Antibiotics Early in Life May Boost Obesity Risk
Published: Aug 17, 2014
By Salynn Boyles, Contributing Writer, MedPage Today
Exposure to antibiotics early in life may permanently alter gut microbes in a way that could increase obesity risk years later, researchers reported.
In a study that compared outcomes in mice given low-dose penicillin versus those who were not, infancy was identified as a critical window of host-microbe metabolic interaction, suggesting that early-life antibiotic exposure can lead to lifelong metabolic changes, wrote Martin Blaser, MD, of NYU Langone Medical Center in New York City, and colleagues in the Aug. 14 issue of Cell.
This new finding expands on previous research by Blaser's group that tied antibiotic treatment from birth to accelerated growth in mice.
"We showed that the earlier we gave the antibiotic, the stronger the effect, and when we combined antibiotics with a high-fat diet the effect was potentiated and the mice got very fat," Blaser told MedPage Today. "We also showed that the metabolic effects remained when antibiotics were given for just 4 weeks in infancy, suggesting that early life exposure can have lifelong effects."
The Antibiotic-Obesity Link
Early life has been shown to be a critical period for metabolic development, and several epidemiological studies suggested a link between early antibiotic exposure to an increase in overweight status later in childhood, the researchers wrote.
Earlier this month, a study published in the International Journal of Obesity found exposure to antibiotics during the first year of life to be associated with a small increase in body mass index (BMI) in boys between the ages of 5 and 12, but not girls.
Blaser's team has studied the impact of antibiotic use on animal and human microbiome and how microbiome alteration impacts health for several years.
Microbes begin to colonize in the gut at birth, and Blaser and colleagues hypothesized that disruption of these communities with antibiotics early in life have long-term effects on weight and the risk for diseases associated with obesity, such as diabetes.
"For decades, farmers have been exposing livestock to low doses of antibiotics to promote growth; the earlier in life that exposure begins the more profound the effects," they wrote.
For the current study, they examined antibiotic exposure timing in an effort to determine if a critical window of exposure exists. They also addressed whether synergies exist between antibiotic exposure and dietary effects, and whether microbiota alterations are sufficient to impact metabolic phenotypes.
"Hypothesizing that early life was the critical period for programming host-microbe metabolic interactions, we sought to determine whether microbiota disruption limited to early life could induce metabolic effects," the researchers wrote. "In addition to long-term (28 week) low-dose penicillin (LDP) or none (control), groups of mice received 4 or 8 weeks of LDP, and to accelerate metabolic phenotypes, all were switched to high-fat diet (HFD) at 6 weeks of age."
Penicillin Altered Ileal Tissue
In female mice, all three low-dose penicillin groups developed elevated total, lean, and fat mass compared to controls, irrespective of low-dose penicillin duration. Compared to controls, following switch to high-fat diet, female low-dose penicillin mice had significantly elevated caloric intake and significantly faster total and fat mass accumulation rates from 6 to 20 weeks of age.
Later in life (weeks 20-28), all three low-dose penicillin groups showed significantly slower rates in lean mass growth compared to controls, indicating catch-up by the control mice.
Male mice on low-dose penicillin showed early elevations in total, lean, and fat mass but did not have increased food intake or feed efficiency from 6 to 8 weeks of age. The early-life changes in body composition were lost with age, which was consistent with an earlier reported increased early-life and gender-dependent sensitivity to high-fat diet that may override microbe-mediated effects, the researchers noted.
"By age 4 weeks, LDP induced substantial histopathologic effects in ileal tissues, notably shortened villi, which is consistent with changed ileal architecture in LDP-mediated livestock growth promotion," the researchers wrote. "Transcriptional profiling analysis of intestinal tissue by microarray and subsequent validation by Nanostring analysis revealed that the ileal atrophy from LDP was associated with a general decreased expression of genes involved in intestinal immune responses, with numerous consistencies across gender."
"Low-dose penicillin decreased expression of genes related to several biological functions, such as differentiation, activation, recruitment, and adhesion of immune cells, and functions specifically related to androgen-presenting cells, T cells, B cells and phagocytic cells," they explained.
High-Fat Diet Exacerbated Changes
Antibiotic exposure also induced numerous compositional changes in the microbiota, and introduction of the high-fat diet had further effects. After antibiotics were stopped in the mice given low-dose penicillin for both 4 and 8 weeks, the patterns associated with high-fat diet exposure of the control mice began to emerge, the group stated, but were never present in mice exposed to 28 weeks of low-dose penicillin.
"The persistent phenotypes after LDP cessation, despite microbiota normalization, provide evidence that the early-life microbiota influences adult body composition," the researchers wrote.
Low-dose penicillin suppressed early-life Lactobacillus, Allobaculum, Rikenellaceae, and Candidatus Arthromitus. This finding suggests a protective role for these organisms in the modulation of host metabolism.
"All microbiota members do not equally impact the host; prior studies indicate that these four organisms have either metabolic and/or immunologic interactions which may contribute to the observed protection from weight gain in the control animals," the researchers wrote.
Future Plans
Blaser's team is currently conducting research designed to determine if re-introducing these bacteria following antibiotic therapy will impact weight gain.
"Our findings imply that restoring good bacteria could prevent the long-term metabolic effects of early antibiotic exposure," stated co-author Laura M. Cox, PhD, in an accompanying statement.
Blaser said some combination of these bacteria or others that have not yet been identified could prove critical in early-life metabolic protection.
He added that the research team is also investigating the impact of early antibiotic use on diabetes risk.
In a prospective study reported earlier this summer, a different group of researchers showed that composition of gut bacteria in patients with type 2 diabetes differed from those of people without the disease.
Obese patients and those with diabetes had lower proportions of the bacteria Firmicutes, Bifidobacteria, and Clostridium Leptum, compared to healthy controls, Yalcin Basaran, MD, of Gulhane Military Medical Academy in Ankara, Turkey, and colleagues reported at the joint meeting of the Endocrine Society and the International Congress on Endocrinology in Chicago.
The analysis revealed that metabolic parameters such as weight (P<0.001), BMI (P<0.001), HbA1c (P=0.011), waist circumference (P<0.001), and fasting blood glucose (P=0.005) were significantly associated with reduced levels of these three types of bacteria in the gut.
Blaser said all of these studies point to an important developmental window early in life during which antibiotic exposure can have long-term effects on metabolism.
"We can't say what this window is, but the epidemiological studies have focused on the first year of life," he said. "Physicians need to know that antibiotics use could have long-term costs, and this needs to be factored into decisions about when to use them."
The research was supported by the NIH, the Diane Belfer Program in Human Microbial Ecology, the Knapp Family Foundation, and the Daniel Ziff Foundation.
The authors disclosed no relevant relationships with industry.
Published: Aug 17, 2014
By Salynn Boyles, Contributing Writer, MedPage Today
Exposure to antibiotics early in life may permanently alter gut microbes in a way that could increase obesity risk years later, researchers reported.
In a study that compared outcomes in mice given low-dose penicillin versus those who were not, infancy was identified as a critical window of host-microbe metabolic interaction, suggesting that early-life antibiotic exposure can lead to lifelong metabolic changes, wrote Martin Blaser, MD, of NYU Langone Medical Center in New York City, and colleagues in the Aug. 14 issue of Cell.
This new finding expands on previous research by Blaser's group that tied antibiotic treatment from birth to accelerated growth in mice.
"We showed that the earlier we gave the antibiotic, the stronger the effect, and when we combined antibiotics with a high-fat diet the effect was potentiated and the mice got very fat," Blaser told MedPage Today. "We also showed that the metabolic effects remained when antibiotics were given for just 4 weeks in infancy, suggesting that early life exposure can have lifelong effects."
The Antibiotic-Obesity Link
Early life has been shown to be a critical period for metabolic development, and several epidemiological studies suggested a link between early antibiotic exposure to an increase in overweight status later in childhood, the researchers wrote.
Earlier this month, a study published in the International Journal of Obesity found exposure to antibiotics during the first year of life to be associated with a small increase in body mass index (BMI) in boys between the ages of 5 and 12, but not girls.
Blaser's team has studied the impact of antibiotic use on animal and human microbiome and how microbiome alteration impacts health for several years.
Microbes begin to colonize in the gut at birth, and Blaser and colleagues hypothesized that disruption of these communities with antibiotics early in life have long-term effects on weight and the risk for diseases associated with obesity, such as diabetes.
"For decades, farmers have been exposing livestock to low doses of antibiotics to promote growth; the earlier in life that exposure begins the more profound the effects," they wrote.
For the current study, they examined antibiotic exposure timing in an effort to determine if a critical window of exposure exists. They also addressed whether synergies exist between antibiotic exposure and dietary effects, and whether microbiota alterations are sufficient to impact metabolic phenotypes.
"Hypothesizing that early life was the critical period for programming host-microbe metabolic interactions, we sought to determine whether microbiota disruption limited to early life could induce metabolic effects," the researchers wrote. "In addition to long-term (28 week) low-dose penicillin (LDP) or none (control), groups of mice received 4 or 8 weeks of LDP, and to accelerate metabolic phenotypes, all were switched to high-fat diet (HFD) at 6 weeks of age."
Penicillin Altered Ileal Tissue
In female mice, all three low-dose penicillin groups developed elevated total, lean, and fat mass compared to controls, irrespective of low-dose penicillin duration. Compared to controls, following switch to high-fat diet, female low-dose penicillin mice had significantly elevated caloric intake and significantly faster total and fat mass accumulation rates from 6 to 20 weeks of age.
Later in life (weeks 20-28), all three low-dose penicillin groups showed significantly slower rates in lean mass growth compared to controls, indicating catch-up by the control mice.
Male mice on low-dose penicillin showed early elevations in total, lean, and fat mass but did not have increased food intake or feed efficiency from 6 to 8 weeks of age. The early-life changes in body composition were lost with age, which was consistent with an earlier reported increased early-life and gender-dependent sensitivity to high-fat diet that may override microbe-mediated effects, the researchers noted.
"By age 4 weeks, LDP induced substantial histopathologic effects in ileal tissues, notably shortened villi, which is consistent with changed ileal architecture in LDP-mediated livestock growth promotion," the researchers wrote. "Transcriptional profiling analysis of intestinal tissue by microarray and subsequent validation by Nanostring analysis revealed that the ileal atrophy from LDP was associated with a general decreased expression of genes involved in intestinal immune responses, with numerous consistencies across gender."
"Low-dose penicillin decreased expression of genes related to several biological functions, such as differentiation, activation, recruitment, and adhesion of immune cells, and functions specifically related to androgen-presenting cells, T cells, B cells and phagocytic cells," they explained.
High-Fat Diet Exacerbated Changes
Antibiotic exposure also induced numerous compositional changes in the microbiota, and introduction of the high-fat diet had further effects. After antibiotics were stopped in the mice given low-dose penicillin for both 4 and 8 weeks, the patterns associated with high-fat diet exposure of the control mice began to emerge, the group stated, but were never present in mice exposed to 28 weeks of low-dose penicillin.
"The persistent phenotypes after LDP cessation, despite microbiota normalization, provide evidence that the early-life microbiota influences adult body composition," the researchers wrote.
Low-dose penicillin suppressed early-life Lactobacillus, Allobaculum, Rikenellaceae, and Candidatus Arthromitus. This finding suggests a protective role for these organisms in the modulation of host metabolism.
"All microbiota members do not equally impact the host; prior studies indicate that these four organisms have either metabolic and/or immunologic interactions which may contribute to the observed protection from weight gain in the control animals," the researchers wrote.
Future Plans
Blaser's team is currently conducting research designed to determine if re-introducing these bacteria following antibiotic therapy will impact weight gain.
"Our findings imply that restoring good bacteria could prevent the long-term metabolic effects of early antibiotic exposure," stated co-author Laura M. Cox, PhD, in an accompanying statement.
Blaser said some combination of these bacteria or others that have not yet been identified could prove critical in early-life metabolic protection.
He added that the research team is also investigating the impact of early antibiotic use on diabetes risk.
In a prospective study reported earlier this summer, a different group of researchers showed that composition of gut bacteria in patients with type 2 diabetes differed from those of people without the disease.
Obese patients and those with diabetes had lower proportions of the bacteria Firmicutes, Bifidobacteria, and Clostridium Leptum, compared to healthy controls, Yalcin Basaran, MD, of Gulhane Military Medical Academy in Ankara, Turkey, and colleagues reported at the joint meeting of the Endocrine Society and the International Congress on Endocrinology in Chicago.
The analysis revealed that metabolic parameters such as weight (P<0.001), BMI (P<0.001), HbA1c (P=0.011), waist circumference (P<0.001), and fasting blood glucose (P=0.005) were significantly associated with reduced levels of these three types of bacteria in the gut.
Blaser said all of these studies point to an important developmental window early in life during which antibiotic exposure can have long-term effects on metabolism.
"We can't say what this window is, but the epidemiological studies have focused on the first year of life," he said. "Physicians need to know that antibiotics use could have long-term costs, and this needs to be factored into decisions about when to use them."
The research was supported by the NIH, the Diane Belfer Program in Human Microbial Ecology, the Knapp Family Foundation, and the Daniel Ziff Foundation.
The authors disclosed no relevant relationships with industry.
