Complex interactions among diet, gastrointestinal transit, and gut microbiota in humanized mice

Abstract

Background & aims: Diet has major effects on the intestinal microbiota, but the exact mechanisms that alter complex microbial communities have been difficult to elucidate. In addition to the direct influence that diet exerts on microbes, changes in microbiota composition and function can alter host functions such as gastrointestinal (GI) transit time, which in turn can further affect the microbiota.

Methods: We investigated the relationships among diet, GI motility, and the intestinal microbiota using mice that are germ-free (GF) or humanized (ex-GF mice colonized with human fecal microbiota).

Results: Analysis of gut motility revealed that humanized mice fed a standard polysaccharide-rich diet had faster GI transit and increased colonic contractility compared with GF mice. Humanized mice with faster transit due to administration of polyethylene glycol or a nonfermentable cellulose-based diet had similar changes in gut microbiota composition, indicating that diet can modify GI transit, which then affects the composition of the microbial community. However, altered transit in mice fed a diet of fermentable fructooligosaccharide indicates that diet can change gut microbial function, which can affect GI transit.

Conclusions: Based on studies in humanized mice, diet can affect GI transit through microbiota-dependent or microbiota-independent pathways, depending on the type of dietary change. The effect of the microbiota on transit largely depends on the amount and type (fermentable vs nonfermentable) of polysaccharides present in the diet. These results have implications for disorders that affect GI transit and gut microbial communities, including irritable bowel syndrome and inflammatory bowel disease.

Conflict of interest statement

Conflicts of interest: The authors disclose no conflicts.

Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Figures

Model for interactions between diet, gut microbiota, and GI transit time. (A) GI motility and gut microbiota are closely interrelated and can significantly affect one another. (B) Diet-induced changes in GI transit may partially mediate the effect of diet on microbial composition. (C) Diet-induced changes in microbiota composition and function may alter GI transit time. (D) Together, these factors result in a complex interplay between diet, the gut microbiota, and GI transit.

Figure 1

Humanization of GF mice alters GI transit time. (A) Whole gut transit time measured by the carmine red dye method in GF, humanized, conventional, or conventionalized mice. (B) Distal colonic intraluminal pressure changes recorded using a pressure transducer catheter in conscious GF mice or mice that were humanized 3 days (D3 Post-humanization) or 1 month (Humanized) before measurement. Data are representative of 3 groups of mice for each condition and smoothed with a 2-second time constant to remove breathing artifact and abdominal contractions. (C) Motility index for distal colonic contractility in humanized mice (age matched with GF mice and humanized for 1 month) and ex-GF mice 3 days after humanization as compared with GF mice. Data represent the phasic component of area under the respective curves (pAUC). (D) Mean pAUC for the first 20 minutes (stress period) versus the subsequent 40 minutes and the entire 60 minutes of recording. ANOVA, *P < .05. NS, not significant.

Figure 2

Alterations in GI transit time influence the microbial composition of the distal gut. (A) Whole gut transit time measured by the carmine dye method in humanized mice before, during, and 7 or 14 days after treatment with PEG or loperamide. (B) Unweighted UniFrac-based PCoA plot (2-dimensional representation of 3-dimensional plot) of gut microbial communities in humanized mice shows that pretreatment samples cluster together and posttreatment samples cluster based on treatment with PEG or loperamide. (C and E) Significant family-level differences in gut microbial communities of humanized mice treated with (C) PEG or (E) loperamide compared with pretreatment controls. (D and F) Unweighted Uni-Frac-based PCoA plots (2-dimensional representation of 3-dimensional plots with x-axis fixed as time) of gut microbial communities in humanized mice before, during, and 7 or 14 days after treatment with (D) PEG or (F) loperamide show change in microbial community structure upon treatment, which are reversible after discontinuation of treatment. *P < .05. NS, not significant.

Figure 3

Alterations in carbohydrate content of diet alter GI transit time. (A) Whole gut transit time in GF or humanized mice fed (A) a cellulose-enriched diet, (B) a PSD diet, or (C) an FOS-enriched diet compared with standard diet controls. *P < .05.

Figure 4

Polysaccharide content of diet affects distal gut microbial composition. (A, B, and D) Unweighted UniFrac-based PCoA plot (2-dimensional representation of 3-dimensional plot) of gut microbial communities in humanized mice before and during administration of (A) a cellulose- enriched diet, (B) a PSD diet, or (D) FOS-enriched diet shows that samples cluster based on diet. (C) Significant family-level differences in gut microbial communities of humanized mice fed a cellulose-enriched diet compared with standard diet (Pre-cellulose).

Figure 5

Effect of diet on distal gut microbial composition may be mediated in part by changes in GI transit time. Unweighted UniFracbased PCoA plot of gut microbial communities from humanized mice before (Standard), during (PEG), and 7 (post-PEG D7) or 14 (post-PEG D14) days after treatment with PEG compared with mice fed a celluloseenriched diet shows clustering of microbial communities with accelerated transit (cellulose, PEG, and Post-PEG D7).

Figure 6

Diet induces changes in microbiota function. (A) Short-chain fatty acid levels in the feces of mice fed FOS-enriched diet compared with a standard diet. No succinate was detected in either condition. (B) Volcano plot showing metabolites that are significantly higher (>100-fold change and P<.01) in feces of mice fed a standard diet (blue) or FOS-enriched diet (red). (C) Increase in normalized concentration of a metabolite with a mass corresponding to 5-HIAA, 191.07. *P < .05.