XEN-101, Xeno's lead product candidate, is an oral-pill formulation designed to deliver molecular oxygen to the lower gut, and thereby mimic the microbiome shift and weight loss induced by Roux-en-Y Gastric Bypass (RYGB) surgery.
To date, XEN-101 has shown profound weight loss efficacy in human subjects and animal models.
XEN-101 is designed to mimic RYGB, based on a mechanism of action described here as "Air Hypothesis":
- RYGB leads to rapid and excessive transit of swallowed air (oxygen) into the colon.
- Oxygen alters the gut microbiome (bacteria, fungi, archaea, viruses) and leads to weight loss.
Air Hypothesis is derived from the following facts:
(1) Humans swallow many liters of air into the stomach during the day.
(2) Stomach and pylorus normally prevent air from passing into the small bowel.
(3) RYGB abrogates stomach’s function to keep out air from the small bowel.
- Levine MS, Carucci LR. Imaging of bariatric surgery: normal anatomy and postoperative complications. Radiology (2014)
- Air contains orders of magnitude more oxygen than the same volume of water, because oxygen is poorly soluble in water.
(4) Small bowel transfers intra-luminal air rapidly to the proximal colon, where excess oxygen can alter the growth dynamics and function of the colonic gut microbiome.
- Gas mixtures, with partial pressures (N2 & O2) equivalent to venous blood gas tensions, transit rapidly to colon with minimal absorption after jejunal infusion in healthy subjects:
- Dainese R. et. al. Influence of body posture on intestinal transit of gas. Gut, (2003)
- RYGB patients experience large increase in flatulence symptoms despite negligible food malabsorption.
(5) 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 AP, Paziuk M, Luevano J-MM, Machineni S, Turnbaugh PJ, Kaplan LM. Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci Transl Med (2013)
(6) Construction of an unhindered, low pressure route from the esophagus to the small bowel leads to weight loss regardless of GI surgery type.
- Roux-en-Y gastric bypass (RYGB)
- Mini-gastric bypass (MGB)
- Billroth I
- Billroth II
- Total gastrectomy
(7) Proximal bypass or resection of the small intestine (without bypass of the stomach) does not lead to significant weight loss or change in gut microbiome, despite causing exaggerated post-prandial release of incretins (GLP-1, PYY etc.).
- Duodenal-jejunal Bypass (DJB)
- Ileal transposition (IT)
- Jejunum-ileum circuit
- Bile diversion to jejunum
- Partial jejunal diversion
- Small intestinal resection (<50%)
(8) Mechanical restriction of food intake or malabsorption are not the drivers of RYGB weight loss.
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 efficacy of gastric bypass. Instead, mounting evidence shows that altered gut neuroendocrine signaling drives all the weight reducing effects of RYGB:
Hao Z, Mumphrey MB, Townsend RL, et al. Reprogramming of defended body weight after Roux-En-Y gastric bypass surgery in diet-induced obese mice. Obesity (Silver Spring) (2016)
Evers, Simon S., Darleen A. Sandoval, and Randy J. Seeley. "The physiology and molecular underpinnings of the effects of bariatric surgery on obesity and diabetes." Annual Review of Physiology (2016).
Strong Evidence for Air Hypothesis: Gastro-Gastric Fistula (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. 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).