Investigating host-microbe interactions after weight loss surgery
Obesity is a major public health problem, which significantly increases the risk of a range of chronic diseases, including cardiovascular disease, type 2 diabetes and some forms of cancer. In the EU, over half of people aged 16 or older were classed as overweight or obese in 2022, and this rate is rising rapidly. Surgical (bariatric) treatment has proven to be effective in improving morbid obesity and type 2 diabetes, including the weight loss surgery Roux-en-Y Gastric Bypass (RYGB), a procedure that limits food intake and calorie absorption using a small pouch connected to the small intestine. However, previous research has found RYGB alters the gut microbiome, including a change in composition from Firmicutes (Bacillota) to the Proteobacteria (new name: Pseudomonadota) phylum. The long-term effects are still unknown. “This shift is generally thought to be negative for health outcomes,” explains Jia Li(opens in new window), associate professor in Biological Chemistry at Imperial College London. “In patients, the causal effects of these gut microbiome changes on appetite and food preference have not yet been elucidated,” she adds. In the EnteroBariatric(opens in new window) project, which was funded by the European Research Council(opens in new window), Li and her colleagues investigated the microbial, metabolic and immunological impacts induced by bariatric surgery.
Exploring the impacts of weight loss surgery on gut microbiota
To investigate the RYGB-gut microbiota’s function in relation to colon cancer risk, the researchers first used mouse models, with RYGB-gut microbiota transplanted to non-surgical mice. However, these RYGB-specific microbes (such as from the Enterobacteriaceae family) did not colonise the recipients’ gut. So the team shifted their focus to small biochemicals known as metabolites, which are produced by the RYGB-gut microbiota. “These metabolites derived from the diet-gut microbiota interactions can have substantial influence on our gut physiology,” says Li.
Uncovering colon cancer risk factors
Through their research, the team found that faecal tyramine (a natural compound) was elevated in patients post RYGB surgery(opens in new window). “We found that tyramine, derived from diet and/or the gut microbiota, increased colon cancer risk factors such as increased DNA damage, cell proliferation and inflammation,” remarks Li. Another metabolite, trimethylamine N-oxide (TMAO), is a host-microbial co-metabolite and elevated in blood post RYGB surgery. Using a genetically altered colorectal cancer (CRC) mouse model, the researchers showed that high circulating levels of TMAO protected against CRC development in males but not in females. These results are soon to be published in a peer-reviewed journal.
Improving healthcare outcomes for patients of bariatric surgery
“I hope by understanding the function of these metabolites, we will be able to improve post-surgery healthcare for the patients and reduce disease risk, particularly the ones that are associated with Proteobacteria or Pseudomonadota,” says Li. CRC remains a leading cause of cancer deaths globally, and an effective prevention strategy is crucial for reducing the CRC-associated burden. This ERC-funded project has led to several future research directions which Li is eager to pursue, including a precision preventive strategy for CRC, and deeper mechanistic insights into gut microbial and dietary metabolite function in CRC risk and development. “In addition, a large proportion of women who had bariatric surgery are of reproductive age,” notes Li. “It remains unclear if these surgery-associated metabolites and gut microbiome affect the offspring’s health.”
