Role of Gut Microbiome Nutrient Sensing Molecules in Modulating Weight Gain and Glucose Metabolism

Article by Nayaab Punjani

Graphic design by Amy Assabgui

By the year 2040, it is estimated that 600 million people will develop diabetes.¹ Even more will have pre-diabetes, which is marked by blood glucose levels that exceed the normal range and is influenced by various lifestyle factors. For example, obesity puts individuals at risk for this condition, and if left untreated, may progress to type 2 diabetes (T2D).¹ With the obesity and diabetes epidemics exacerbated by increasingly sedentary lifestyles, a greater understanding of the underlying factors controlling glucose metabolism and weight gain is key. This is what Dr. Tony Lam’s lab aims to examine, through their study of the role of nutrient sensing molecules in the gut microbiome.

Beginning with his Ph.D. at the University of Toronto, Dr. Lam investigated how “nutrients such as fatty acids could affect insulin action in the liver, and eventually affect glucose homeostasis.” He continued in this field during his post-doctoral appointment in New York City by examining the role of the hypothalamus in modulating glucose levels. He explains, “the end result for me is always the same: how glucose homeostasis is achieved and how [it] is disrupted in the context of diabetes type 2, as well as obesity.” Following this work, Dr. Lam concluded that one of the initial points of nutrient processing and absorption following a meal occurs at the site of the upper small intestine. This led him to study nutrient processing in the gastrointestinal (GI) tract and the complex interactions with diet, glucose homeostasis, obesity, diabetes, and the gut microbiome. 

Dr. Lam explains, “nutrients such as glucose and fatty acids, once ingested from the meal, will trigger various signaling pathways within the upper small intestine. It will tell the body to lower glucose levels. In the context of diabetes and obesity, this control is disrupted. We want to find out how this control is disrupted and how it can be restored.” His research highlights the role of the gut microbiome in altering gut nutrient sensing molecules. He studies the impact of sodium glucose cotransporter 1 (SGLT1), which is present in the upper small intestine and acts to lower glucose levels. High fat diets inhibit the activity of SGLT1 and disrupt the microbiome by decreasing levels of healthy bacteria, such as Lactobacillus, required in nutrient processing.² In order to mediate these impacts, Dr. Lam’s lab has also examined the role of metformin, a medication used to treat T2D, to regulate glucose levels in the rodent gut microbiome. His research has demonstrated that metformin helps to restore Lactobacillus and SGLT1-mediatiated glucose sensing in rodents.² 

Dr. Lam also illustrates the role of the enzyme acyl-CoA synthetase 3 (ACSL3) in pre-absorptive fatty-acid sensing in the upper small intestine. Pre-absorptive ACSL3-mediated fatty acid sensing is involved in moderating glucose tolerance. Rodents fed high fat diets were observed to have decreased Lactobacillus levels and disrupted ACSL3. However, healthy microbiome transplantation restored ACSL3 fatty acid sensing and thus glucose homeostasis, along with Lactobacillus levels.³ These studies demonstrate the regulatory role of these nutrient sensing molecules and the impact of high fat feeding on their activity.

Dr. Lam has also explored other applications of these nutrient-sensing molecules beyond, and in relation to, the gut microbiome. His lab recently discovered that changes in the gut microbiome result in altered production of secondary bile acids. Once these secondary bile acids are absorbed into the blood through the small intestine, cross the blood-brain-barrier, and bind to bile acid receptors, this may induce insulin resistance and affect glucose homeostasis. Increased production of these bile acids occurs in T2D as well as during short-term high fat feeding. Interestingly, healthy microbiome transplantation into the upper small intestine results in reduced production of these bile acids and improved glucose regulation.⁴ 

Based on his current findings, Dr. Lam has various next steps for his research. This includes further investigating the impact of the microbiome on bile acids, the receptors involved in this interaction, and eventually how this alters the gene expression of nutrient sensing molecules. This would be followed by determining the cells impacted in maintaining glucose homeostasis, as well as the therapeutic potential of metformin in helping mediate altered nutrient sensing and restoring the gut microbiome.

In addition to his research, Dr. Lam works closely with the Banting and Best Diabetes Centre (BBDC) as the Associate Director. The goal of the BBDC is to promote diabetes research through various funded summer studentships as well as graduate and post-doctoral studentships. These studentship applications are examined through a rigorous peer-review process involving ten faculty members and chaired by himself, providing fair grounds for selection. He mentions, “[these studentships are] not just going into one single lab or person, it is benefiting the whole Toronto community at all levels.” The BBDC also conducts a seminar series, inviting key researchers in the fields of diabetes and obesity, with plans of offering this in-person beginning in January 2022. 

For students planning to pursue research in the diabetes field, Dr. Lam offers various suggestions. The first is to apply for BBDC summer studentships. These paid positions provide students with the opportunity to get hands-on experience in a lab for 12 weeks, allowing you to determine whether you would like to continue pursuing this research field for graduate studies. There are also undergraduate courses taught by various faculty members, such as Dr. Lam’s PSL425 course, which focus on studying metabolism, with certain lectures through the lens of the gut microbiome. 

Dr. Lam summarizes the application of his work to everyday life: “the general public should be aware of the fact that there are many molecules that could be activated or inhibited by nutrients that we take in each day—each meal. These signaling pathways could eventually affect glucose levels as well as weight in the body.” Furthermore, he reflects on how sedentary lifestyles result in excess calories that could greatly influence these nutrient-dependent molecules. From alterations to the gut microbiome composition, to nutrient metabolism, we must be cognizant of the types of foods that we consume and their effect on our body.

References:

1. Boles A, Kandimalla R, Reddy PH. Dynamics of diabetes and obesity: Epidemiological perspective. Biochim Biophys Acta BBA – Mol Basis Dis. 2017 May 1;1863(5):1026–36. 
2. Bauer PV, Duca FA, Waise TMZ, et al. Metformin Alters Upper Small Intestinal Microbiota that Impact a Glucose-SGLT1-Sensing Glucoregulatory Pathway. Cell Metab. 2018 Jan 9;27(1):101-117.e5. 
3. Bauer PV, Duca FA, Waise TMZ, et al. Lactobacillus gasseri in the Upper Small Intestine Impacts an ACSL3-Dependent Fatty Acid-Sensing Pathway Regulating Whole-Body Glucose Homeostasis. Cell Metab. 2018 Mar 6;27(3):572-587.e6. 
4. Zhang S-Y, Li RJW, Lim Y-M, et al. FXR in the dorsal vagal complex is sufficient and necessary for upper small intestinal microbiome-mediated changes of TCDCA to alter insulin action in rats. Gut. 2021 Sep;70(9):1675–83.