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. 2015 Jul 7:6:692.
doi: 10.3389/fmicb.2015.00692. eCollection 2015.

Fecal microbiota transplantation and bacterial consortium transplantation have comparable effects on the re-establishment of mucosal barrier function in mice with intestinal dysbiosis

Ming Li  1 , Pin Liang  2 , Zhenzhen Li  3 , Ying Wang  3 , Guobin Zhang  3 , Hongwei Gao  3 , Shu Wen  1 , Li Tang  1
Affiliations

Fecal microbiota transplantation and bacterial consortium transplantation have comparable effects on the re-establishment of mucosal barrier function in mice with intestinal dysbiosis

Ming Li et al. Front Microbiol. .

Abstract

Fecal microbiota transplantation (FMT) is a promising therapy, despite some reports of adverse side effects. Bacterial consortia transplantation (BCT) for targeted restoration of the intestinal ecosystem is considered a relatively safe and simple procedure. However, no systematic research has assessed the effects of FMT and BCT on immune responses of intestinal mucosal barrier in patients. We conducted complementary studies in animal models on the effects of FMT and BCT, and provide recommendations for improving the clinical outcomes of these treatments. To establish the dysbiosis model, male BALB/c mice were treated with ceftriaxone intra-gastrically for 7 days. After that, FMT and BCT were performed on ceftriaxone-treated mice for 3 consecutive days to rebuild the intestinal ecosystem. Post-FMT and post-BCT changes of the intestinal microbial community and mucosal barrier functions were investigated and compared. Disruption of intestinal microbial homeostasis impacted the integrity of mucosal epithelial layer, resulting in increased intestinal permeability. These outcomes were accompanied by overexpression of Muc2, significant decrease of SIgA secretion, and overproduction of defensins and inflammatory cytokines. After FMT and BCT, the intestinal microbiota recovered quickly, this was associated with better reconstruction of mucosal barriers and re-establishment of immune networks compared with spontaneous recovery (SR). Although based on a short-term study, our results suggest that FMT and BCT promote the re-establishment of intestinal microbial communities in mice with antibiotic-induced dysbiosis, and contribute to the temporal and spatial interactions between microbiota and mucosal barriers. The effects of BCT are comparable to that of FMT, especially in normalizing the intestinal levels of Muc2, SIgA, and defensins.

Keywords: bacterial consortia transplantation; fecal microbiota transplantation; intestinal dysbiosis; intestinal microbiota; mucosal barrier function.

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Figures

Figure 1
Figure 1
Schematic overview of ceftriaxone treatment and FMT/BCT. (A) To establish the intestinal dysbiosis model, BALB/c mice were treated with ceftriaxone sodium for 7 days. After that, they were divided into 3 experimental groups: the spontaneous recovery group (SR), the fecal microbiota transplantation group (FMT), and the bacterial consortium transplantation group (BCT). The red vertical bars indicate sampling dates. The recovery of intestinal ecosystem was observed for 3 weeks. (B) Mean body weights, (C) Cecal index, and (D) The number of mice with diarrhea were investigated respectively. ***p < 0.001; *, FMT compared with SR, p < 0.05; Δ, BCT compared with FMT, p < 0.05.
Figure 2
Figure 2
Ceftriaxone induced intestinal dysbiosis in mice. (A) DGGE pattern of the cecal microbial community of mice. C1–C3, control mice, D1–D3, dysbiosis mice. a–c, the bands differ from control were extracted from the DGGE gel and sequenced. (B) PCA of the DGGE profile. Community similarity was calculated using the weighted UniFrac distance metric, which incorporates phylogenetic as well as relative abundance information. PC1 and PC2 account for 76.70% of the variation. White dots, healthy mice; red dots, ceftriaxone-treated mice. (C) The total population of intestinal microbes in control and ceftriaxone-treated mice detected by qPCR. (D) The population of selected commensal bacteria in control and ceftriaxone-treated mice detected by qPCR. *p < 0.05; **p < 0.01; ***p < 0.001.
Figure 3
Figure 3
The intestinal phenotype of ceftriaxone-treated mice. (A) Representative patterns of HE-stained sections of distal ileum and colon in mice. Magnification, ×200. The red arrows indicate inflammatory cell infiltration, or vascular dilatation and congestion. (B) Histological evaluation of the HE-stained sections. (C) Trans-epithelial resistance (TER) of mouse distal ileum and colon was determined by measuring the average changes in potential difference in response to 3 μA current generated across the tissue segments every 6 s for 30 min. (D) Muc2 immunostaining in mouse distal ileum (top) and proximal colon (bottom), Magnification, ×200. (E) The concentration of Muc2 in intestinal mucus of mice. (F) The concentration of SIgA in intestinal mucus and serum IgA of mice. (G) The concentration of defensins in intestinal mucus of mice. (H) Serum levels of IL1-ß, IL-6, and TNF-α in mice. *p < 0.05; ***p < 0.001. All the samples were taken at day 8.
Figure 4
Figure 4
The recovery of intestinal microbiota in different mice groups. (A) PCA of the cecal microbiota in different experimental mice groups during the 3-week recovery. PC1 and PC2 account for 66.66, 59.62, and 51.26% of the variation in different weeks. Each symbol represents one microbiota (dot). White dots, healthy mice; red dots; SR mice, blue dots, FMT mice; green dots, BCT mice. (B) The population of total intestinal microbes in different mice groups detected by qPCR. *p < 0.05; w, week(s) after ceftriaxone treatment.
Figure 5
Figure 5
Post-FMT or BCT changes of the mechanical barriers in intestinal mucosa of different mice groups. (A) Representative patterns of HE-stained sections of distal ileum and proximal colon in mice after 1 week recovery. Magnification, ×200. The red arrows indicate inflammatory cell infiltration, or vascular dilatation and congestion. (B) Histological analysis was performed after 1 week recovery. **p < 0.001 compared with control. (C) TER of distal ileum in different mice groups detected after 1 week recovery, *, FMT compared with SR, p < 0.05. The X axes indicate days after ceftriaxone treatment. (D) The concentration of Muc2 in intestinal mucus of mice. *, FMT compared with SR, p < 0.05. All values are means ± SD of 5 mice per group. (E) Muc2 immunostaining in mouse distal ileum and proximal colon.
Figure 6
Figure 6
Post-FMT or BCT changes of intestinal SIgA, defensins and serum inflammatory cytokines. The concentration of SIgA (A), α-defensin 5 (B), 6 (C), β-defensin 1 (D), and 2 (E) in intestinal mucus of mice, and the serum levels of IL1-β (F), IL-6 (G), TNF-α (H) in mice post-FMT or BCT were measured by ELISA. Values are means ± SD of 5 mice per group. *, FMT compared with SR p < 0.05. Δ, BCT compared with FMT p < 0.05. The X axes indicate days after ceftriaxone treatment.
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