Abstract
The influence of gut microbiota on host immunity is widely studied, and its disturbance has been linked to several immune-mediated disorders. Conversely, whether and how inherently disturbed canonical Th1 (pro-inflammatory) and/or Th2 (anti-inflammatory) immune pathways modify the host microbiome is not sufficiently investigated. Here, we characterized the humoral, cellular, and cytokine immunity, and associated alterations in gut microbiota of naïve wild-type mice (C57BL/6 and BALB/c), and mice with deficiencies in Th2 responses (IL-4Rα and IL-33 knockout mice) or in both Th1 and Th2 responses (NOD scid gamma, NSG mice). A global analysis by de novo clustering of 16S rRNA profiles of the gut microbiota independently grouped wild-type immunocompetent (C57BL/6 and BALB/c), Th2-deficient (IL-4Rα-/- and IL-33-/-), and severely immunodeficient (NSG) mice; where wild-type mice, but not Th2 or severely immunodeficient mice, were enriched in gut bacteria that produce short-chain fatty acids. These include members of phyla Firmicutes, Verrucomicrobia, and Bacteroidetes such as Lactobacillus spp., Akkermansia muciniphila, and Odoribacter spp. Further comparison of the two naïve wild-type mouse strains showed higher microbial diversity (Shannon), primarily linked to higher richness (Chao1), as well as a distinct difference in microbial composition (weighted UniFrac) in BALB/c mice compared to C57BL/6. T-cell and blood cytokine analyses demonstrated a Th1-polarization in naïve adaptive immunity in C57BL/6 animals compared to BALB/c mice, and an expected Th2 deficient cellular response in IL-4Rα-/- and IL-33-/- mice compared to its genetic background BALB/c strain. Together, these data suggest that alterations in the Th1/Th2 balance or a complete ablation of Th1/Th2 responses can lead to major alterations in gut microbiota composition and function. Given the similarities between the human and mouse immune systems and gut microbiota, our finding that immune status is a strong driver of gut microbiota composition has important consequences for human immunodeficiency studies.
Highlights
The mammalian gastrointestinal tract harbors a large community of microorganisms consisting of bacteria, viruses, and fungi that play an important role in digestion, metabolism, and immunity in the host [1, 2]
We identified patterns of inflammatory mediators associated with C57BL/6 and BALB/c by partial least-squares discriminant analysis (PLS-DA), which led to an overall classification accuracy of 97.6% between the two wild-type strains (R2 = 0.92, Q2 = 0.87 for 2 components, Figure 1A, Table 1)
Other cytokines that were significantly different between C57BL/6 and BALB/c were IL-10, GM-CSF, and MCP-1, where 2 to 10-fold elevation in levels were observed for C57BL/6 compared to BALB/c (P < 0.001 for all except GM-CSF where P = 0.025, Figure 2C, D)
Summary
The mammalian gastrointestinal tract harbors a large community of microorganisms consisting of bacteria, viruses, and fungi that play an important role in digestion, metabolism, and immunity in the host [1, 2]. The intestinal commensal microbiota of healthy adults is shown to be primarily composed of Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria, and Verrucomicrobia of which the first two phyla are predominant [3, 4]. This microbial community reportedly interacts in health and disease with gut tissue, brain, lungs and other organs mostly by producing essential metabolites such as vitamins, indoles, bacteriocins, and shortchain fatty acids (SCFAs), and by direct transfer of gut microbiota to respiratory tract especially in immunocompromised conditions [1, 5–9]. Pro-inflammatory cytokines are secreted by T helper type 1 (Th1) cells and promote inflammation necessary for clearance of pathogens and for perpetuating autoimmune responses in the gut and other tissue [10–12]. There is growing evidence that nutrients that fuel metabolic processes impact on the ways immune cells, in particular, macrophages, respond to different stimuli under physiological and pathological conditions [14]
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