NOVEL DREAM (DISTAL RECIRCULATION OF ENTERAL CONTENTS AUGMENTED MECHANICALLY) MITIGATES PARENTRAL NUTRITION ASSOCIATED LIVER AND GUT INJURY

Background: Short bowel syndrome (SBS) is a devastating condition typically occurring because of significant reduction in intestinal length preventing tolerance and absorption of needed nutrients through gastrointestinal tract. In absence of enteral nutrition (EN), patients are dependent on Total Parenteral Nutrition (TPN) but suffer severe morbidity in the form of intestinal failure associated liver disease and gut atrophy. Intestinal adaptation (IA) and enteral autonomy (EA) remains the clinical goal. We hypothesized that EA can be achieved despite SBS with our novel DREAM (Distal Recirculation of Enteral contents Augmented Mechanically) system, (U.S. patent serial No. 63 / 413,988) which allows EN via the stomach and then a mechanism for cyclical recirculation of nutrient rich distal intestinal content into proximal bowel enabling full EN despite SBS.

Methods: 24 neonatal pigs were randomly allocated to enteral nutrition (EN; n=8); TPN-SBS (on TPN only, n=8); or DREAM that were transitioned to EN by day 3 (n=8). Liver, gut, and serum were collected for histology, and serum biochemistry. Pairwise t-tests were used for normally distributed data, otherwise Mann-Whitney U test were conducted. All tests were 2-tailed using a significance level of 0.05.

Results: TPN-SBS piglets had significant cholestasis vs DREAM (p=0.001) with no statistical difference between DREAM and EN (p=0.14). The mean serum conjugated bilirubin for EN was 0.037 mg/dL, TPN-SBS 1.2 mg/dL, and DREAM 0.05 mg/dL. Serum bile acids were significantly elevated in TPN-SBS animals vs EN (p=0.007) and DREAM (p=0.03). The mean serum bile acids were EN 9.1 mg/dL, TPN-SBS 33.42 mg/dL, and DREAM 8.4 mg/dL. The mean GGT, a marker of cholangiocytic injury was significantly higher in TPN-SBS vs EN (p<0.001) and DREAM (p<0.001) with values of EN 21.2 U/L, TPN-SBS 47.9 U/L, and DREAM 22.5 U/L. p=0.89 DREAM vs EN. To evaluate gut growth, we measured the lineal gut mass (LGM), calculated as the weight of the bowel per centimeter. There was significant preservation in gut atrophy with DREAM. The mean proximal gut LGM was EN 0.21 g/cm, TPN-SBS 0.11 g/cm, and DREAM 0.31 g/cm (p=0.004, TPN-SBS vs DREAM). Distal gut LGM was for EN 0.34 g/cm, TPN-SBS 0.13 g/cm, and DREAM 0.43 g/cm (p=0.006, TPN-SBS vs DREAM). On IHC, DREAM has similar hepatic CK-7 (marker for bile duct epithelium), p=0.18 and hepatic Cyp7A1, p=0.3 vs EN. No statistical differences were noted in LGR5 positive intestinal stem cells between EN and DREAM, p=0.18.

Conclusion: DREAM resulted in a significant reduction in cholestatic injury markers and prevented gut atrophy. DREAM presents a novel method which enables early full EN despite SBS. This methodology highlights a major advancement in the management of SBS bringing a paradigm change in life saving therapeutic strategies for patients by driving intestinal adaptation and EN autonomy.