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. 2013 Mar 27;5(178):178ra41.
doi: 10.1126/scitranslmed.3005687.

Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity

Alice P Liou  1 , Melissa Paziuk, Jesus-Mario Luevano Jr, Sriram Machineni, Peter J Turnbaugh, Lee M Kaplan
Affiliations

Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity

Alice P Liou et al. Sci Transl Med. .

Abstract

Roux-en-Y gastric bypass (RYGB) results in rapid weight loss, reduced adiposity, and improved glucose metabolism. These effects are not simply attributable to decreased caloric intake or absorption, but the mechanisms linking rearrangement of the gastrointestinal tract to these metabolic outcomes are largely unknown. Studies in humans and rats have shown that RYGB restructures the gut microbiota, prompting the hypothesis that some of the effects of RYGB are caused by altered host-microbial interactions. To test this hypothesis, we used a mouse model of RYGB that recapitulates many of the metabolic outcomes in humans. 16S ribosomal RNA gene sequencing of murine fecal samples collected after RYGB surgery, sham surgery, or sham surgery coupled to caloric restriction revealed that alterations to the gut microbiota after RYGB are conserved among humans, rats, and mice, resulting in a rapid and sustained increase in the relative abundance of Gammaproteobacteria (Escherichia) and Verrucomicrobia (Akkermansia). These changes were independent of weight change and caloric restriction, were detectable throughout the length of the gastrointestinal tract, and were most evident in the distal gut, downstream of the surgical manipulation site. Transfer of the gut microbiota from RYGB-treated mice to nonoperated, germ-free mice resulted in weight loss and decreased fat mass in the recipient animals relative to recipients of microbiota induced by sham surgery, potentially due to altered microbial production of short-chain fatty acids. These findings provide the first empirical support for the claim that changes in the gut microbiota contribute to reduced host weight and adiposity after RYGB surgery.

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Figures

Fig. 1
Fig. 1
Schematic of experimental design. (A) DIO C57BL/6J mice fed a 60% HFD underwent either RYGB or sham operations and 2-week recovery on liquid diet before returning to HFD (blue bars). Sham animals that had successfully regained body weight within 3 weeks after surgery were divided into an ad libitum–fed SHAM group or food-restricted to match the weight of the RYGB animals (WMS). Fresh fecal samples were collected preoperatively and weekly for 12 weeks after surgery for microbiota analysis (red arrows). (B) Graphic of the RYGB anatomy and segments collected for luminal content and mucosal scrapings along the length of the gastrointestinal tract. Segments representative of the RYGB anatomy were also collected in SHAM and WMS animals. (C) Design of microbiota transfer experiments of the cecal contents from a representative donor animal from each group, depicted in (A), into germ-free mice (star), indicating timing of collection of fecal samples for microbiota analysis (red arrows), body weights (blue asterisks), and food intake (triangles). At the end of the colonization period, animals were fasted overnight (double lines), and final body weights, serum metabolic parameters, and adiposity scores were obtained.
Fig. 2
Fig. 2
Phenotypic data from the RYGB mouse model. Characteristics of DIO C57BL/6J mice undergoing either RYGB (n = 11 to 17), sham operation (SHAM; n = 4 to 6), or sham operation with weight matching to the RYGB group by food restriction (WMS; n = 5 to 6). (A) Body weight curves after surgery. (B) Body composition analysis. (C) Adiposity index calculated from epididymal and retroperitoneal fat pad weights. (D) Liver triglyceride content. (E) Liver histology (×20). (F to H) One-week cumulative (F) food intake, (G) fecal energy output, and (H) net energy intake in RYGB (n = 14), SHAM (n = 11), and WMS (n = 6) animals. Measurements for (B) to (E) were taken at the end of study, 15 weeks after surgery. Food intake and energy output studies were performed 4 to 6 weeks after surgery. *P < 0.05, **P < 0.01, ***P < 0.001, one-way analysis of variance (ANOVA) and post hoc Tukey test. Values represent means ± SEM.
Fig. 3
Fig. 3
RYGB causes marked, rapid, and sustained changes in gut microbial ecology that are independent of weight and diet. (A) Heat map of pairwise Spearman rank correlations between species-level OTUs from fecal samples, ordered by treatment, individual, and time. Within-individual rank correlations in RYGB, SHAM, and WMS mice (n = 4 to 5 animals per group) compare weekly postoperative samples to a preoperative sample. Rank correlations between endpoint samples taken from unoperated DIO, unoperated NC-fed (NC), and RYGB-operated mice maintained on NC (NC-RYGB) are also included (n = 2 to 4 per group). Each correlation is colored from dark blue (no correlation) to dark red (perfect positive correlation). (B) Temporal effects of gastric bypass on overall community membership among fecal samples from RYGB (pink circles), SHAM (orange squares), and WMS (olive triangles) animals [first principal coordinate from an unweighted UniFrac-based analysis over time]. Includes endpoint fecal samples from age-matched DIO (purple circle), NC (green triangle), and NC-RYGB (blue diamond) mice. Values represent means ± SEM.
Fig. 4
Fig. 4
Bacterial taxonomic groups that discriminate among RYGB-, SHAM-, and WMS-derived samples. (A) Average relative abundance of bacterial orders in RYGB, SHAM, and WMS mice before and up to 12 weeks after surgery. (B) LEfSe-derived (27) phylogenetic tree depicting nodes within the bacterial taxonomic hierarchy that are significantly enriched in fecal samples from RYGB (red), SHAM (green), and WMS (blue) mice. Significant phyla are labeled, with the genera in parentheses. LEfSe was used with the default parameters (n = 5000 sequences per sample; OTUs with <10 sequences and preoperation samples removed).
Fig. 5
Fig. 5
Relative abundance of bacterial taxa throughout the gastrointestinal tract of RYGB, SHAM, and WMS mice. (A) Spatial effects of gastric bypass. The first principal coordinate from an unweighted UniFrac-based analysis is shown for luminal and mucosal samples taken from the stomach, small intestine, cecum, and colon. Values represent means ± SEM. DS, distal stomach; GP, gastric pouch; BP, biliopancreatic limb. (B) The dominant bacterial orders are shown for samples from the stomach, small intestine, cecum, and colon. Mean values are shown for samples isolated from the lumen (blue squares) and mucosa (red squares).
Fig. 6
Fig. 6
Decreased weight and adiposity is transmissible via the gut microbiota. (A) Body weight curves for SHAM-R (n = 6) and RYGB-R (n = 10) mice, represented as change from initial body weight. (B) Change in body weights (BW) among the groups relative to baseline. (C) Cumulative food intake over the 13-day colonization period. (D and E) Visceral fat pad weights (D) and plasma leptin levels (E) in the RYGB-R (n = 10), uninoculated germ-free (n = 7), and consolidated SHAM-R (n = 10) groups. Values in (A) to (E) are means ± SEM. *P < 0.05, **P < 0.01, ANOVA post hoc test. Representative of three experiments. (F) Relative abundance of bacterial taxa in recipient animals after gavage with cecal contents from RYGB, SHAM, and WMS donors. Mean values across each time point (1 to 13 days after gavage) are shown (n = 3 to 15 samples per time point; 10,000 sequences per sample).
Fig. 7
Fig. 7
SCFA levels are consistent between donor and recipient animals. (A and B) Total cecal SCFAs (A) and percentage of total SCFAs (B) of acetate, propionate, and butyrate in RYGB-operated (n = 6), SHAM-operated (n = 4), and WMS-operated (n = 5) animals. (C) Total cecal SCFAs of RYGB-R (n = 5), SHAM-R (n = 6), and germ-free (GF; n = 4) mice 2 weeks after colonization of their respective operated donor cecal microbiota. (D) Percentage of total SCFA of acetate, propionate, and butyrate in RYGB-R and SHAM-R mice. Values represent means ± SEM. *P < 0.05, **P < 0.01, ****P < 0.001, one-way ANOVA post hoc Tukey test or Student’s t test.
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