Safety and efficacy of a side-to-side duodeno-ileal anastomosis for weight loss and type-2 diabetes: duodenal bipartition, a novel metabolic surgery procedure
© Gagner. 2015
Received: 28 May 2015
Accepted: 6 October 2015
Published: 14 October 2015
Partial bypass of the GI tract may promote weight loss by decreased absorption of nutrients and changes in incretins. The aim of the study was to evaluate the safety and efficacy of performing a side-to-side duodeno-ileal anastomosis.
Seven 40–50 kg female Yorkshire pigs were allocated to a duodeno-ileal anastomosis (DIA), and were compared to a control group (SHAM). Swine’s weights were followed for 56 days. Gastroscopies were also performed at 28 days. Blood samples were also taken at regular intervals (CBC and Basic biochemistry profiles). At autopsy, gross changes and histological changes of the liver, duodenum and ileum samples were performed.
While the SHAM group gained 33.2 % more weight at 56 days, the DIA group had shown a weight loss of −6.8 %, for a difference of 40.0 % between the 2 groups (p < 0.05). One pig developed an incisional hernia. Gastroscopies demonstrated normal healing without ulceration or inflammation at 28 days. Histological examination of the anastomosis at 56 days showed normal and smooth healing, with absence of liver toxicity.
In this porcine model with short follow-up, a side-to-side duodeno-ileal anastomosis provided excellent weight loss without apparent nutritional or grossly aberrant histological changes.
KeywordsDuodeno-ileal anastomosis Duodeno-jejunal bypass Bariatric surgery New technology Weight loss surgery Obesity treatment Anastomotic device Duodenal bipartition
In the purest form of malabsorptive surgery for weight loss, the jejunoileal bypass (JIB), one of the earliest types of bariatric surgery, was introduced with its many variations, four and five decades ago. The JIB was performed end-to-side, with the proximal thirty centimeters jejunum anastomosed to the distal 15 cm of ileum, or end-to-end, with bypassed small bowel derived end-to-side to the colon. In both instances more than 90 % of small intestine was bypassed, unexcised, excluding it from the alimentary channel leaving a blind end, causing bacterial overgrowth.
Excellent weight loss and complete resolution of type-2 diabetes mellitus were reported after JIB [1, 2]. However, a variety of complications related to JIB were reported, including: hypoalbuminemia, hypokalemia, hypocalcemia, hyperbilirubinemia, migratory polyarthralgias, calcium oxalate urinary calculi, and elevated liver enzymes levels and deaths due to liver failure [3, 4]. Diarrhea and flatulence were common. The excluded intestinal segment was associated with various problems, including intussusceptions; bypass enteritis, and colonic pseudo-obstruction. Other authors reported that the risk of progressive liver disease existed indefinitely and that ongoing careful follow-up was necessary [5, 6].
Compression anastomotic devices for the performance of gastrointestinal anastomosis have been available for more than a century and used extensively in colon surgery in its resorbable form, and more recently simulating a commercial end-to-end anastomotic device [8–10].
The aim of the study was to evaluate the safety and efficacy of using a compression anastomotic device to create a permanent anastomosis between the small bowel and duodenum. Also, to evaluate the effect of a side-to-side duodeno-ileal anastomosis on weight loss, in the short term.
The animal protocol was approved by the institutional Animal care and use Committee (IACUC) of American Preclinical Services, LLC (APS) facility licensed with the United States Department of Agriculture. We used 7 Yorkshire pigs, >2 months old, weighing approximately 40–60 kg, housed individually. The porcine diet consisted of a fixed formula certified by the manufacturer to be free of environmental contaminants; tap water was given ad libitum.
Blood samples were taken for minimal hematology parameters (red blood cell count, hemoglobin, hematocrit, platelet count, white blood cell count and differential), minimal serum biochemistry parameters (Urea nitrogen (BUN), creatinin, total protein, albumin, aspartate aminotransferase (AST), gamma glutamyltransferase (GGT), glucose, sodium, potassium, chloride, calcium, phosphorus, bicarbonate). Prior to surgery, animals have been administered a 3 days bowel prep with 2 l/day of Golitely (PEG-3350, Braintree Laboratories, Inc., Braintree, MA, USA) and Ensure (Abbott Nutrition, Columbus, OH, USA) to cleanse the colon, and were fasted the night before except for water. Preoperative medication included; Telazol 2–8 mg/kg for anesthesia induction (Tiletamine HCl and Zolazepram HCl, Animal Healthcare, Wyeth (now Pfizer, Inc.), Fort Dodge, IA), Xylazine 2–8 mg/kg (Bayer Healthcare, Leverkusen, Germany) for anesthesia induction, Buprenorphine 0.01–0.05 mg/kg for pain management (Buprenex, Reckitt & Colman Pharmaceuticals, Inc., Richmond, VA, USA), and Oxytetracycline (long acting) 20 mg/kg (Hebei New Century Pharmaceutical Co., Ltd., Hebei, China)for infection prophylaxis.
Four animals were allocated to a side-to-side duodeno-ileostomy with the compression anastomotic device and 3 to a control group. After endotracheal intubation, anesthesia was maintained with isoflurane in 100 % O2 and propofol at 2–8 mg/kg, with an intravenous Ringers’ lactate solution at 2–10 ml/kg/h. After laparotomy with a 25 cm upper midline incision, a duodenotomy of approximately 2.5 cm was created anterior to admit the proximal part of the compression anastomotic device, and an ileotomy approximately 50 cm from the ileocecal valve was made to insert the distal part compression anastomotic device. The anastomosis was performed by compression of both parts away from the duodenotomy and ileotomy (Fig. 2). Both openings of the small bowel were closed with a running suture of 3-0 Vicryl (Polyglactin-910, Ethicon, Cincinnati, OH). The control group had both enterotomies closed with a running suture only. A liver biopsy was also performed by a wedge. The abdominal wound is closed with Vicryl 1-0 for fascia and 3-0 for skin.
During recovery in the pen and postoperative period, the animals received Buprenorphine 0.01–0.05 mg/kg IM as needed, ketoprofen 1.8–2.2 mg/kg IM daily for the first 3 days (Ketofen, Fort Dodge Animal Health, Fort Dodge, IA, USA), Prilosec 20 mg once daily (Omeprazole, AstraZeneca, Wilmington, DE, USA), and Oxytetracycline (long acting) 18–25 mg/kg IM on day 3. During the first 24 h, the animals were allowed to drink water, and afterwards soft food was introduced to gradually progress to a normal solid diet over 10 days. Elimination of the device was recorded, including signs of infection. Blood samples were taken at day 0, 3 and 56.
On Day 28, a gastroscopy (Olympus, GIF-2T20, 11.2 mm diameter) was performed under general anesthesia, using a similar protocol, and photographs were obtained of the anastomosis, and nearby intraluminal organs, to assess patency, diameter, and degree of inflammation and presence of macroscopic abnormalities. An attempt was made to measure the intestinal shunting from the procedure by introducing approximately 25 radiopaque doughnut-type markers (Sitzmark, Konsyl Pharmaceutis, Inc., TX, USA) in the proximal stomach for a gastrointestinal transit study, by taking abdominal x-rays every 2 h for 6 h.
At 8 weeks, euthanasia and necropsy of the abdominal cavity is performed. Samples of the liver were taken at the time of the anastomotic procedure (pre-sample) and at necropsy (left medial liver lobe, post-sample) and immersion-fixed in 10 % neutral buffered formalin (NBF). The gastrointestinal tract was rinsed with water to remove food content and images were taken of each excised anastomotic site. Additionally, a sample of the right gluteus maximus was procured from each animal. All tissue samples were immersion-fixed in 10 % NBF. Two sections from each anastomotic site were trimmed, sections of pre- and post-anastomosis lever samples, and a section of right gluteus maximus skeletal muscle were taken for histological processing. The sections were placed in labeled cassettes and tissues were processed through a graded series of alcohols, embedded in paraffin, cut with a rotary microtome to approximately 5 µm in thickness, mounted on microscopic slides, and stained with hematoxylin and eosin (H & E) and Masson’s trichrome stains. American Preclinical Services (APS) sent the digital images taken at necropsy, completed gross pathology forms, trim sheets, and microscopic slides to a board-certified veterinary pathologist for independent interpretation. The sections of the anastomotic sites were evaluated for healing response and the presence of inflammation, infection, or dehiscence at the site of apposition.
Mean values of hematological profiles at baseline, day 3 and 56
Time after duodeno-ilial anastomosis
Mean values of serum biochemical profiles at baseline, day 3 and 56
Time after duodenum-ileal anastomosis
The use of a new compressive device for GI anastomosis allowed a safe and effective creation of an anastomosis between two portions of the small bowel. The anastomosis created was robust, healthy and permanent, which facilitated a partial diversion of nutrient flow and thus altered nutrients absorption, causing effective weight loss in this porcine model with short follow-up. A side-to-side duodeno-ileal anastomosis provided excellent weight loss, without diarrhea or grossly aberrant histological changes, especially in the liver. However, a notable decline in serum total protein and albumin levels (and elevated BUN) may point towards inadequate protein/calorie absorption. In the absence of proper nitrogen balance measurements, resting energy expenditure, one cannot conclude that inadequate intake resulted in this early phenomenon, especially taking into account the energetic and protein needs to heal a midline laparotomy and 2 enterotomies. It is also possible that if the animal had access to an ad libitum diet that serum protein and albumin levels would have been maintained.
In the real clinical world, humans have free access to nutrients, and are provided with protein supplementation and nutritional counseling after surgery. It is expected that any malabsorptive procedure, must include these components and serial serum levels of protein, albumin, minerals, fat soluble vitamins and liver enzymes, similarly to gastric bypass, biliopancreatic diversion with or without duodenal switch must be carried out at regular intervals. Equally remarkable, is that the bypassed intestine in the pig, is greater with (97 % bypass, 50 cm from 18 meters) a ratio of 1: 36 when compared to humans (90 % bypass, 50 cm from 5 meters) with a ratio of 1:10 . Therefore, this phenomenon may be seen less in humans.
Recent literature still appears on jejuno-ileal bypass and its’ modifications. Recently, Fazel et al. have reported a successful consecutive series of forty-three patients who underwent a modified jejunoileal bypass where the defunctionalyzed limb was anastomosed to the gall bladder and cecum, resulting in a loss of 43 kg (or 15 kg/m2 of BMI) at 5 years, without changes in liver histology .
One of the main reason why jejunoileal bypass was abandoned were reports of deaths from liver failure. Meinhardt and colleagues have followed carefully 50 consecutive patients who underwent JIB, in which liver biopsies were performed intraoperatively in 41 patients and in follow-up of 31 patients. With good weight loss at a mean of 67 months, no deaths occurred from liver failures and liver histology was stable .
The team of Rosina on 49 patients extensively studied bacterial overgrowth. Only 45 % of patients had some colonic micro flora in the excluded limb of jejunoileal bypass. The colonization appeared to correlate with clinical symptoms of bloating, migratory arthralgia, and rashes and skin lesions. But conversely, the positive cultures were not always associated with symptoms. No specific bacteriology was associated with this phenomenon. According to Rosina, the “success of an intestinal bypass may depend not only on anatomic and functional adaptation to the new, surgically created conditions, but also to the attainment of microbiological equilibrium in the intestinal ecosystem” .
Riordan et al. have reported that bacterial overgrowth does not necessarily correlates with neither liver damage nor increased intestinal permeability in human subjects .
The main advantage of a duodeno-ileostomy would be the fast ileal stimulation, causing an early incretin release and offering a potential tool for the resolution of type-2 diabetes. Recent hypothesis concerning the resolution of type-2 diabetes after weight loss surgery seems to point out that distal bowel stimulation may promote the production of glucagon-like peptide-1 (GLP-1) from the ileal and colonic L cells. There has been some evidence of this phenomenon when ileal transposition has been performed in Goto-Kakizaki type-2 diabetic rats . Mason had proposed an ileal transposition to promote the early release of GLP-1 for the cure of type-2 diabetes . Although we did not measure this hormone in pigs after duodeno-ileostomy, we postulate that an early release of GLP-1 will be a main endocrine feature of this operation.
Peptide YY (PYY) is also released from the distal small bowel endocrine cells is released in the circulation after a fatty meal, and PYY seemed to appear in the ileal lumen at greater concentration when glucose is used predominantly in the diet . In fact when oleic acid is infused into the duodenum, PYY is released approximately 10–30 min after. The site of production of circulating PYY appears to be the ileum, colon and rectum. If an ileocolectomy is performed, an abolished production of PYY to intraduodenal stimulation of oleic acid is observed. This release is not mediated by neural pathway, but solely from endocrine nature .
In turn, the increasing concentration of intravenous infusion of PYY reduces the glucose stimulated insulin release. This suggests that PYY affects the Beta-cell function by a possible autonomic regulation . Similarly, we are postulating that an early ileal release of PYY will occur after a side-to-side duodeno-ileostomy, and could be one hypothesis behind the effective weight loss seen in these animals.
In this porcine model with short follow-up, a side-to-side duodeno-ileal anastomosis provided excellent weight loss without apparent nutritional or grossly aberrant histological changes. This intervention is likely to cause weight loss by numerous mechanisms including decreased food absorption and decreased satiety from endocrine stimulation [20, 21].
Supported in part by a Research grant from EndoMetabolic Solutions, Inc. (Minneapolis, MN, USA).
The author declares that he was vice-president of EndoMetabolic Solutions Inc. until May 2011 and is owner of several related patents.
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- Våge V, Solhaug JH, Berstad A, Svanes K, Viste A. Jejunoileal bypass in the treatment of morbid obesity: a 25-year follow-up study of 36 patients. Obes Surg. 2002;12(3):312–8.View ArticlePubMedGoogle Scholar
- Näslund E, Backman L, Holst JJ, Theodorsson E, Hellström PM. Importance of small bowel peptides for the improved glucose metabolism 20 years after jejunoileal bypass for obesity. Obes Surg. 1998;8(3):253–60.View ArticlePubMedGoogle Scholar
- Singh D, Laya AS, Clarkston WK, Allen MJ. Jejunoileal bypass: a surgery of the past and a review of its complications. World J Gastroenterol. 2009;15(18):2277–9.PubMed CentralView ArticlePubMedGoogle Scholar
- Vyberg M, Ravn V, Andersen B. Pattern of progression in liver injury following jejunoileal bypass for morbid obesity. Liver. 1987;7(5):271–6.View ArticlePubMedGoogle Scholar
- Meinhardt NG, Souto KE, Ulbrich-Kulczynski JM, Stein AT. Hepatic outcomes after jejunoileal bypass: is there a publication bias? Obes Surg. 2006;16(9):1171–8.View ArticlePubMedGoogle Scholar
- Wills CE. Long-term follow-up of jejunoileal bypass patients with preoperative cirrhosis of the liver. Obes Surg. 1994;4(1):37–9.View ArticlePubMedGoogle Scholar
- Viddal KO, Midtvedt T, Nygaard K. Comparison of bypass and resection of the small intestine in germfree rats. Eur Surg Res. 1984;16(suppl 2):147–53.View ArticlePubMedGoogle Scholar
- Mayo WJ, Mayo CH. V. Clinical report—I. Complete section of the vas deferens, end-to-end union; II. acute suppuration of knee-joint: open treatment; III. gastro-enterostomy by the murphy button: anastomoses by this method. Ann Surg. 1895;21(1):35–44.PubMed CentralView ArticlePubMedGoogle Scholar
- Corman ML, Prager ED, Hardy TG Jr, Bubrick MP. Comparison of the Valtrac biofragmentable anastomosis ring with conventional suture and stapled anastomosis in colon surgery. Results of a prospective, randomized clinical trial. Dis Colon Rectum. 1989;32(3):183–7.View ArticlePubMedGoogle Scholar
- Stewart D, Hunt S, Pierce R, Dongli M, Frisella M, Cook K, Starcher B, Fleshman J. Validation of the NITI endoluminal compression anastomosis ring (EndoCAR) device and comparison to the traditional circular stapled colorectal anastomosis in a porcine model. Surg Innov. 2007;14(4):252–60.PubMedGoogle Scholar
- Kararli TT. Review article: Comparison of the gastrointestinal anatomy, physiology, and biochemistry of humans and commonly used laboratory animals. Biopharm Drug Dispos. 1995;16:351–80.View ArticlePubMedGoogle Scholar
- Fazel I, Pourshams A, Merat S, Hemayati R, Sotoudeh M, Malekzadeh R. Modified jejunoileal bypass surgery with biliary diversion for morbid obesity and changes in liver histology during follow-up. J Gastrointest Surg. 2007;11(8):1033–8.View ArticlePubMedGoogle Scholar
- Rosina M, Micheletto G, Vita PM, Restelli A, Caspani P, Ferla G, Doldi SB. Intestinal microflora settlement in patients with jejunoileal bypass for morbid obesity. Obes Surg. 1993;3(3):239–45.View ArticlePubMedGoogle Scholar
- Riordan SM, McIver CJ, Williams R. Liver damage in human small intestinal bacterial overgrowth. Am J Gastroenterol. 1998;93(2):234–7.View ArticlePubMedGoogle Scholar
- Patriti A, Aisa MC, Annetti C, Sidoni A, Galli F, Ferri I, Gullà N, Donini A. How the hindgut can cure type 2 diabetes. Ileal transposition improves glucose metabolism and beta-cell function in Goto-kakizaki rats through an enhanced Proglucagon gene expression and L-cell number. Surgery. 2007;142(1):74–85.View ArticlePubMedGoogle Scholar
- Mason EE. Ileal [correction of ilial] transposition and enteroglucagon/GLP-1 in obesity (and diabetic?) surgery. Obes Surg. 1999;9(3):223–8.View ArticlePubMedGoogle Scholar
- McFadden DW, Rudnicki M, Nussbaum MS, Balasubramaniam A, Fischer JE. Independent release of peptide YY (PYY) into the circulation and ileal lumen of the awake dog. J Surg Res. 1989;46(4):380–5.View ArticlePubMedGoogle Scholar
- Greeley GH, Jeng YJ, Gomez G, Hashimoto T, Hill FL, Kern K, Kurosky T, Chuo HF, Thompson JC. Evidence for regulation of peptide-YY release by the proximal gut. Endoscrinology. 1989;124(3):1438–43.View ArticleGoogle Scholar
- Greeley GH Jr, Lluis F, Gomez G, Ishizuka J, Holland B, Thompson JC. Peptide YY antagonizes beta-adrenergic-stimulated release of insulin in dogs. Am J Physiol. 1988;254(4 Pt 1):E513–7.PubMedGoogle Scholar
- Sclafani A, Koopmans HS, Vasselli JR, Reichman M. Effects of intestinal bypass surgery on appetite, food intake, and body weight in obese and lean rats. Am J Physiol. 1978;234(4):E389–98.PubMedGoogle Scholar
- Näslund E, Melin I, Grybäck P, Hägg A, Hellström PM, Jacobsson H, Theodorsson E, Rössner S, Backman L. Reduced food intake after jejunoileal bypass: a possible association with prolonged gastric emptying and altered gut hormone patterns. Am J Clin Nutr. 1997;66(1):26–32.PubMedGoogle Scholar