Periodic Reporting for period 5 - EnteroBariatric (Investigating Host-Microbial Interactions after Bariatric Surgery)
Periodo di rendicontazione: 2023-08-01 al 2025-01-31
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.
The project findings indicated that metabolites produced by RYGB-associated gut microbiota modulate the colorectal cancer risk. For example, tyramine, which can directly come from diet or produced by intestinal Enterobacteriaceae and Enterococcaceae promotes colon cancer risk via increased DNA damage, cell proliferation, and inflammation.
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.
The project findings indicated that metabolites produced by RYGB-associated gut microbiota modulate the colorectal cancer risk. For example, tyramine, which can directly come from diet or produced by intestinal Enterobacteriaceae and Enterococcaceae promotes colon cancer risk via increased DNA damage, cell proliferation, and inflammation.
We have (1) elucidated the metabolic behaviour of the RYGB microbiota, (2) established an animal model for studying tumours in large intestine, and (3) investigated the impact of the selected microbial metabolites on colorectal cancer (CRC) risk in vivo and in vitro
Main results:
(1) the metabolic behaviour of the RYGB microbiota
We isolated 31 faecal bacteria from patients post RYGB surgery and extensively evaluated their metabolic behaviour, with a focus on amino acids as substrates. We observed that some isolates from Enterobacteriaceae and Enterococcaceae families converted tyrosine to tyramine.
(2) an animal model for studying tumours in large intestine
We successfully established a genetically modified mouse model for colorectal cancer and conducted baseline characteristic experiments to evaluate the phenotype of the line, which has been subsequently used to study function of various metabolites associated with diet-gut microbiota-RYGB.
(3) the impact of the selected microbial metabolites on colorectal cancer risk in vivo and in vitro
Faecal concentrations of tyramine have been observed to be higher patients with inflammatory bowel disease or undergone RYGB. Based on both wild-type and genetically altered mice and human colonic cancer cells-based experiments, we found that tyramine induced DNA damage and increased intestinal tumour loads and inflammation. Monitoring and modulating tyramine concentrations in high-risk individuals could aid CRC prognosis and management.
Dissemination:
The findings have been presented in multiple conferences (British Society of Immunology Annual Conference 2021, Gordon Research Conference 2023, Metabolomics in Human Health Symposium 2024) and published in journal Microbiome in January 2025 (PMID: 40022152). A video promoting the findings in the general public has been made https://www.youtube.com/watch?v=_M1kMwO2Cr4(si apre in una nuova finestra).
The team has presented the importance of gut microbiota and the dietary impact on the gut microbial metabolic activities in various outreach activities, such as Great Exhibition, Imperial Late, and Pint of Science.
Main results:
(1) the metabolic behaviour of the RYGB microbiota
We isolated 31 faecal bacteria from patients post RYGB surgery and extensively evaluated their metabolic behaviour, with a focus on amino acids as substrates. We observed that some isolates from Enterobacteriaceae and Enterococcaceae families converted tyrosine to tyramine.
(2) an animal model for studying tumours in large intestine
We successfully established a genetically modified mouse model for colorectal cancer and conducted baseline characteristic experiments to evaluate the phenotype of the line, which has been subsequently used to study function of various metabolites associated with diet-gut microbiota-RYGB.
(3) the impact of the selected microbial metabolites on colorectal cancer risk in vivo and in vitro
Faecal concentrations of tyramine have been observed to be higher patients with inflammatory bowel disease or undergone RYGB. Based on both wild-type and genetically altered mice and human colonic cancer cells-based experiments, we found that tyramine induced DNA damage and increased intestinal tumour loads and inflammation. Monitoring and modulating tyramine concentrations in high-risk individuals could aid CRC prognosis and management.
Dissemination:
The findings have been presented in multiple conferences (British Society of Immunology Annual Conference 2021, Gordon Research Conference 2023, Metabolomics in Human Health Symposium 2024) and published in journal Microbiome in January 2025 (PMID: 40022152). A video promoting the findings in the general public has been made https://www.youtube.com/watch?v=_M1kMwO2Cr4(si apre in una nuova finestra).
The team has presented the importance of gut microbiota and the dietary impact on the gut microbial metabolic activities in various outreach activities, such as Great Exhibition, Imperial Late, and Pint of Science.
This project advances the state of the art in gut microbiome research, particularly in the context of bariatric surgery, by establishing a causal link between gut microbial metabolites and gut health outcomes. While previous studies have largely focused on correlative associations, our work provides empirical evidence that elucidates mechanistic pathways. Beyond our published findings, we have uncovered novel insights into how dietary components modulate the metabolic activity of RYGB-associated microbiota. Notably, we observed that certain microbial metabolites influence CRC risk in a sex-dependent manner - an area that has been underexplored. These findings open new avenues for personalised dietary interventions and risk stratification strategies post-bariatric surgery.