In recent years, the rate of global migration has accelerated significantly, with North American countries like Canada and the United States serving as leading destinations for immigrants. Within the North American community, chronic inflammatory diseases, characterized by long-term inflammation and persistent detrimental effects to the human body, are the most significant cause of mortality and impose an enormous burden. Over the past decade, our understanding of inflammation has been radicalized by an ever-growing appreciation of the role of the microbiome in the education and priming of the mammalian immune system. The microbiome consists of the symbiotic commensal organisms that reside within the mammalian body and their respective genomes. A significant body of work has established that two environmental factors, geographical environment and diet, are key forces at play in modifying the microbiome structure and function. Current research is now pointing towards the possibility that alterations in the microbiome in immigrant communities, as a consequence of changing environmental factors, could explain the rise of chronic diseases. However, despite an increase in global immigration, very little is clear as to how migration affects the microbiome and subsequent inflammatory parameters.
The Generation Differences in Environmental Exposures Caused by Migration: Impact on Incidence and Inflammatory Disease (GEMINI) study is an on-going research study that aims to understand why the South Asian community in Canada is experiencing a dramatic increase in the incidence of chronic inflammatory disease upon exposure to the North American environment. The GEMINI study aims to elucidate how alterations to the microbiome, as a consequence of geographic and dietary changes, might influence one’s inflammatory tone. We sat down with Dr. Jennifer Gommerman, one of the co-leads of the GEMINI study and a researcher at the University of Toronto’s Department of Immunology, to better understand the long-term goals and origins of the study.
Anecdotal Observations Necessitate a Robust Study
Dr. Gommerman explained that while auto-immune diseases are appreciated to be on the rise, their “increase in incidence is accelerating in a manner that can no longer be explained by genetic studies alone.” This consideration, coupled with an anecdotal observation made by clinical colleagues, that an increasing frequency of patients exhibiting symptoms of autoimmune diseases were from the South Asian community, fueled the origins of the GEMINI study. In fact, this observation was supported by some smaller hospital based findings elsewhere, like in the United Kingdom and Vancouver. However, Dr. Gommerman acknowledged that these studies faced some limitations such as being subject to several confounders and not being statistically well-powered.
The Microbiome: The Ultimate Environmental Barometer
Observations and studies reporting altered incidence of autoimmune diseases in the South Asian community sparked the interest of Dr. Gommerman and her colleagues, encouraging them to obtain pilot money to follow up on this more robustly. They collaborated with Dr. Eric Benchimoal from the University of Ottawa’s Institute for Clinical Evaluative Studies (ICES) and performed a thorough analysis on the Ontario Health Insurance Plan (OHIP) database and immigration database. Their findings demonstrated that first generation South Asians residing in Ontario had a lower risk of developing inflammatory bowel disease and asthma than the general population, however this protection was lost in the second generation South Asians residing in Ontario. This led the researchers of the GEMINI study to focus on first and second generation healthy South Asians to determine whether there was anything different about their environmental exposures. Dr. Gommerman added that her team believes that the microbiome is the “most sensitive barometer for environmental change and is in ways the canary in the mine-shaft”. The project was initially funded by the UofT Connaught Fund, which allowed them to get the team together and establish pipelines for various experimental parameters, and is now funded by the Canadian Institute of Health Research (CIHR).
Dr. Gommerman further explained that a changing environment is ultimately the factor that is responsible for the microbiome changes that are observed in immigrant communities. Is the relationship between the environment, genetics, and the microbiome linear or inter-connected in the context of chronic inflammatory diseases? Dr. Gommerman clarified that currently a large amount of literature indicates that one’s diet and nutrition can dramatically modify the microbiome. However, it is unclear how temporary these modifications are and whether the microbiome can bounce back. Dr. Gommerman explained that while there are some examples of the host’s genetics influencing the microbiome, these studies are limited, and what’s more likely is that the microbiome is influenced by gene-environment interactions. “It’s as if the person’s genetics and environment conspire with the microbiome to affect disease development.”
Dr. Gommerman added that her team was recently encouraged by a study published in Cell in 2018 that had a similar experimental design as the GEMINI study but were focusing on the immigrant Thai population. The study titled “US Immigration Westernizes the Human Gut Microbiome” concluded that immigration of Hmong and Karen individuals to the United States of America was associated with perturbations to the gut microbiome as a consequence of displacement from their home country, and that these alterations could partly be explained by variations in diet as a consequence of dietary acculturation. These findings further support the hypothesis at the center of the GEMINI study: that the environment is responsible for a modified microbiome and subsequent altered inflammatory tone in the immigrant South Asian communities.
The Nuts and Bolts of the GEMINI Study
When questioned about the overall process and pipeline that has been established for the GEMINI study, Dr. Gommerman explained that when participants come in they are asked to complete a health and lifestyle questionnaire, which includes a wide variety of questions on socioeconomic status, living situation, lifestyle habits and as well as a detailed food frequency questionnaire. The participants are also asked to provide blood and stool samples which are then used to supplement data from the questionnaires by performing HLA genotyping, shotgun sequencing for metagenomics analysis of the microbiome, immune cell analysis assays and nutritional proteomics. Dr. Gommerman added that the preliminary questionnaire can further help elucidate certain factors that might synergize with their biological readouts. As an example, she mentioned how they are interested in determining whether their participants are residing at home with their parents or individually on their own. She explained that those who are living at home are perhaps more inclined to consume more traditional foods than those who live on their own, which might ultimately be a factor influencing the microbiome.
Throughout the course of their study, recruitment has been one of the most significant challenges the GEMINI study has faced, as the team wants to ensure that their work is well-powered. She explains that since its inception they’ve hit several plateaus in recruitment which have been overcome by the efforts of project manager Dr. Gary Chao. They found that recruiting through campus was ineffective and that websites such as Kijiji and Craiglist were useful tools. Furthermore, they had to re-evaluate their compensation and improve the kits that they were providing to participants for sample collection, to enhance participant satisfaction.
The Microbiome: Friend or Foe?
“It can be kind of like a roommate – it can be great or it can be awful.” Dr. Gommerman added that although we tend to think of the microbiome as promoting a pathogenic phenotype, a substantial amount of data is emerging that compels us to believe that the microbiome also influences regulatory aspects of the immune system. An example of this phenomenon has recently been described in a study published by her group in Cell titled “Recirculating IgA-Producing Cells Regulate Neuroinflammation via IL-10” showing that the protist Trichomonas musculius is capable of protecting against severe experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, by elevating regulatory IgA-producing cells. She concludes that “we shouldn’t always be chasing after a bad microbiome – ideally we need to be seeking communities that promote a healthy immune system that is able to self-regulate.”
Long Term Goals & Concluding Remarks
When asked about the long-term goals of the GEMINI study, Dr. Gommerman explained that her team hopes to identify modifiable risk behaviors or factors by assessing the first and second generation of South Asians living in Ontario. Ultimately, the results of the study will allow them to identify factors within the environment, such as dietary differences, that predispose individuals to a higher risk of developing inflammatory disease, thus influencing future health practices and specific approaches to autoimmune disease.
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