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Bacterial infiltration into the colonic mucosa was associated with type 2 diabetes mellitus in humans, confirming prior findings in mice, investigators said.
Unlike in mice, however, microbiota encroachment did not correlate with human adiposity per se, reported Benoit Chassaing, PhD, of Georgia State University, Atlanta, and his associates. Their mouse models all have involved low-grade inflammation, which might impair insulin/leptin signaling and thereby promote both adiposity and dysglycemia, they said. In contrast, “we presume that humans can become obese for other reasons not involving the microbiota,” they added. The findings were published in the September issue of Cellular and Molecular Gastroenterology and Hepatology (2017;2[4]:205-21. doi: 10.1016/j.jcmgh.2017.04.001).
For the study, the investigators analyzed colonic mucosal biopsies from 42 middle-aged diabetic adults who underwent screening colonoscopies at a single Veteran’s Affairs hospital. All but one of the patients were men, 86% were overweight, 45% were obese, and 33% (14 patients) had diabetes. The researchers measured the shortest distance between bacteria and the epithelium using confocal microscopy and fluorescent in situ hybridization.
Nonobese, nondiabetic patients had residual bacteria “almost exclusively” in outer regions of the mucus layer, while obese diabetic patients had bacteria in the dense inner mucus near the epithelium, said the investigators. Unlike in mice, bacterial-epithelial distances did not correlate with adiposity per se among individuals without diabetes (P = .4). Conversely, patients with diabetes had bacterial-epithelial distances that were about one-third of those in euglycemic individuals (P less than .0001), even when they were not obese (P less than .001).
“We conclude that microbiota encroachment is a feature of insulin resistance–associated dysglycemia in humans,” Dr. Chassaing and his associates wrote. Microbiota encroachment did not correlate with ethnicity, use of antibiotics or diabetes treatments, or low-density lipoprotein levels, but it did correlate with a rise in CD19+ cells, probably mucosal B cells, they said. Defining connections among microbiota encroachment, B-cell responses, and metabolic disease might clarify the pathophysiology and treatment of metabolic syndrome, they concluded.
The investigators also induced hyperglycemia in wild-type mice by giving them water with 10% sucrose and intraperitoneal streptozotocin injections. Ten days after the last injection, they measured fasting blood glucose, fecal glucose, and colonic bacterial-epithelial distances. Even though fecal glucose rose as expected, they found no evidence of microbiota encroachment. They concluded that short-term (2-week) hyperglycemia was not enough to cause encroachment. Thus, microbiota encroachment is a characteristic of type 2 diabetes, not of adiposity per se, correlates with disease severity, and might stem from chronic inflammatory processes that drive insulin resistance, they concluded.
Funders included the National Institutes of Health, VA-MERIT, and the Crohn’s and Colitis Foundation of America. The investigators had no relevant conflicts of interest.
Dr. Chassaing and his colleagues examined the possible importance of the bacteria-free layer adjacent to the colonic epithelium in metabolic syndrome. A shrinking of this layer, termed “bacterial encroachment,” has been associated with human inflammatory bowel disease as well as mouse models of both colitis and metabolic syndrome, but the current study represents its first clear demonstration in human diabetes. In a cohort of 42 patients, the authors found that the epithelial-bacterial distance was inversely correlated with body mass index, fasting glucose, and hemoglobin A1c levels.
Interestingly, the primary predictor of encroachment in these patients was dysglycemia, not body mass index. This could not have been tested in standard mouse models where, because of the nature of the experimental insult, obesity and dysglycemia are essentially linked. Comparing obese human patients with and without dysglycemia, on the other hand, showed that encroachment is only clearly correlated with failed glucose regulation. This, however, is not the end of the story: In coordinated experiments with a short-term murine dysglycemia model, high glucose levels were not sufficient to elicit encroachment, suggesting a more complex metabolic circuit as the driver.
Mark R. Frey, PhD, is associate professor of pediatrics and biochemistry and molecular medicine at the Saban Research Institute, Children’s Hospital Los Angeles, University of Southern California.
Dr. Chassaing and his colleagues examined the possible importance of the bacteria-free layer adjacent to the colonic epithelium in metabolic syndrome. A shrinking of this layer, termed “bacterial encroachment,” has been associated with human inflammatory bowel disease as well as mouse models of both colitis and metabolic syndrome, but the current study represents its first clear demonstration in human diabetes. In a cohort of 42 patients, the authors found that the epithelial-bacterial distance was inversely correlated with body mass index, fasting glucose, and hemoglobin A1c levels.
Interestingly, the primary predictor of encroachment in these patients was dysglycemia, not body mass index. This could not have been tested in standard mouse models where, because of the nature of the experimental insult, obesity and dysglycemia are essentially linked. Comparing obese human patients with and without dysglycemia, on the other hand, showed that encroachment is only clearly correlated with failed glucose regulation. This, however, is not the end of the story: In coordinated experiments with a short-term murine dysglycemia model, high glucose levels were not sufficient to elicit encroachment, suggesting a more complex metabolic circuit as the driver.
Mark R. Frey, PhD, is associate professor of pediatrics and biochemistry and molecular medicine at the Saban Research Institute, Children’s Hospital Los Angeles, University of Southern California.
Dr. Chassaing and his colleagues examined the possible importance of the bacteria-free layer adjacent to the colonic epithelium in metabolic syndrome. A shrinking of this layer, termed “bacterial encroachment,” has been associated with human inflammatory bowel disease as well as mouse models of both colitis and metabolic syndrome, but the current study represents its first clear demonstration in human diabetes. In a cohort of 42 patients, the authors found that the epithelial-bacterial distance was inversely correlated with body mass index, fasting glucose, and hemoglobin A1c levels.
Interestingly, the primary predictor of encroachment in these patients was dysglycemia, not body mass index. This could not have been tested in standard mouse models where, because of the nature of the experimental insult, obesity and dysglycemia are essentially linked. Comparing obese human patients with and without dysglycemia, on the other hand, showed that encroachment is only clearly correlated with failed glucose regulation. This, however, is not the end of the story: In coordinated experiments with a short-term murine dysglycemia model, high glucose levels were not sufficient to elicit encroachment, suggesting a more complex metabolic circuit as the driver.
Mark R. Frey, PhD, is associate professor of pediatrics and biochemistry and molecular medicine at the Saban Research Institute, Children’s Hospital Los Angeles, University of Southern California.
Bacterial infiltration into the colonic mucosa was associated with type 2 diabetes mellitus in humans, confirming prior findings in mice, investigators said.
Unlike in mice, however, microbiota encroachment did not correlate with human adiposity per se, reported Benoit Chassaing, PhD, of Georgia State University, Atlanta, and his associates. Their mouse models all have involved low-grade inflammation, which might impair insulin/leptin signaling and thereby promote both adiposity and dysglycemia, they said. In contrast, “we presume that humans can become obese for other reasons not involving the microbiota,” they added. The findings were published in the September issue of Cellular and Molecular Gastroenterology and Hepatology (2017;2[4]:205-21. doi: 10.1016/j.jcmgh.2017.04.001).
For the study, the investigators analyzed colonic mucosal biopsies from 42 middle-aged diabetic adults who underwent screening colonoscopies at a single Veteran’s Affairs hospital. All but one of the patients were men, 86% were overweight, 45% were obese, and 33% (14 patients) had diabetes. The researchers measured the shortest distance between bacteria and the epithelium using confocal microscopy and fluorescent in situ hybridization.
Nonobese, nondiabetic patients had residual bacteria “almost exclusively” in outer regions of the mucus layer, while obese diabetic patients had bacteria in the dense inner mucus near the epithelium, said the investigators. Unlike in mice, bacterial-epithelial distances did not correlate with adiposity per se among individuals without diabetes (P = .4). Conversely, patients with diabetes had bacterial-epithelial distances that were about one-third of those in euglycemic individuals (P less than .0001), even when they were not obese (P less than .001).
“We conclude that microbiota encroachment is a feature of insulin resistance–associated dysglycemia in humans,” Dr. Chassaing and his associates wrote. Microbiota encroachment did not correlate with ethnicity, use of antibiotics or diabetes treatments, or low-density lipoprotein levels, but it did correlate with a rise in CD19+ cells, probably mucosal B cells, they said. Defining connections among microbiota encroachment, B-cell responses, and metabolic disease might clarify the pathophysiology and treatment of metabolic syndrome, they concluded.
The investigators also induced hyperglycemia in wild-type mice by giving them water with 10% sucrose and intraperitoneal streptozotocin injections. Ten days after the last injection, they measured fasting blood glucose, fecal glucose, and colonic bacterial-epithelial distances. Even though fecal glucose rose as expected, they found no evidence of microbiota encroachment. They concluded that short-term (2-week) hyperglycemia was not enough to cause encroachment. Thus, microbiota encroachment is a characteristic of type 2 diabetes, not of adiposity per se, correlates with disease severity, and might stem from chronic inflammatory processes that drive insulin resistance, they concluded.
Funders included the National Institutes of Health, VA-MERIT, and the Crohn’s and Colitis Foundation of America. The investigators had no relevant conflicts of interest.
Bacterial infiltration into the colonic mucosa was associated with type 2 diabetes mellitus in humans, confirming prior findings in mice, investigators said.
Unlike in mice, however, microbiota encroachment did not correlate with human adiposity per se, reported Benoit Chassaing, PhD, of Georgia State University, Atlanta, and his associates. Their mouse models all have involved low-grade inflammation, which might impair insulin/leptin signaling and thereby promote both adiposity and dysglycemia, they said. In contrast, “we presume that humans can become obese for other reasons not involving the microbiota,” they added. The findings were published in the September issue of Cellular and Molecular Gastroenterology and Hepatology (2017;2[4]:205-21. doi: 10.1016/j.jcmgh.2017.04.001).
For the study, the investigators analyzed colonic mucosal biopsies from 42 middle-aged diabetic adults who underwent screening colonoscopies at a single Veteran’s Affairs hospital. All but one of the patients were men, 86% were overweight, 45% were obese, and 33% (14 patients) had diabetes. The researchers measured the shortest distance between bacteria and the epithelium using confocal microscopy and fluorescent in situ hybridization.
Nonobese, nondiabetic patients had residual bacteria “almost exclusively” in outer regions of the mucus layer, while obese diabetic patients had bacteria in the dense inner mucus near the epithelium, said the investigators. Unlike in mice, bacterial-epithelial distances did not correlate with adiposity per se among individuals without diabetes (P = .4). Conversely, patients with diabetes had bacterial-epithelial distances that were about one-third of those in euglycemic individuals (P less than .0001), even when they were not obese (P less than .001).
“We conclude that microbiota encroachment is a feature of insulin resistance–associated dysglycemia in humans,” Dr. Chassaing and his associates wrote. Microbiota encroachment did not correlate with ethnicity, use of antibiotics or diabetes treatments, or low-density lipoprotein levels, but it did correlate with a rise in CD19+ cells, probably mucosal B cells, they said. Defining connections among microbiota encroachment, B-cell responses, and metabolic disease might clarify the pathophysiology and treatment of metabolic syndrome, they concluded.
The investigators also induced hyperglycemia in wild-type mice by giving them water with 10% sucrose and intraperitoneal streptozotocin injections. Ten days after the last injection, they measured fasting blood glucose, fecal glucose, and colonic bacterial-epithelial distances. Even though fecal glucose rose as expected, they found no evidence of microbiota encroachment. They concluded that short-term (2-week) hyperglycemia was not enough to cause encroachment. Thus, microbiota encroachment is a characteristic of type 2 diabetes, not of adiposity per se, correlates with disease severity, and might stem from chronic inflammatory processes that drive insulin resistance, they concluded.
Funders included the National Institutes of Health, VA-MERIT, and the Crohn’s and Colitis Foundation of America. The investigators had no relevant conflicts of interest.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: Microbiota encroachment into colonic mucosa characterizes type 2 diabetes in humans.
Major finding: Regardless of whether they were obese or normal weight, patients with diabetes had bacterial-epithelial colonic distances that were one-third of those in euglycemic individuals (P less than .001).
Data source: A study of 42 Veterans Affairs patients with and without type 2 diabetes mellitus.
Disclosures: Funders included the National Institutes of Health, VA-MERIT, and the Crohn’s and Colitis Foundation of America. The investigators had no relevant conflicts of interest.