Vitamin D and lactoferrin attenuate stress‐induced colitis in Wistar rats via enhancing AMPK expression with inhibiting mTOR–STAT3 signaling and modulating autophagy

Abstract

Irritable bowel syndrome (IBS) is a global gastrointestinal disorder closely related to psychological stress exposure and local colonic inflammation. Herein, we investigated the effect of wrap‐restraint stress (WRS) on rat behavior, on adenosine monophosphate‐activated protein kinase–mammalian/mechanistic target of rapamycin–signal transducer and activator of transcription 3 (AMPK–mTOR–STAT3) signaling, and autophagy in colonic mucosa. The impact of chronic administration of vitamin D3 and lactoferrin was compared. Twenty‐four male Wistar rats were randomly divided into four groups. Chronic WRS protocol was applied as a rodent model of IBS. Group I: naïve animals, Group II: WRS animals, Group III: WRS‐exposed and treated with vitamin D3 (500 IU/kg/day), and Group IV: WRS‐exposed and treated with lactoferrin (300 mg/kg/day). In this study, we found that chronic administration of each of vitamin D3 and lactoferrin resulted in a significant increase in social interaction test, interleukin‐10, AMPK, optical density of LC3B, goblet cell count and marked decrease in serum cortisol level, STAT3, inflammatory cell count, and optical density of mTOR in comparison to the WRS rats. Our findings suggest that both vitamin D3 and Lactoferrin could augment colonic autophagy through enhanced AMPK expression and inhibition of mTOR–STAT3 signaling, which offers practical insights into their clinical use in the prevention and therapy of IBS. However, lactoferrin intake as a nutritional supplement could be more helpful for stress‐induced colitis treatment than vitamin D3.

Morphological and biochemical characteristics associated with autophagy in gastrointestinal diseases

“…In recent years, more and more animal experiments have revealed the presence of a large number of autophagic vesicles accompanied by mitochondrial vacuolization in DSS-induced colitis. In Wistar rats, vitamin D has been shown to alleviate stress colitis through mTOR-STAT3 signaling and regulation of autophagy[ 34 ]. Similarly, we found that activation of estrogen receptor β, which is highly expressed in intestinal tissues, can inhibit colitis by promoting NLRP6-mediated autophagy[ 35 ].…”

Vitamin D is a potential treatment for the management of gastrointestinal mucositis

“…Reportedly, a dose of 500 IU/kg of vitamin D for 14 days in rats alleviated stress-induced colitis 41 . AMPK and STAT3 play a role in the immune system, with AMPK responsible for shifting macrophages to the anti-inflammatory M2 phenotype and STAT3 activating AMPK via IL-10 regulation 41 . mTOR is a serine/threonine kinase that regulates cell proliferation, apoptosis and autophagy through multiple pathways 42 .…”

“…mTOR is a serine/threonine kinase that regulates cell proliferation, apoptosis and autophagy through multiple pathways 42 . AMPK is thought to alleviate colitis by repairing the colonic intestinal barrier and its tight junction proteins once induced by IL-10 41 . The vitamin D-treated groups demonstrated a significant increase in the serum levels of AMPK and IL-10 and a decrease in STAT3.…”

“…The exact mechanisms and pathways through which vitamin D exerts its therapeutic effects are yet to be fully understood. Abdelmalak et al [41] suggest that vitamin D exerts its anti-inflammatory effect via the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/ signal transducer and activator of transcription (STAT)3 pathway. Reportedly, a dose of 500 IU/kg of vitamin D for 14 days in rats alleviated stressinduced colitis [41].…”

“…Abdelmalak et al [41] suggest that vitamin D exerts its anti-inflammatory effect via the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/ signal transducer and activator of transcription (STAT)3 pathway. Reportedly, a dose of 500 IU/kg of vitamin D for 14 days in rats alleviated stressinduced colitis [41]. AMPK and STAT3 play a role in the immune system, with AMPK responsible for shifting macrophages to the anti-inflammatory M2 phenotype and STAT3 activating AMPK via IL-10 regulation [41].…”