Attenuation of Doxorubicin‐Induced Small Intestinal Mucositis by Pectins is Dependent on Pectin's Methyl‐Ester Number and Distribution

Abstract

Scope Intestinal mucositis is a common side effect of the chemotherapeutic agent doxorubicin, which is characterized by severe Toll‐like receptor (TLR) 2‐mediated inflammation. The dietary fiber pectin is shown to prevent this intestinal inflammation through direct inhibition of TLR2 in a microbiota‐independent manner. Recent in vitro studies show that inhibition of TLR2 is determined by the number and distribution of methyl‐esters of pectins. Therefore, it is hypothesized that the degree of methyl‐esterification (DM) and the degree of blockiness (DB) of pectins determine attenuating efficacy on doxorubicin‐induced intestinal mucositis. Methods and Results Four structurally different pectins that differed in DM and DB are tested on inhibitory effects on murine TLR2 in vitro, and on doxorubicin‐induced intestinal mucositis in mice. These data demonstrate that low DM pectins or intermediate DM pectins with high DB have the strongest inhibitory impact on murine TLR2‐1 and the strongest attenuating effect on TLR2‐induced apoptosis and peritonitis. Intermediate DM pectin with a low DB is, however, also effective in preventing the induction of doxorubicin‐induced intestinal damage. Conclusion These pectin structures with stronger TLR2‐inhibiting properties may prevent the development of doxorubicin‐induced intestinal damage in patients undergoing chemotherapeutic treatment with doxorubicin.

Chemotherapeutics Combined with Luminal Irritants: Effects on Small-Intestinal Mannitol Permeability and Villus Length in Rats

“…For instance, IRI and 5-FU generate a strong increase in the proinflammatory cytokines TNFα and IL-1β [31,32]. In contrast, DOX has no effect on TNFα but increases IL-6 sharply [33]. Following 5-FU dosing in mice, a possible relationship is also seen between an increased intestinal permeability of 99mTc-DTPA (MW: 487 Da) and increased expression of TNFα and IL-6 [34].…”

Nonpharmacological approaches for improving gut resilience to chemotherapy

“…It is well known that a diet high in fiber is beneficial to gut health. Recently, fiber-rich diets, particularly soluble fibers like pectins, have been investigated for their ability to improve gut resilience with chemotherapy [49,50 ▪▪ ]. A preclinical study by Gallotti et al [50 ▪▪ ], reported that a high-fiber diet decreased immune cell influx, improved intestinal morphology, and decreased intestinal permeability following treatment with irinotecan.…”

Effects of pectins on colorectal cancer: targeting hallmarks as a support for future clinical trials

“…78 While only pectins with a high DM (DM74) activated TLR2 in a dose-dependent manner, TLR4 was responsive to pectins with different DM, even at low doses. 76,78,79 In contrast, the inhibition of the dimer TLR2-TLR1 was more pronounced for pectins with a low DM (DM7). 78 Pectins from ripe and unripe papayas activated TLR2 and TLR4.…”