Gastric Bypass Mechanism

Roux-en-Y gastric bypass (RYGB) surgery is one of the most effective treatments for obesity and type II diabetes. RYGB was originally believed to work by mechanically restricting caloric intake or causing macronutrient malabsorption. However, it is now understood that such mechanical effects are not responsible for the remarkable weight loss efficacy of gastric bypass. Instead, mounting evidence shows that altered gut neuro-immune signaling drives all the weight reducing effects of RYGB. The surgery works by altering the chemical environment in the lumen of the gut.

Various other mechanisms for the weight loss have been proposed including bypass of the small bowel, rapid delivery of nutrients to small intestine, changes in bile acids and incretins. However, there is a large body of evidence that has accumulated against these ideas over the past few decades.

AIR HYPOTHESIS

At Xeno, we believe the disruption of intestinal gas homeostasis is responsible for the altered neuronal and immune signaling after RYGB. Due to new GI anatomy, swallowed air transits into the intestines leading to high oxygen levels in the normally anaerobic distal gut, which then changes the chemical and microbial environment in the lumen (Air hypothesis, Celiker 2017).

Humans swallow many liters of air into the stomach during the day. Stomach and pylorus normally prevent air from passing into the small bowel. RYGB abrogates stomach’s function to keep out air from the small bowel due to removal of the stomach (Levine 2014). In this new anatomy, small bowel transfers intra-luminal air rapidly to the proximal colon, where excess oxygen can alter the gut chemical environment and the function of microbiota (Palleja 2016). This altered environment in the gut is sensed by the immune cells and the nervous system lining the gut.

Supporting air hypothesis, in healthy subjects, it is observed that gas mixtures with partial pressures (N2 & O2) equivalent to venous blood gas tensions transit rapidly to colon with minimal absorption after jejunal infusion (Dainese 2003). Moreover, as expected, RYGB patients experience large increase in flatulence symptoms despite negligible food malabsorption. Similarly; people, who are unable to belch, suffer from excessive flatulence due to air transit to colon (Bastian 2019).

RYGB drives an expansion of aerobic microbes in the gut. Transfer of fecal material from rodents or humans, who had RYGB, into germ-free mice leads to fat mass reduction in the recipient animals (Liou 2013).

RESTRICTION OF MEAL SIZE OR MALABSORPTION?

It is commonly believed that the efficacy of RYGB is caused by macronutrient malabsorption or mechanical limitations (smaller food portions) which restrict caloric intake. However, although patients decrease their meal size after the surgery, they often consume a daily calorie count similar to BMI matched control levels by 6-12 months post surgery, indicating no fundamental restriction to food intake. There is also no significant caloric malabsorption after RYGB in humans or animals (Stylopoulos 2009; Mahawar 2017)

The lower body weight is actively defended after the surgery at a physiological level (Frikke-Schmidt 2016; Hao 2016). Supporting this, patients report that they are less hungry after the surgery despite the fact that they lose substantial amounts of weight. In contrast, it is well known that the body induces hunger and decreases metabolic rate to defend against weight loss during normal caloric restriction (i.e dieting).

INCREASED LUMINAL PRESSURE?

Gastric bypass does not increase luminal pressure in the proximal gut lumen during eating in humans as measured by high-resolution manometry (Björklund 2015). Similarly one-anastomosis gastric bypass (OAGB) causes a decrease in gastric pressure compared to normal anatomy (Tolone 2019).

Such low luminal pressure after gastric bypass is in stark contrast to the effects of vertical sleeve gastrectomy (VSG) on intra-gastric pressure (Tolone 2016). VSG is another type of bariatric surgery that causes a large increase in intra-gastric pressure due to reduced stomach size and intact pylorus (Mion 2016). This is also evidenced by high rates of reflux and belching induced by this type of surgery (Burgerhart 2016).

BYPASS OF SMALL INTESTINE?

Bypass of duodenum and proximal jejunum without bypass of stomach or pylorus (DJB, duodenal jejunal bypass) leads to rapid food delivery to distal small intestine and exaggerated post-prandial incretin (GLP-1, PYY) release like RYGB, in addition to hypertrophy in the roux limb exposed to undigested nutrients; but achieves no weight loss in humans or rodents (Geloneze 2009; Kindel 2011; Klein 2012, Li 2013; Sun 2013). RYGB works normally in GLP-1R knockout, PYY receptor (Y2R) knockout or GLP-1R and Y2R double knockout rodents (Ye 2014; Boland 2019; Boland 2019).

DJB mimics RYGB bile diversion effect and leads to increased serum bile acids without any weight loss (Wei 2017). RYGB still works in FXR knockout (unpublished data) and TGR5 knockout rodents and does not change bile acid metabolism in intestinal lumen in rodents (Hao 2018; Duboc 2019).

Bypass of small bowel is not required for RYGB weight loss, as anastomosis of esophagus to duodenal bulb leads to weight loss such as in the case of gastroduodenostomy, i.e Billroth I (Choi 2017; He 2018).