Molecular Gastroenterology and HepatologyVol. 4Issue 2
- PreviewMucoid structures that coat the epithelium play an essential role in keeping the intestinal microbiota at a safe distance from host cells. Encroachment of bacteria into the normally almost-sterile inner mucus layer has been observed in inflammatory bowel disease and in mouse models of colitis. Moreover, such microbiota encroachment has also been observed in mouse models of metabolic syndrome, which are associated low-grade intestinal inflammation. Hence, we investigated if microbiota encroachment might correlate with indices of metabolic syndrome in humans.
- Full-Text
- Preview
