Abstract
The intestinal gut microbiota is essential for maintaining host health. Concerns have been raised about the possible connection between antibiotic use, causing microbiota disturbances, and the increase in allergic and autoimmune diseases observed during the last decades. To elucidate the putative connection between antibiotic use and immune regulation, we have assessed the effects of the antibiotic amoxicillin on immune regulation, protein uptake, and bacterial community structure in a Brown Norway rat model. Daily intra-gastric administration of amoxicillin resulted in an immediate and dramatic shift in fecal microbiota, characterized by a reduction of within sample (α) diversity, reduced variation between animals (β diversity), increased relative abundance of Bacteroidetes and Gammaproteobacteria, with concurrent reduction of Firmicutes, compared to a water control group. In the small intestine, amoxicillin also affected microbiota composition significantly, but in a different way than observed in feces. The small intestine of control animals was vastly dominated by Lactobacillus, but this genus was much less abundant in the amoxicillin group. Instead, multiple different genera expanded after amoxicillin administration, with high variation between individual animals, thus the small intestinal α and β diversity were higher in the amoxicillin group compared to controls. After 1 week of daily amoxicillin administration, total fecal IgA level, relative abundance of small intestinal regulatory T cells and goblet cell numbers were higher in the amoxicillin group compared to controls. Several bacterial genera, including Escherichia/Shigella, Klebsiella (Gammaproteobacteria), and Bifidobacterium, for which the relative abundance was higher in the small intestine in the amoxicillin group than in controls, were positively correlated with the fraction of small intestinal regulatory T cells. Despite of epidemiologic studies showing an association between early life antibiotic consumption and later prevalence of inflammatory bowel diseases and food allergies, our findings surprisingly indicated that amoxicillin-induced perturbation of the gut microbiota promotes acute immune regulation. We speculate that the observed increase in relative abundance of small intestinal regulatory T cells is partly mediated by immunomodulatory lipopolysaccharides derived from outgrowth of Gammaproteobacteria.
Highlights
The gut associated lymphoid tissue is continuously exposed to a vast amount of bacterial and food derived antigens
A healthy gut microbiota is important to avoid detrimental responses against harmless antigens (Stephen-Victor and Chatila, 2019), and epidemiological studies suggest that perturbation of the early life gut microbiota by pre- or post-natal exposure to antibiotics increases the risk of food allergies (Metsälä et al, 2013; Hirsch et al, 2017; Mitre et al, 2018) and autoimmune disorders including inflammatory bowel diseases (IBD) (Hviid et al, 2011; Shaw et al, 2011; Kronman et al, 2012)
The 1st day after onset, a statistically significant reduction of total bacterial load was observed in the amoxicillin group as compared to both the baseline level and to the level in the control group (Figure 1A)
Summary
The gut associated lymphoid tissue is continuously exposed to a vast amount of bacterial and food derived antigens. Failure to develop tolerance toward these antigens may lead to inflammatory bowel diseases (IBD) or food allergies, both characterized by an adverse immune response directed against either commensal bacteria or dietary components. Intestinal bacteria influence the secretion of mucus by goblet cells (Jung et al, 2015) and of immunoglobulin A (IgA) by plasma cells (Moreau et al, 1978; Shroff et al, 1995), both of which contribute to (I) antigen presentation and tolerogenic immune priming (Weltzin et al, 1989; McDole et al, 2012), (II) intestinal barrier function, and (III) balancing the microbial community (Martens et al, 2009; Donaldson et al, 2018). While multiple studies have assessed the influence of gut microbiota perturbation on immune regulation using broad-spectrum antibiotic cocktails (OchoaRepáraz et al, 2009; Hill et al, 2010; Nakamura et al, 2016) and germ-free (GF) animals (Ishikawa et al, 2008; Cahenzli et al, 2013), only few studies have investigated how administration of a single, clinically relevant antibiotic affects immune regulation (Tulstrup et al, 2015; Benakis et al, 2016)
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