Antibiotic-Induced Changes in the Intestinal Microbiota and Disease

Abstract

The gut microbiota is a key player in many physiological and pathological processes occurring in humans. Recent investigations suggest that the efficacy of some clinical approaches depends on the action of commensal bacteria. Antibiotics are invaluable weapons to fight infectious diseases. However, by altering the composition and functions of the microbiota, they can also produce long-lasting deleterious effects for the host. The emergence of multidrug-resistant pathogens raises concerns about the common, and at times inappropriate, use of antimicrobial agents. Here we review the most recently discovered connections between host pathophysiology, microbiota, and antibiotics highlighting technological platforms, mechanistic insights, and clinical strategies to enhance resistance to diseases by preserving the beneficial functions of the microbiota.

Keywords: antibiotic resistance; antibiotics; disease; gut microbiota; immunity.

Figure 1. Roles of the Microbiota in the Development and Maintenance of the Intestinal Immune System

The gut microbiota is separated from the intestinal epithelium by a thin layer of mucus, secreted by Goblet cells in a microbiota- and NLRP6-dependent manner. The mucus layer has a different structure in small and large intestine (not depicted in the figure). Microbial-associated molecular patterns (MAMPS) can be sensed by IECs as well as by myeloid cells in the lamina propria and induce a variety of effects, including tissue repair, and production of antimicrobial peptides such as RegIIIγ in intestinal epithelial and Paneth cells through a DC-ILC axis. Luminal ATP and SAA/IL1β produced by IECs and DCs in response to adhesion of segmented filamentous bacteria (SFB) promote Th17 development. Antigens presented during this process are largely derived from SFB. Treg induction is also regulated by bacterial cues. Clostridia of the IV and XIVa groups induce Tregs in a TGFβ-dependent manner. Short chain fatty acids (SCFA) promote Treg differentiation by acting directly on T cells and indirectly on DCs. Macrophages in the lamina propria are involved in a pathway that includes also ILCs (not shown) resulting in production of IL-10 and Retinoic Acid (RA), and also sustaining expansion of Tregs. All pathways illustrated in the figure were shown to be affected by the use of antibiotics, leading to a lack of homeostasis, an increased sensitivity to infection and an increase in the severity of various conditions, as in the case of allergy.

Figure 2. Antibiotic-Mediated Microbiota Depletion Causes Disease in Multiple Organs

Antibiotics act on the gut microbiota by decreasing its density and modifying its composition in a long-lasting fashion. This causes reduced signaling to the intestinal mucosa and peripheral organs, which results in impaired functioning of the immune system. Depicted are examples of diseases that were shown to arise or be worsened as a consequence of antibiotic treatment in mouse models (see main text).

Figure 3. Generation and Spread of Antibiotic Resistance

Left panel: antibiotic resistance is generated by mutations that can be induced by several driving forces. From the top: competition of bacteria (inter- or intra- species, here depicted as intersections between circles representing population niches) mainly mediated by bacteriocins, induces a selective pressure that favors development of resistance. Some TLRs or host-derived antimicrobial peptides (AMPs) target bacterial molecules that can undergo mutations and provide resistance to clinically-relevant antibiotics. Exogenous antibiotic pressure through medical or industrial practices (e.g.. antibiotic use in livestock) promotes the generation and selection of resistant strains that can rapidly diffuse. Right panel: antibiotic resistance genes can be exchanged among bacteria also of different species (not shown) through horizontal gene transfer, i.e. conjugation, transduction or transformation. Notably, these three mechanisms are all enhanced upon antibiotic exposure, resulting in a faster and more efficient spread of ARGs in the gut as well as in the environment.

Figure 4. Novel Approaches to Substitute or Complement Antibiotic Therapies

Antibiotic treatment depletes commensal communities in the gut, decreases mucus layer thickness and expression of AMPs, and predisposes to infection (upper panel). Transfer of microbiota by fecal transplantation can restore a healthy microbiota, mucus production, antimicrobial peptide secretion, and provide colonization resistance against pathogens, that can no longer expand or are cleared. Transfer of selected bacterial communities, as shown in mouse models, can achieve the same effect. Similarly, administration of microbial ligands, here depicted as fragments of bacteria, can restore basal production of mucus and antimicrobial peptides following antibiotic treatment. Lower panel: strategies to selectively deplete pathogens without perturbing the microbiota. All the approaches illustrated have proven to be successful in mouse models, providing high levels of protection and leaving the composition of the surrounding communities, unaltered. Consequently, colonization resistance mechanisms can be potentially preserved.