Lymphatic network remodeling after small bowel resection

Abstract

Background: Short gut syndrome (SGS) following massive small bowel resection (SBR) is a major cause of pediatric mortality and morbidity secondary to nutritional deficiencies and the sequelae of chronic total parenteral nutrition use, including liver steatosis. Despite the importance of lymphatic vasculature in fat absorption, lymphatic response after SBR has not been studied. We hypothesize that lymphatic vessel integrity is compromised in SGS, potentially contributing to the development of impaired lipid transport leading to liver steatosis and metabolic disease.Methods: Mice underwent 50% proximal SBR or sham operations. Imaging of lymphatic vasculature in the lamina propria and mesentery was compared between sham and SBR Prox1 ERCre-Rosa26 LSL TdTomato mice. mRNA expression levels of lymphangiogenic markers were performed in C57BL/6J mice.Results: Lymphatic vasculature was significantly altered after SBR. Mesenteric lymphatic collecting vessels developed new branching structures and lacked normal valves at branch points, while total mucosal lymphatic capillary area in the distal ileum decreased compared to both sham and intraoperative controls. Intestinal Vegfr3 expression also increased significantly in resected mice. Conclusions:Intestinal lymphatics, in both the lamina propria and mesentery, dramatically remodel following SBR. This remodeling may affect lymphatic flow and function, potentially contributing to morbidities and nutritional deficiencies associated with SGS.

The asymmetric Pitx2 gene regulates gut muscular-lacteal development and protects against fatty liver disease

“…In contrast, non-fatty nutrients and shorter-chain fatty acids are able to directly enter the hepatic portal circulation for processing within the liver ( Zhou et al, 2020 ). This lymphatic system-independent portal transport is insignificant compared with the lymphatic route, except under pathological conditions leading to hepatic lipid accumulation ( Anwar et al, 2007 ; Cabré et al, 2005 ; Courtney and Warner, 2017 ; Ee et al, 2000 ; Fujimoto et al, 1991 ; Hussain, 2014 ; Kurtel et al, 1991 ; McDonald et al, 1980 ; Onufer et al, 2019 ; Young et al, 1995 ). To assess whether ASE deletion impaired dietary lipid transport, we orally administered fluorescent BODIPY C16, a fluorescent long-chain fatty acid tracer, to WT and Pitx2 ASE/ASE neonates to follow lipid trafficking ( Figure 6A ; Dixon et al, 2009 ).…”

“…The portal lipid transport is insignificant compared with the lymphatic pathway but increases during disease where lymphatic clearance is impaired ( Cabré et al, 2005 ; Courtney and Warner, 2017 ; Fujimoto et al, 1991 ; Kurtel et al, 1991 ; Onufer et al, 2019 ). Lymphatic transport distributes dietary lipids to peripheral tissues for direct energy consumption, whereas the lymphatic system-independent portal route delivers lipids to the liver and reduces accessibility to peripheral tissues.…”

Lipid absorption and overall intestinal lymphatic transport are impaired following partial small bowel resection in mice

“…In addition to the alterations observed in the distal lymphatic network, we examined the effect of resection on the mesenteric lymphatic vessels. At postoperative week 13, collecting lymphatic vessels present in the mesentery and emerging from the intestinal wall distal to the anastomosis still showed the substantially altered morphology following 50% SBR versus sham control mice (Figure 6A) that we had earlier observed at day 7 (15). The resected mice had an average 31% increase in mesenteric branch width compared to sham controls (Figure 6B; p<0.05).…”

“…As described previously, intestinal tissue from 50% SBR and sham control mice 1cm distal to their anastomosis was harvested 12 weeks post-operatively, xed in 10% formalin and embedded in para n similar to the IO samples taken from the distal bowel resected in the 50% SBR mice at operation (15). Additionally, proximal gut was obtained from both sham and 50% SBR mice 15 weeks after operation at approximately 5cm from the gastro-duodenal junction.…”

The Interplay between Nutrition, Innate Immunity, and the Commensal Microbiota in Adaptive Intestinal Morphogenesis

“…Interestingly, small bowel resection evokes intestinal adaptation, comprising the lengthening of villus structures, crypt deepening, and an increase in the density of villus capillaries [ 218 , 226 ]. In contrast, the mucosal lymphatic area is reduced following small bowel resection [ 227 ]. In conclusion, Western diet is a strong factor initating or exacerbating vascular dysfunction but still molecular mechanism of nutrition-dependent vascular adaptation in the gastrointestinal tract awaits further investigation.…”