The leading cause of death from burn injury is uncontrolled infection and consequent organ failure. Infections after burn and other traumatic injuries stem from pathogenic bacteria via the gastrointestinal tract. Burn injury resulted in severe intestinal epithelial barrier dysfunction by increasing the translocation of bacterial or their products [1], [2], accelerating the apoptosis of intraepithelial lymphocytes (IELs) located between the intestinal epithelial cells (IECs) and lymphocytes in Peyer's patch, and changing the gastrointestinal microbial composition [3]. Therefore, control of bacterial interactions with the intestinal mucosal surface is critical for host defense that relies on IELs and the antibodies-producing mucosal plasma cells in the lamina propria.

Increased interest in prebiotics as a means to modulate gut microbiota has accumulated rapidly. Prebiotic is a non-digestible food ingredient belonging to a family of covalently linked galacturonic acid-rich polymers. It could be fermented by the intestinal microbiota to selectively stimulate the growth or activity of the beneficial bacteria [4], [5]. Although clinical trial indicated that the intake of oligofructose could not accelerate the normalization of gastrointestinal permeability in burn injury, addition of dietary fiber, chitosan and possibly lignin, may reduce bacterial translocation in mice [6]. Positive findings were also demonstrated in burn patients that pectin therapy could accelerate burn wounds healing, lower microbial dissemination, improve dysbacteriosis, as well as normalize the blood immune parameters [7]. Modified citrus pectin has immunomodulatory potential in mice [8] and immunostimulatory properties in humans [9], and could attenuate endotoxin shock via suppression of Toll-like receptor signaling in myeloid cells in Peyer’s patch of mice [10]. A distinct structural region of pectin, rhamnogalacturonan-I (RG-I) [11], is increasingly gaining attention because of its variety of bioactivities, e.g., reducing cancer progression and metastasis [12], preventing blood–brain barrier disruption [13], as well as with immunomodulating [8], [10] and prebiotic activities [14], [15]. Recently, a water-soluble RG-I-enriched citrus pectins (WRPs) were recovered from citrus canning processing basic water [16], [17] by either ascorbic acid technology or followed by alkaline treatment, resulting in an acidic or a neutral suspension with different RG-I content and molecular weight [18], [19]. WRPs could positively modulate gut microbiota by elevating the short-chain fatty acids (SCFA) content in the colon [18], [20] so as to prevent obesity in high-fat diet mice [18].

The gut microbiota interacts not only with the intestinal immune system but also with the neuroendocrine system. Intestinal microbiota would affect the incretin hormone glucagon-like peptide (GLP)-1 secretion from intestinal L-cell by generating a range of active products and metabolites including SCFA and endotoxin. SCFA was also found to trigger the secretion of GLP-1 from mixed colonic cultures in vitro [21]. In diabetic patients, dietary fibers could promote a selective group of SCFA-producing strains in gut along with higher plasma GLP-1 level in a meal tolerance test [22]. On the contrary, reduced SCFAs in a diet with high-fat, sugar, and sodium would potentially lower GLP-1 level [23]. Moreover, gut microbiota itself may influence GLP-1 availability indirectly through modulating IELs function which limits GLP-1 bioavailability via GLP-1R expressed on IELs [24]. L-cell-derived GLP-1 may play a role in ameliorating burn-induced insulin resistance through stimulating nutrient-induced insulin release and reducing glucagon secretion [25]. Thus, admission elevated GLP-1 level could discriminate hospital-acquired-infection free survival in burn patients [26]. Since WRPs could positively modulate gut microbiota, it in turn may modulate GLP-1 secretion as well.

The intestinal mucosa is in a state of hypoxia even in physiologic state [27], which is more severe and extensive in a pathophysiologic state that associated with acute inflammatory diseases, e.g. burn injury. The hypoxia-inducible factor (HIF), a transcriptional regulator of anti- inflammatory or cellular responding to hypoxia [28], was recently shown to drive a protective effect on epithelial barrier function during inflammation [29]. Moreover, HIF-1α has been shown to affect the differentiation and function of different T cell subsets in both hypoxic and normoxic conditions [30]. IL-22 production induced by SCFAs from intestinal CD4 + T cell and innate lymphoid cells was also mediated by HIF-1α [31]. Whether the citrus pectin could modulate intestinal HIF-1α production in burn injury remains unclear.

So far, the impact of RG-I-enriched pectin on burn-induced intestinal epithelial barrier dysfunction has never been explored yet. We propose that WRPs could normalize intestinal homeostasis via GLP-1R-HIF-1α pathway by positively modulating the gut microbiota, the intestinal GLP-1 availability, and the adaptive immune response following burn injury.