Multiomics Advances: Patient Stratification for Treatment and Response

Multiomics is a computational approach that integrates two or more omics datasets. It is a recent method, first cited in the literature around 2005, which has since grown exponentially in popularity. Multiomics can be leveraged to develop a more realistic and multi-level perspective of complex biological systems and diseases. Single-omics analyses simplify biological systems that are comprised of interacting multi-level entities. For instance, the epigenome influences the transcriptome, and, ultimately, the proteome and metabolome, which feedback through active metabolites to impact the epigenome.

Given its advantages and more realistic representation of complex systems, multiomics has a wide range of applications from basic research to disease pathophysiology. Moreover, multiomics is anticipated to have future clinical applications, such as for personalized medicine and for identifying prognostic biomarkers. This article will present two multiomics vignettes. One involves the search for a deeper understanding of food allergies and a potential path forward for treatment. Another will describe the response to bariatric surgery, a growing need as obesity trends upwards in many parts of the world.

Allergies abound: Using multiomics to shed light

Food allergies are a common health problem, which affect around 8% of children and 11% of adults in the US. They are triggered by various foods, but peanut allergy is the best known. Individuals with severe, life-threatening allergies may live in fear of potential exposure to allergens. With such high prevalence, food allergies already impact daily life for a substantial number of individuals, which is only projected to rise over the next couple of decades. “True food allergies, a state of immune “hyperactivity”, are most commonly mediated by immunoglobulin E (IgE),” explained Dr. Annette Kuehn, at the Department of Infection and Immunity at the Luxembourg Institute of Health. Kuehn investigates the origins of food allergies and seeks to understand the underlying mechanisms. “The basis of allergies is an imbalance in the immune system. In cancer, immune activity is too low. By contrast, in people who suffer from allergies, it is too high, and the balance shifts towards excessive immune system activation, Kuehn added.”

Allergies frequently begin in childhood, although the origins are not fully understood. “There is good evidence to support that IgE-mediated food allergies occur from a dysfunction of epithelial barriers in the skin, gut or lung,” Kuehn elaborated. Indeed, children that develop skin issues, such as the inflammatory disorder ectopic dermatitis, often go on to develop food allergies. “The initial disruption to the epithelium triggers an immune response, which sensitizes the person’s immune cells to food proteins. When this happens, the immune cells begin to recognize the food proteins as invaders and mount an immune response upon each encounter, such as histamine release, which manifests clinically as allergies.”

Food allergies vary in severity across individuals, which impacts the appropriate treatment approach. “Previously, patients were advised to strictly avoid the food they were allergic to. However, we have entered a new era of treatment for allergies, so there are now more options available,” Kuehn continued. “However, to select the optimal treatment for each patient, we must have a deeper understanding of their underlying allergy mechanisms. For example, two patients may present with the same type of allergy, but have different underlying causes, the so-called endotypes; so, there is a lot of variability across patients. Optimally, the treatment approach should target the underlying mechanisms to increase the likelihood it will be effective.”

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Omics and their combined multiomics technologies have emerged recently to advance understanding of the factors underlying allergy severity and stratify patients into endotypes.¹

Molecular (allergen) endotyping by allergenomics, a term drawn from parallels to other omics methods, is a deep, system-wide analysis by protein-based technologies to identify allergens from a protein digest mimicking gastrointestinal conditions. Immunological endotyping identifies immune signatures in individuals that are linked to allergy severity. Classically, this was performed by deep immune phenotyping, but omics methods are now emerging, including genomics, transcriptomics, epigenetics and metabolomics. Lastly, commensal endotyping characterizes gut microbiome signatures in patients with allergy linked to response severity. The microbiome has important regulatory roles in host immunity and gastrointestinal barrier integrity and consequently on food allergies.

“Allergy is a very complex, multi-level disease with several distinct layers, such as immune profile, genetic predisposition, diet, lifestyle, all of which influence allergy origin and mechanism. So, advanced methodology, such as multiomics and unbiased machine-learning are needed,” Kuehn said. “We think there may be numerous distinct endotypes, which we can characterize using multiomics to inform personalized treatments for allergy.”

Moreover, multiomics or integrative methods are facilitating mechanistic understanding, in addition to endotyping. For example, a recent dual transcriptomics and epigenomics analysis of peanut allergy identified “peanut severity genes” by RNA sequencing and “peanut severity CpGs” [methylated cytosine bases in DNA] by DNA methylation profiling from blood after peanut challenge. The study then integrated the peanut severity genes with peanut severity CpGs to specifically pinpoint “peanut severity expression CpGs” – meaning CpGs with a methylation state that specifically influenced gene expression related to allergy, which would suggest causal relationships.

Simultaneous epigenetic–transcriptomic analysis revealed two genes that were implicated with peanut allergy severity. This indicates that methylation may, at least in part and at specific loci, mediate gene expression-modulated reaction severity. Furthermore, the study highlighted overrepresentation during allergy of neutrophil-mediated immunity, in addition to pathways related to immune response, chemotaxis and regulation of macroautophagy.

When asked about future directions, Kuehn replied, “There is growing interest in better understanding allergy onset to guide prevention efforts. Allergies have been on the rise since the 1960s; if trends hold, then we face higher prevalence in the future. Although diagnosis and treatment can help manage allergies in patients, we will need preventative solutions to mitigate the sheer number of individuals anticipated to develop allergies.”

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Multiomics for metabolic disease

Type 2 diabetes and obesity, which primarily develop due to overeating and a sedentary lifestyle, have grown to epidemic proportions in many countries. Worldwide, an estimated 537 million people are living with type 2 diabetes and approximately 650 million individuals are obese. Although type 2 diabetes and obesity mostly occur from excessive food intake, additional factors exert important effects, such as genetic predisposition, epigenetic regulation and microbiome composition. Therefore, disease pathophysiology is complex and multi-dimensional.

Many approaches are available for treating patients with type 2 diabetes and/or obesity, which are frequently comorbid. Medication that can control patients’ glucose levels constitute a significant avenue of treatment. Lifestyle changes for weight loss, such as diet and exercise, are also highly recommended. “Unfortunately, many patients struggle to adhere to dietary or exercise regimens, for example due to exercise intolerance. Bariatric surgery is one option, which can help patients achieve their weight loss goals and improve their systemic metabolism,” explained Dr. Nicholas Penney, consultant esophagogastric surgeon at Norfolk and Norwich University Hospitals NHS Foundation Trust.

Penney’s research interest lies on the impact of bariatric surgery and other interventions on metabolic and microbiome profiles in patients, leveraging omics and multiomics to understand response to treatment. In a recent paper, through research conducted as clinical research fellow at the Department of Surgery and Cancer at Imperial College London, Penney performed multiomics phenotyping of patients that had undergone bariatric surgery. “Most previous studies looked in isolation at the effect of bariatric surgery on gut microbial community by metagenomic analysis or on host plasma metabolites by metabolomics. Few prior studies have applied multiomics analysis of both the gut microbiome and plasma metabolome,” Penney elaborated. “By integrating the two datasets (i.e., microbiome, metabolome), we were able to generate a deeper understanding of how bariatric surgery influences gut–host co-metabolism, and how this in turn affects diabetic control and weight loss.”

The study examined 80 participants with obesity, of which 42 had type 2 diabetes, 11 had impaired glucose tolerance (a prediabetic state preceding overt type 2 diabetes), and 27 were non-diabetic.² “Prior to surgery, we found distinct differences in gut microbiome and metabolome signatures in participants with obesity and type 2 diabetes versus those without type 2 diabetes. We also found that bariatric surgery profoundly shifted the microbiota and metabolic signatures,” Penney said. Regarding metabolic changes, bariatric surgery was linked to 207 metabolites, which overlapped, to some extent, with metabolites associated with improved glycemic control, weight loss and dietary changes. Thus, metabolic changes post-bariatric surgery, were achieved by both weight-dependent and weight-independent processes. Regarding microbiota changes, surgery altered the abundance of several microbial genera, and altered functional pathways related to amino acid and lipid metabolism.

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“The multiomic signatures of obesity and type 2 diabetes and then that of bariatric surgery were especially interesting. They allowed us to establish multiple associations between gut microbes and host metabolites, which we could not have done separately from metagenomic or metabolomic data alone,” Penney said. “A number of these microbially derived metabolites have important roles in glycemic control. A better understanding of how these gut microbes influence metabolism may lead to novel treatments for weight loss and type 2 diabetes. Moreover, although body mass index, a metric of obesity, is closely related to glycated hemoglobin, a metric of diabetes, they were each associated with distinct microbiome-metabolite networks and our findings suggest that bariatric surgery potentially improves body weight and glycemic status through distinct pathways,” Penney concluded.

Looking ahead to upcoming research, Penney said, “Future experiments are needed to establish causality between the microbes and metabolites we identified by multiomics, which could include fecal transplant experiments. In addition, to fully elucidate the contribution of microbiota–metabolite correlations in response to bariatric surgery, we would require a standardized dietary intervention incorporating one or more stable-isotope-labelled substrates. This would allow us to pinpoint metabolites produced by microbial biotransformation, and we would also be able to incorporate metabolic flux into our metagenomic and multiomics analyses.”

Bariatric surgery achieves sustainable weight loss and successfully resolves other co-morbidities, such as type 2 diabetes. However, not all patients with type 2 diabetes respond. “Multiomics profiling of patients before surgery may allow us to identify the individuals most likely to benefit from bariatric surgery, including those that may experience a complete resolution of their type 2 diabetes,” Penney concluded.

Overall, and in a very short time, multiomics analysis has grown to encompass a suite of applications. It is now poised to make important advances for patients, by profiling individuals to match them to potential treatments or identify those most likely to benefit from a therapy.

References

1. Czolk R, Klueber J, Sørensen M, et al. IgE-Mediated peanut allergy: Current and novel predictive biomarkers for clinical phenotypes using multi-omics approaches. Front Immunol. 2020;11:594350. doi: 10.3389/fimmu.2020.594350

2. Penney NC, Yeung DKT, Garcia-Perez I, et al. Multi-omic phenotyping reveals host-microbe responses to bariatric surgery, glycaemic control and obesity. Commun Med (Lond). 2022;2:127. doi: 10.1038/s43856-022-00185-6