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SAN DIEGO – results from a mouse study demonstrated.
The finding raises the question of whether patients with suboptimal outcomes following vertical sleeve gastrectomy may benefit from microbial modulation.
According to Dr. Jahansouz of the University of Minnesota Microbiota Transplantation Program, mechanisms mediating metabolic improvement following bariatric surgery remain incompletely understood. “Outcomes are also somewhat variable: As many as 40%-75% of patients regain weight in the years following nadir of weight loss,” he said. “Human studies have shown an acute and sustained shift in the gut microbiota, and an altered bile acid profile. Bile acids increase following surgery.”
Meanwhile, mice deficient in Farnesoid X-receptor (FXR) and Takeda G protein–coupled Receptor 5 (TGR5) do not experience metabolic improvement following bariatric surgery; the composition of the microbiome can significantly impact the composition of bile acids.
“By altering the postsurgical composition of mice following bariatric surgery, we eliminate the metabolic benefits of surgery, possibly by altering bile acid profiles,” Dr. Jahansouz said.
For the trial, diet-induced obese mice were randomized to vertical sleeve gastrectomy (VSG) or sham surgery, with or without exposure to antibiotics that selectively suppress mainly gram-positive (fidaxomicin, streptomycin) or gram-negative (ceftriaxone) bacteria on postoperative days 1-4. The researchers characterized fecal microbiota before surgery and on postoperative days 7 and 28. Mice were metabolically characterized on postoperative days 30-32 and euthanized on postoperative day 35.
Mice in the VSG group experienced weight loss and shifts in the intestinal microbiota composition, compared with those in the sham surgery group.
“Antibiotic exposure resulted in sustained reductions in alpha (within sample) diversity of microbiota and shifts in its composition,” the researchers wrote in their abstract. “Different antimicrobial specificity of antibiotics led to functionally distinct physiologic effects. Specifically, fidaxomicin and streptomycin markedly altered hepatic bile acid signaling and lipid metabolism, while ceftriaxone resulted in greater reduction in the expression of key antimicrobial peptides.
“However, VSG mice exposed to antibiotics, regardless of their specificity, had significantly increased subcutaneous adiposity and impaired glucose homeostasis without changes in food intake, relative to control mice,” the investigators noted.
Dr. Jahansouz said that he was surprised by the fact that all three antibiotics tested, no matter their specificity in gut bacteria eliminated, resulted in significantly diminished weight loss and metabolic improvement following vertical sleeve gastrectomy in the mouse model. He acknowledged that translating the findings from mice to humans is a key limitation of the analysis.
“There are fundamental physiologic differences between mice and humans that need consideration in all murine models of metabolic disorders,” he said. “Therefore, it is critical that insights gained from these models are followed up in human studies.”
The study was funded by the American Diabetes Association and a Minnesota Discovery, Research and InnoVation Economy grant from the University of Minnesota. Dr. Jahansouz reported having no financial disclosures.
SAN DIEGO – results from a mouse study demonstrated.
The finding raises the question of whether patients with suboptimal outcomes following vertical sleeve gastrectomy may benefit from microbial modulation.
According to Dr. Jahansouz of the University of Minnesota Microbiota Transplantation Program, mechanisms mediating metabolic improvement following bariatric surgery remain incompletely understood. “Outcomes are also somewhat variable: As many as 40%-75% of patients regain weight in the years following nadir of weight loss,” he said. “Human studies have shown an acute and sustained shift in the gut microbiota, and an altered bile acid profile. Bile acids increase following surgery.”
Meanwhile, mice deficient in Farnesoid X-receptor (FXR) and Takeda G protein–coupled Receptor 5 (TGR5) do not experience metabolic improvement following bariatric surgery; the composition of the microbiome can significantly impact the composition of bile acids.
“By altering the postsurgical composition of mice following bariatric surgery, we eliminate the metabolic benefits of surgery, possibly by altering bile acid profiles,” Dr. Jahansouz said.
For the trial, diet-induced obese mice were randomized to vertical sleeve gastrectomy (VSG) or sham surgery, with or without exposure to antibiotics that selectively suppress mainly gram-positive (fidaxomicin, streptomycin) or gram-negative (ceftriaxone) bacteria on postoperative days 1-4. The researchers characterized fecal microbiota before surgery and on postoperative days 7 and 28. Mice were metabolically characterized on postoperative days 30-32 and euthanized on postoperative day 35.
Mice in the VSG group experienced weight loss and shifts in the intestinal microbiota composition, compared with those in the sham surgery group.
“Antibiotic exposure resulted in sustained reductions in alpha (within sample) diversity of microbiota and shifts in its composition,” the researchers wrote in their abstract. “Different antimicrobial specificity of antibiotics led to functionally distinct physiologic effects. Specifically, fidaxomicin and streptomycin markedly altered hepatic bile acid signaling and lipid metabolism, while ceftriaxone resulted in greater reduction in the expression of key antimicrobial peptides.
“However, VSG mice exposed to antibiotics, regardless of their specificity, had significantly increased subcutaneous adiposity and impaired glucose homeostasis without changes in food intake, relative to control mice,” the investigators noted.
Dr. Jahansouz said that he was surprised by the fact that all three antibiotics tested, no matter their specificity in gut bacteria eliminated, resulted in significantly diminished weight loss and metabolic improvement following vertical sleeve gastrectomy in the mouse model. He acknowledged that translating the findings from mice to humans is a key limitation of the analysis.
“There are fundamental physiologic differences between mice and humans that need consideration in all murine models of metabolic disorders,” he said. “Therefore, it is critical that insights gained from these models are followed up in human studies.”
The study was funded by the American Diabetes Association and a Minnesota Discovery, Research and InnoVation Economy grant from the University of Minnesota. Dr. Jahansouz reported having no financial disclosures.
SAN DIEGO – results from a mouse study demonstrated.
The finding raises the question of whether patients with suboptimal outcomes following vertical sleeve gastrectomy may benefit from microbial modulation.
According to Dr. Jahansouz of the University of Minnesota Microbiota Transplantation Program, mechanisms mediating metabolic improvement following bariatric surgery remain incompletely understood. “Outcomes are also somewhat variable: As many as 40%-75% of patients regain weight in the years following nadir of weight loss,” he said. “Human studies have shown an acute and sustained shift in the gut microbiota, and an altered bile acid profile. Bile acids increase following surgery.”
Meanwhile, mice deficient in Farnesoid X-receptor (FXR) and Takeda G protein–coupled Receptor 5 (TGR5) do not experience metabolic improvement following bariatric surgery; the composition of the microbiome can significantly impact the composition of bile acids.
“By altering the postsurgical composition of mice following bariatric surgery, we eliminate the metabolic benefits of surgery, possibly by altering bile acid profiles,” Dr. Jahansouz said.
For the trial, diet-induced obese mice were randomized to vertical sleeve gastrectomy (VSG) or sham surgery, with or without exposure to antibiotics that selectively suppress mainly gram-positive (fidaxomicin, streptomycin) or gram-negative (ceftriaxone) bacteria on postoperative days 1-4. The researchers characterized fecal microbiota before surgery and on postoperative days 7 and 28. Mice were metabolically characterized on postoperative days 30-32 and euthanized on postoperative day 35.
Mice in the VSG group experienced weight loss and shifts in the intestinal microbiota composition, compared with those in the sham surgery group.
“Antibiotic exposure resulted in sustained reductions in alpha (within sample) diversity of microbiota and shifts in its composition,” the researchers wrote in their abstract. “Different antimicrobial specificity of antibiotics led to functionally distinct physiologic effects. Specifically, fidaxomicin and streptomycin markedly altered hepatic bile acid signaling and lipid metabolism, while ceftriaxone resulted in greater reduction in the expression of key antimicrobial peptides.
“However, VSG mice exposed to antibiotics, regardless of their specificity, had significantly increased subcutaneous adiposity and impaired glucose homeostasis without changes in food intake, relative to control mice,” the investigators noted.
Dr. Jahansouz said that he was surprised by the fact that all three antibiotics tested, no matter their specificity in gut bacteria eliminated, resulted in significantly diminished weight loss and metabolic improvement following vertical sleeve gastrectomy in the mouse model. He acknowledged that translating the findings from mice to humans is a key limitation of the analysis.
“There are fundamental physiologic differences between mice and humans that need consideration in all murine models of metabolic disorders,” he said. “Therefore, it is critical that insights gained from these models are followed up in human studies.”
The study was funded by the American Diabetes Association and a Minnesota Discovery, Research and InnoVation Economy grant from the University of Minnesota. Dr. Jahansouz reported having no financial disclosures.
AT THE ACS CLINICAL CONGRESS
Key clinical point: Postsurgical disruption of intestinal microbiota composition attenuates the metabolic efficacy of vertical sleeve gastrectomy.
Major finding: VSG mice exposed to antibiotics had significantly increased subcutaneous adiposity and impaired glucose homeostasis without changes in food intake, compared with control mice.
Study details: A study of diet-induced obese mice that were randomized to VSG or sham surgery, with or without exposure to antibiotics.
Disclosures: The study was funded by the American Diabetes Association and a Minnesota Discovery, Research and InnoVation Economy grant from the University of Minnesota. Dr. Jahansouz reported having no financial disclosures.