Investigating Host-Microbial Interactions after Bariatric Surgery

Obesity affects almost half a billion adults worldwide and almost one third of children under 11 years old in Europe are obese/overweight. Bariatric surgery, also called weight loss surgery or metabolic surgery, includes Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy and adjustable gastric banding, and is currently the most effective strategy for achieving sustained weight loss in morbidly obese patients. In addition to the clinical benefits of bariatric surgery, it results in altered urinary and faecal metabolic composition and an increase in the faecal abundance of Enterobacteriaceae bacterial family. Enterobacteriaceae are Gram-negative bacteria and generally present in very low densities in the normal gut. However, higher levels of Enterobacteriaceae are often detected in an inflamed gut, such as in patients with inflammatory bowel disease (IBD). Furthermore, chronic inflammation is associated with colon cancer risk and patients with IBD are five times more likely to develop colorectal cancer than the general population. Recent studies also reported an increased colon cancer risk following bariatric surgery compared to obese patients not treated with bariatric surgery. However, the relationship between Enterobacteriaceae and colon cancer remains unknown. The gut microbiota is a complex and highly interconnected population; hence, it is essential that we take this into account when we study the host-microbial crosstalk. Therefore, this project addresses the association between Enterobacteriaceae, colonic inflammation and colon cancer risk.

This research programme will have significant impact on the following areas: (1) Systems-level insights into the host-microbial interaction: This will underpin the fundamental understanding of how bacteria regulate host physiology; (2) Translational medicine: this research will study the gut microbiota as a whole, taking into account the inter-connective nature of the gut microbes, which makes this research highly translational; (3) Contribution to other research fields: Alongside the direct outcomes of this proposed research, the obtained results would provide insight into the long-term effect of RYGB surgery, which would be particularly valuable in RYGB-operated children and adolescents, and women of childbearing age. For paediatric bariatric patients, it is crucial to understand the potential long-term risk of bariatric surgery in order to reduce adverse effect and optimise surgical outcomes. Additionally, we know that the maternal microbiota has profound effects on the foetus and subsequent development; hence the proposed research will contribute to another exciting research area around the maternal-foetus gut microbiota health axis; (4) Medical and healthcare importance: This research will uncover novel prevention and therapeutic targets to reduce the risk of inflammation and colon cancer, which will benefit both RYGB-operated patients and IBD patients. IBD is now a global disease with increasing prevalence. In Europe, approximately 3 million patients suffer from IBD, resulting in annual healthcare costs of multibillion euros. Therefore, the outcomes of this research programme will be crucial in reducing this financial burden by providing promising experimental evidence for optimising patient healthcare strategies.

The overall objective of the programme is to elucidate the impact of Enterobacteriaceae on the colonic metabolism and colorectal cancer risk.

Up to now, we have (1) investigated the impact of the selected microbial metabolites on colorectal cancer (CRC) risk in vivo and in vitro, (2) established an animal model for studying tumours in large intestine, and (3) elucidated the metabolic behaviour of the RYGB microbiota.

Main results:
(1) the impact of the selected microbial metabolites on colorectal cancer risk in vivo and in vitro
We observed increased CRC in the metabolite-treated groups compared to the controls.

(2) an animal model for studying tumours in large intestine
We have successfully bred this strain of the mice and are currently characterising its phenotype. The preliminary results showed a much higher tumour numbers in the large intestine compared to the small intestine.

(3) the metabolic behaviour of the RYGB microbiota
We observed different metabolic behaviours of RYGB microbiota compared to controls.

We expected to gain mechanistic insight of how these metabolites produced by RYGB microbiota relate to CRC risk.

Periodic Reporting for period 4 - EnteroBariatric (Investigating Host-Microbial Interactions after Bariatric Surgery)

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