Potential of Omega-3 Polyunsaturated Fatty Acids in Managing Chemotherapy- or Radiotherapy-Related Intestinal Microbial Dysbiosis

Abstract

Chemotherapy- or radiotherapy-related intestinal microbial dysbiosis is one of the main causes of intestinal mucositis. Cases of bacterial translocation into peripheral blood and subsequent sepsis occur as a result of dysfunction in the intestinal barrier. Evidence from recent studies depicts the characteristics of chemotherapy- or radiotherapy-related intestinal microbial dysbiosis, which creates an imbalance between beneficial and harmful bacteria in the gut. Decreases in beneficial bacteria can lead to a weakening of the resistance of the gut to harmful bacteria, resulting in robust activation of proinflammatory signaling pathways. For example, lipopolysaccharide (LPS)-producing bacteria activate the nuclear transcription factor-κB signaling pathway through binding with Toll-like receptor 4 on stressed epithelial cells, subsequently leading to secretion of proinflammatory cytokines. Nevertheless, various studies have found that the omega-3 (n-3) polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid and eicosapentaenoic acid can reverse intestinal microbial dysbiosis by increasing beneficial bacteria species, including Lactobacillus, Bifidobacterium, and butyrate-producing bacteria, such as Roseburia and Coprococcus. In addition, the n-3 PUFAs decrease the proportions of LPS-producing and mucolytic bacteria in the gut, and they can reduce inflammation as well as oxidative stress. Importantly, the n-3 PUFAs also exert anticancer effects in colorectal cancers. In this review, we summarize the characteristics of chemotherapy- or radiotherapy-related intestinal microbial dysbiosis and introduce the contributions of dysbiosis to the pathogenesis of intestinal mucositis. Next, we discuss how n-3 PUFAs could alleviate chemotherapy- or radiotherapy-related intestinal microbial dysbiosis. This review provides new insights into the clinical administration of n-3 PUFAs for the management of chemotherapy- or radiotherapy-related intestinal microbial dysbiosis.

FIGURE 1

LPS-TLR4 activates the NF-κB signaling pathway. During this process, MyD88 is recruited to TLR4. Then, IRAKs and TRAF6 are activated step by step. Herein, TRAF6 activates the TAK1 molecule, which is essential for subsequent activation of the IKK complex. The IKK complex can phosphorylate the IκB molecule, which ultimately undergoes ubiquitination and degradation. Then, the NF-κB, consisting of the subunits p50 and p65, will translocate into the nucleus to initiate the transcriptions of genes encoding IL-1β, IL-6, and TNF-α. IKK, inhibitor of κB kinase; IRAK, IL-1 receptor–associated kinase; I-κB, inhibitor of κB; MyD88, myeloid differentiation factor 88; NEMO, NF-κB essential modulator; P, phosphorylation; TAK1, TGF-β–activated kinase 1; TLR4, Toll-like receptor 4; TRAF6, TNF receptor–associated factor 6; Ub, ubiquitination; ↑, increase.

FIGURE 2

Inflammation provokes oxidative stress. Proinflammatory cytokines, such as IL-1β, IL-6, IL-17A, and TNF-α, can increase oxidative stress by recruiting neutrophils as well as inducing neutrophils to produce ROS. AT1 receptor, angiotensin II type 1 receptor; G-CSF, granulocyte colony-stimulating factor; MKK3/6, mitogen-activated protein kinase kinase 3/6; p38 MAPK, p38 mitogen-activated protein kinase; ROS, reactive oxygen species.

FIGURE 3

Chemotherapy- or radiotherapy-related intestinal microbial dysbiosis leads to dysfunction in the intestinal barrier. First, the intestinal barrier can be compromised by LPS-producing bacteria, leading to increased permeability. Second, the reduced proportion of butyrate-producing bacteria enables the mucus layer to be thinner than before. Third, gut concentrations of sIgA are decreased after chemotherapy or radiotherapy. sIgA, secretory IgA; ↑, increased; ↓, decreased.

FIGURE 4

n–3 PUFAs attenuate chemotherapy- or radiotherapy-related intestinal microbial dysbiosis. n–3 PUFAs revert chemotherapy- or radiotherapy-related dysbiosis and maintain the intestinal barrier. Intake of n–3 PUFAs restores the beneficial microbiota via increasing the proportions of beneficial bacteria and reducing the proportions of harmful bacteria. As a result, the mucus layer is consolidated, intestinal permeability is reduced, and the concentration of sIgA is restored. Reg 3γ, regenerating islet derived protein 3γ; sIgA, secretory IgA; ↑, increased; ↓, decreased.

FIGURE 5

n–3 PUFAs attenuate inflammation and oxidative stress. Herein, n–3 PUFAs directly interact with TLR4, IKK, and PPAR-γ to inhibit the activation of NF-κB. As a result, secretions of IL-1β, IL-6, and TNF-α by stressed cells are inhibited. In addition, n–3 PUFAs can induce Nrf2 to dissociate from Keap1 to initiate the expressions of antioxidative genes encoding SOD, HO-1, and NQO-1. HO-1, heme-oxygenase 1; IKK, inhibitor of κB kinase; I-κB, inhibitor of κB; Keap1, Kelch-like ECH–associated protein 1; NQO-1, NAD(P)H-quinone oxidoreductase 1; Nrf2, nuclear factor erythroid 2 p45-related factor 2; P, phosphorylation; SOD, superoxide dismutase; TLR4, Toll-like receptor 4; Ub, ubiquitination; ↑, increase; ↓, decrease.