How does gastric bypass surgery work?
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 hypotheses as listed below.
AIR HYPOTHESIS
At Xeno, we believe the disruption of intestinal gas homeostasis due to the new surgical anatomy is responsible for the altered neuronal and immune signaling. Air transit to the colon leads 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).
Roux-en-Y Gastric Bypass (RYGB)
Restriction of meal size or malabsorption?
It is commonly believed that the efficacy of RYGB is caused by mechanical limitations (smaller food portions) which restrict caloric intake or by macronutrient malabsorption.
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.
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).
There is no significant caloric malabsorption after RYGB in humans or animals (Stylopoulos 2009; Mahawar 2017)
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 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).
Björklund et al (2015)
Duodenal Jejunal bypass (DJB)
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).
Anatomical failure modes of RYGB point to Air Hypothesis as the weight loss mechanism
Certain anatomical failure modes of RYGB have been extensively documented in the past. Three types of altered anatomy have been described which cause inadequate weight loss or weight regain (Karmali 2013):
Gastro-gastric fistula (GGF)
Large gastric pouch
Stoma dilatation
A common feature of these anatomical failure modes is the restoration of the reservoir function in the proximal gut. Air hypothesis is consistent with and can explain why restoration of such reservoir function can lead to failure of weight loss after RYGB. A large reservoir in the proximal gut can hold air for prolonged periods of time and therefore prevent its transit to the distal gut. As the air stays in the upper gut, this would enable oral eructation of the gas or lead to gradual reduction of oxygen content due to absorption into tissues.
1. Gastro-gastric fistula (GGF)
Upper GI series in a patient with weight regain (Red arrow: GGF)
A rare complication of RYGB is gastro-gastric fistula (GGF), which is a small fistulous connection spontaneously formed between the old stomach (GR) and the new stomach pouch (GP) post-surgery.
GGF leads to weight regain or prevents weight loss in majority of cases, and surgical closure of GGF restores weight loss (Chahine 2018). GGF reverses the weight loss effect of RYGB despite the fact that GGF anatomy is effectively the same as normal RYGB anatomy, except for a small connection between the new and the old stomach. In RYGB patients with GGF, majority of ingested food still flows through the correct path (Roux limb) as the fistula is usually situated at the apex of gastric pouch and is very small. Yet, the weight loss efficacy of the surgery is abolished (example case report).
Air hypothesis can explain this phenomenon. With a GGF, swallowed air can flow through the small fistula and get stored in the large (bypassed) stomach, instead of flowing into the small bowel (see below figure). There, oxygen can be slowly absorbed or expelled orally.
Endoscopic view of GGF (Arrow)
2. Large gastric pouch
A large gastric pouch can lead to inadequate weight loss after RYGB. Similarly, enlargement of gastric pouch in the long term after surgery can lead to weight regain (Karmali 2013). A simplistic assumption as to why enlargement of the gastric pouch may lead to reduction in weight loss efficacy is that small pouch would create more mechanical restriction to food intake. However, as explained above, weight loss effect of the surgery is not related to meal size restriction, nor is it related intra-luminal pressure. After RYGB, pressure in the lumen stays low during eating.
In contrast, Air hypothesis can explain these observations: Restoration of reservoir function due to enlarged pouch would tend to enable storage of swallowed air in the proximal gut for increased periods of time, leading to decreased oxygen transit to the distal gut.
3. Stoma dilatation
Stoma or GJA (gastrojejunal anastomosis) is the connection between the gastric pouch and the small intestine in RYGB anatomy. Enlargement of the stoma diameter over time can lead to inadequate weight loss or weight regain (Heneghan 2011).
These observations are again consistent with predictions of Air hypothesis. Stoma dilatation creates a new functional reservoir in the upper gut consisting of the gastric pouch and the proximal roux limb.
This new reservoir would then enable storage of swallowed air in the proximal gut for increased periods of time, leading to decreased oxygen transit to the distal gut and subsequently less weight loss.
