Probiotics, Prebiotics, Synbiotics, and Paraprobiotics as a Therapeutic Alternative for Intestinal Mucositis

Abstract

Intestinal mucositis, a cytotoxic side effect of the antineoplastic drug 5-fluorouracil (5-FU), is characterized by ulceration, inflammation, diarrhea, and intense abdominal pain, making it an important issue for clinical medicine. Given the seriousness of the problem, therapeutic alternatives have been sought as a means to ameliorate, prevent, and treat this condition. Among the alternatives available to address this side effect of treatment with 5-FU, the most promising has been the use of probiotics, prebiotics, synbiotics, and paraprobiotics. This review addresses the administration of these "biotics" as a therapeutic alternative for intestinal mucositis caused by 5-FU. It describes the effects and benefits related to their use as well as their potential for patient care.

Keywords: chemotherapy; intestinal inflammation; lactic acid bacteria; mucosite; treatment.

FIGURE 1

Chemical structure of 5-fluorouracil (5-FU) and its analogs uracil and thymine. All three structures differ in the radical present at the structure’s fifth position.

FIGURE 2

5-FU’s metabolites and their molecular targets. 5-FU is intracellularly metabolized into fluorodeoxyuridine monophosphate (FdUMP), which binds to the enzyme thymidylate synthetase, resulting in decreased production of dTTP and dATP and blocking cell repair; or into fluorodeoxyuridine triphosphate (FdUTP) and binds to the DNA, inhibiting duplication and transcription; or into 5-fluorouridine triphosphate (FUTP) and binds to RNA, leading to a loss of function. All three metabolites cause damage to the cell on a genomic level, culminating in cell death.

FIGURE 3

The five phases of 5-FU-induced intestinal mucositis: The initiation phase occurs when the intestinal mucosa is first exposed to the toxicity of 5-FU, promoting DNA damage and inducing the production of reactive oxygen species (ROS). Consequently, this activates several signaling transduction pathways (response to primary damage) such as the NF-êB pathway, related to the induction of several inflammatory mediators [interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 enzyme (COX-2), IL-6, and IL-1β)] that play an important role in mucosal toxicity, causing signal amplification via a positive feedback mechanism, activating pathways that increase cytokine production as well as oxidative stress, exacerbating the lesion, progressively destroying the mucosa leading to an ulceration phase. Finally, spontaneous ulcer healing, characterized by cell proliferation and differentiation on average 3–4 days after the end of chemotherapy treatment, leads to mucosal restoration.

FIGURE 4

Probiotic mechanisms of action. Probiotics, after they reach the intestines, promote beneficial effects to the host by various mechanisms. These include mucin production, production of bacteriocins, acids, and short-chain fatty acids (SCFA), which are responsible for the inhibition of pathogens, inhibition of bacterial translocation, and inhibition of pathogens due to competition for receptors and nutrients. There is also stimulation of dendritic cells, which in turn induce the differentiation of T cells into Th1, Th2, and Treg, the latter being responsible for maturation of plasma cells, and thus immunoglobulin A (IgA) production and secretion; stimulation of beta-defensin production; inhibition of signaling pathways, such as nuclear factor κB (NF-kB), MAPK, and STAT, promoting proliferation and survival of the cells; changes in cytokine production profile, enhancing the production of anti-inflammatory cytokines and inhibiting proinflammatory factors; and interaction via the enteric nervous system with the central nervous system, promoting changes in intestinal mobility and pain perception.

FIGURE 5

The mechanisms of action of prebiotics, synbiotics, and paraprobiotics. Prebiotics (A) act as nourishment for beneficial bacteria in the commensal microbiota, inducing the production of mucins, SCFAs, and bacteriocins, the latter two causing pathogen inhibition. Another mechanism by which prebiotics can inhibit pathogens is by interaction with an adhesion receptor, such as the lectin receptor, demonstrating an antiadhesive action. Sub-units of prebiotics and SCFAs can be used by the host cells for energy production and promote directly or indirectly, via dendritic cells, immunomodulation of lymphocytes, stimulating production of IgA and anti-inflammatory cytokines. Synbiotics (B) have mechanisms of action of both probiotics (Figure 4) and prebiotics (A). Moreover, synbiotics have the advantage of generating a synergic effect, which promotes balance in the gut microbiota, increased immunomodulation, reduced bacterial translocation, and reduction of infections due to strong competition by probiotics against pathogens. The mechanism of action of paraprobiotics (C) is still not fully understood, though immunomodulation of T cells by dendritic cells has been reported, stimulating their differentiation into Th1 cells, promoting the production of anti-inflammatory cytokines. Another proposed mechanism is inhibition of signaling pathways related to LPS stimulation, resulting in a reduction of proinflammatory mediators, especially IL-8.