Abstract
The gut mucosa is continuously exposed to a vast community of microorganisms, collectively defined as microbiota, establishing a mutualistic relationship with the host and contributing to shape the immune system. Gut microbiota is acquired at birth, and its composition is relatively stable during the entire adult life. Intestinal dysbiosis, defined as a microbial imbalance of gut bacterial communities, can be caused by several factors, including bacterial infections and antibiotic use, and has been associated with an increased risk to develop or exacerbate immune-mediated pathologies, such as allergic reactions, asthma, and inflammatory bowel diseases. Still, the mechanisms by which antibiotic-induced gut dysbiosis may lead to development of mucosal inflammation are still matter of debate. To this end, we aimed to evaluate the impact of antibiotic treatment on phenotype and functions of intestinal immune cell populations, including invariant natural killer T (iNKT) cells, a subset of lipid-specific T cells profoundly influenced by alterations on the commensal microbiota. To this aim, a cocktail of broad-spectrum antibiotics was administered for 2 weeks to otherwise healthy mice before re-colonization of the intestinal microbial community with oral gavage of eubiotic or dysbiotic mucosa-associated bacteria and luminal colonic content, followed or not by intestinal inflammation induction. Here. we showed that short-term antibiotic treatment alters frequency and functions of intestinal iNKT cells, even in the absence of intestinal inflammation. The presence of a dysbiotic microbiota after antibiotic treatment imprints colonic iNKT and CD4+ T cells toward a pro-inflammatory phenotype that collectively contributes to aggravate intestinal inflammation. Nonetheless, the inflammatory potential of the dysbiotic microbiota decreases over time opening the possibility to temporally intervene on the microbial composition to re-equilibrate dysbiosis, thus controlling concomitantly mucosal immune T cell activations.
Highlights
The gut mucosa is a complex environment, constantly exposed to a vast community of microorganisms, collectively defined as microbiota, which include bacteria, fungi, protozoa, and viruses (1)
Animal procedures were approved by the Italian Ministry of Health (Auth. 127/15, 27/13, 913/16)
What it is emerging is that antibiotic treatment can induce dysbiosis and, as we observed, this can promote activating pro-inflammatory immune cell responses in the colon
Summary
The gut mucosa is a complex environment, constantly exposed to a vast community of microorganisms, collectively defined as microbiota, which include bacteria, fungi, protozoa, and viruses (1). Intestinal microbiota establishes a mutualistic relationship with the host, providing metabolic functions and contributing to shape the immune system (2). Intestinal dysbiosis, defined as a perturbation to the structure of intestinal commensal communities (6), can be triggered by several factors, including a persistent change in dietary habits, gastrointestinal infections, and alcohol misuse (7). Antibiotic administration can lead to a profound perturbation of intestinal commensal communities, which persists after cessation of therapy, as a consequence of their broad-spectrum of action (8, 9). Clinical evidences support a correlation between antibiotic use and emergence or exacerbation of immune-mediated inflammation, as shown for atopic reactions (10), asthma (11), and inflammatory bowel diseases (IBD) (12). Several studies have consistently demonstrated that antibiotic use early in life predisposes to IBD emergence in Western populations (13)
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