Ileal microbial shifts after Roux-en-Y gastric bypass orchestrate changes in glucose metabolism through modulation of bile acids and L-cell adaptation

Jerry T Dang, Valentin Mocanu, Heekuk Park, Michael Laffin, Caroline Tran, Naomi Hotte, Shahzeer Karmali, Daniel W Birch, Karen Madsen, Jerry T Dang, Valentin Mocanu, Heekuk Park, Michael Laffin, Caroline Tran, Naomi Hotte, Shahzeer Karmali, Daniel W Birch, Karen Madsen

Abstract

Roux-en-Y gastric bypass (RYGB)-induced glycemic improvement is associated with increases in glucagon-like-peptide-1 (GLP-1) secreted from ileal L-cells. We analyzed changes in ileal bile acids and ileal microbial composition in diet-induced-obesity rats after RYGB or sham surgery to elucidate the early and late effects on L-cells and glucose homeostasis. In early cohorts, there were no significant changes in L-cell density, GLP-1 or glucose tolerance. In late cohorts, RYGB demonstrated less weight regain, improved glucose tolerance, increased L-cell density, and increased villi height. No difference in the expression of GLP-1 genes was observed. There were lower concentrations of ileal bile acids in the late RYGB cohort. Microbial analysis demonstrated decreased alpha diversity in early RYGB cohorts which normalized in the late group. The early RYGB cohorts had higher abundances of Escherichia-Shigella but lower abundances of Lactobacillus, Adlercreutzia, and Proteus while the late cohorts demonstrated higher abundances of Escherichia-Shigella and lower abundances of Lactobacillus. Shifts in Lactobacillus and Escherichia-Shigella correlated with decreases in multiple conjugated bile acids. In conclusion, RYGB caused a late and substantial increase in L-cell quantity with associated changes in bile acids which correlated to shifts in Escherichia-Shigella and Lactobacillus. This proliferation of L-cells contributed to improved glucose homeostasis.

Conflict of interest statement

The authors declare no competing interests.

© 2021. The Author(s).

Figures

Figure 1
Figure 1
Pre- and post-operative absolute weight on high fat diet; RYGB, Roux-en-Y gastric bypass.
Figure 2
Figure 2
Ileal morphological changes and L-cell density amongst groups: early Roux-en-Y gastric bypass (RYGB) (n = 7), early sham (n = 8), late RYGB (n = 8), late sham (n = 9). Error bars on figures represent standard error of the means and asterisks represent statistical significance with * as p < 0.05, ** as p < 0.01, *** as p < 0.001, **** as p < 0.0001.
Figure 3
Figure 3
Intraperitoneal glucose tolerance testing in gastric bypass (n = 8) versus sham (n = 9) in the late cohorts; RYGB, Roux-en-Y gastric bypass.
Figure 4
Figure 4
Differences in microbial abundance between Roux-en-Y gastric bypass and sham at early and late timepoints. (A) Taxonomic differences in microbial relative abundance between groups. (B) Between group differences in α diversity using the Chao1 and Shannon indices. (C) Between-group differences in β diversity using the Bray–Curtis dissimilarity index.
Figure 5
Figure 5
Heatmap of ileal bile acid concentrations after logarithmic transformation of data.
Figure 6
Figure 6
Heatmap of Spearman correlations of differential microbes and bile acids between late RYGB compared to late sham.

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