The Intestinal Microbiota: Impacts of Antibiotics Therapy, Colonization Resistance, and Diseases

Abstract

Trillions of microbes exist in the human body, particularly the gastrointestinal tract, coevolved with the host in a mutually beneficial relationship. The main role of the intestinal microbiome is the fermentation of non-digestible substrates and increased growth of beneficial microbes that produce key antimicrobial metabolites such as short-chain fatty acids, etc., to inhibit the growth of pathogenic microbes besides other functions. Intestinal microbiota can prevent pathogen colonization through the mechanism of colonization resistance. A wide range of resistomes are present in both beneficial and pathogenic microbes. Giving antibiotic exposure to the intestinal microbiome (both beneficial and hostile) can trigger a resistome response, affecting colonization resistance. The following review provides a mechanistic overview of the intestinal microbiome and the impacts of antibiotic therapy on pathogen colonization and diseases. Further, we also discuss the epidemiology of immunocompromised patients who are at high risk for nosocomial infections, colonization and decolonization of multi-drug resistant organisms in the intestine, and the direct and indirect mechanisms that govern colonization resistance to the pathogens.

Keywords: antibiotics; colonization resistance; diseases; intestinal microbiota; pathogens.

Figure 1

Under homeostatic conditions (left green), certain Gram-negative commensal bacteria induce IgA and IgG antibody production from B cells, recognizing Gram-negative bacteria surface antigens (flagellin, LPS) in the intestinal lumen, thus contributing to host defense against symbionts and pathogens. Symbiotic organisms stimulate mucus production to prevent enteric pathogens from colonizing the intestinal mucosa. However, during dysbiosis (right red), a decrease or loss of commensal bacteria in the intestine may result in opportunistic pathogens (e.g., C. difficile) infection due to the secretion of virulence factors (toxins) that damage and breach the epithelial layer, causing inflammation.

Figure 2

The intestinal microbiota acts as a barrier against enteric pathogens via direct and indirect colonization resistance mechanisms. Direct colonization resistance mechanisms (a): Several commensal Bacteroidetes prevent pathogens from colonizing the intestinal mucosa, and the commensal E. coli Nissle strain consumes nutrients, limiting nutrients availability to specific pathogens (pink color with flagella). The probiotic E. coli Nissle strain can also absorb iron, limiting its availability to the pathogen S. Typhimurium. Commensal bacteria secrete antimicrobial peptides, such as bacteriocins (colicin), SCFAs, and T6SS, to target and kill invading pathogens. Together with antimicrobial peptides, commensal bacteria produce enzymes that convert conjugated primary bile acids to secondary bile acids (toxic to invading pathogens). Indirect colonization resistance mechanisms (b): Surface antigens such as flagellin or LPS from commensals bacteria stimulate host innate immunity via TLRs and MyD88 on epithelial or dendritic cells (DCs). ILC3, γδT, and Th17 cells can be activated to produce interleukin IL-10, IL-17, and IL-22, which promotes secretion of the antimicrobial peptides Reg3γ, Reg3β, Reg3α, α-defensin, and β-defensin from epithelial cells to inhibit pathogen colonization in the intestines (pink color with flagella).