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The microbiome changes induced by bariatric surgery protects against obesity and nonalcoholic fatty liver disease by decreasing gastric inhibitory protein and increasing hepatic NKT cell expression
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Microbiome Changes With Bariatric Surgery Protect From Obesity and NAFLD
AASLD The Liver Meeting Digital Experience, November 13-16, 2020
Mark Mascolini
A microbial transplant study involving 4 bariatric surgery recipients and mice fed high-fat or standard diets found generous evidence that the surgery protects against diet-induced obesity and nonalcoholic fatty liver disease (NAFLD) [1]. Researchers from the University of California, Los Angeles (UCLA) reported that two key changes with bariatric surgery are lower levels of gastric inhibitory peptide (GIP) and higher levels of natural killer (NK)T cells in liver.
The UCLA team pointed to human/mouse research showing that obesity can be transmitted via the gut microbiome [2,3]-the genetic material in all microbes in the gut. In a complementary way, the beneficial effects of bariatric surgery on obesity can also be transmitted by the gut microbiome [4].
Bariatric surgery, the UCLA investigators observed, remains one of the few methods available to sustain weight loss in people with obesity and NAFLD. They conducted this study to see whether the beneficial effects of bariatric surgery are made possible through changes in the gut microbiome and the impact of those changes on immune signaling and hormone secretion in people who undergo bariatric surgery. Results would indicate the potential beneficial role of such microbiome changes in addition to changes in eating behavior and alterations in satiety hormones that follow bariatric surgery.
The efficient design of this study involved collecting stool from 4 people undergoing laparoscopic sleeve gastrectomy-removal of two thirds of the stomach. Stool was collected just before surgery and 6 months after surgery. Researchers transplanted stool samples by oral gavage to antibiotic-treated mice, then split the mice into a group getting a standard diet and a group getting a high-fat, high-fructose, high-cholesterol diet for 12 weeks. They ended up with four groups of mice to compare: presurgery-standard diet, postsurgery-standard diet, presurgery high-fat diet, and postsurgery-high fat diet.
The researchers also tracked key changes after bariatric surgery in 18 people averaging 37.1 years in age. Eight were white, 7 Hispanic, 2 Asian, and 1 black. Their average weight fell from 118.5 kg before surgery to 89.7 kg 6 months after surgery (261 to 198 pounds), a significant difference (P < 0.001). Average body mass index fell from 44.7 kg/m2 before surgery to 33.9 kg/m2 6 months after surgery (P < 0.001). Fasting glucose, inflammation (C-reactive protein), and insulin resistance (lipopolysaccharide-binding protein) all fell significantly from before surgery to 12 months after surgery.
Among the 4 stool donors, 2 were Hispanic, 1 white, and 1 Asian with ages of 21, 43, 25, and 45. Six months after surgery they had lost 23.3%, 20.2%, 20.1%, and 35.3% of body weight. Imaging showed resolution of fatty liver in all 4 people.
Comparing changes in the four sets of mice showed microbiomes that induced weight gain after gavage done before bariatric surgery while protecting from weight gain after gavage done after surgery, regardless of mouse diet. The postsurgery microbiome cut body fat and boosted lean mass regardless of mouse diet. At the same time the transplanted microbiomes protected from insulin resistance measured as serum glucose. Cell studies showed that the presurgery microbiome induced steatosis while the postsurgery microbiome protected against steatosis in both standard-diet and high-fat-diet mice.
Compared with the presurgery microbiome, the postsurgery microbiome yielded significant increases in NKT cells in both standard-diet mice and high-fat-diet mice. Compared with the microbiome before bariatric surgery, the postsurgery microbiome had significantly fewer CD8 T cells, a signal of declining inflammation, regardless of mouse diet. Levels of inflammatory macrophages dropped significantly in the postsurgery microbiome, and this decline was much steeper in the high-fat-diet mice. Levels of Kupffer cells, which protect the liver from bacterial infection, dropped significantly in the microbiome after surgery in high-fat-diet mice but not in mice fed a standard diet.
Gastric inhibitory peptide (GIP) weakly inhibits gastric acid secretion while strongly stimulating insulin secretion. In the microbiome of presurgery mice, GIP levels were almost 3-fold higher in high-fat-diet mice than in standard-diet mice. GIP fell in mice regardless of diet, but the drop was much steeper and statistically significant in mice on a high-fat diet.
The UCLA team believes they successfully "recapitulated" the phenotype seen in humans before and after bariatric surgery in antibiotic-treated mice. The microbiome changes induced by bariatric surgery, they concluded "is protective against diet-induced obesity and NAFLD by lowering levels of GIP and increasing levels of hepatic NKT cell expression independent of diet."
References
1. Dong TS, Katzka W, Arias N, et al. The microbiome changes induced by bariatric surgery protects against obesity and nonalcoholic fatty liver disease by decreasing gastric inhibitory protein and increasing hepatic NKT cell expression. AASLD The Liver Meeting Digital Experience, November 13-16, 2020. Abstract 17.
2. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027-1031. doi: 10.1038/nature05414.
3. Ridaura VK, Faith JJ, Rey FE, et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science. 2013;341:1241214. doi: 10.1126/science.1241214.
4. Tremaroli V, Karlsson F, Werling M, et al. Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation. Cell Metab. 2015;22:228-238. doi: 10.1016/j.cmet.2015.07.009.
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