National Institutes of Health–Wide Workshop: Impact of Diet on Mucosal Immunity and Immune-Mediated Inflammatory Diseases of the Gastrointestinal Tract

Workshop Overview

On August 21–22, 2024, the National Institutes of Health (NIH) Office of Nutrition Research, with contributions from the National Institute of Allergy and Infectious Diseases and other NIH Institutes and Offices, convened an NIH-wide workshop focused on the impact of diet on mucosal immunity and immune-mediated inflammatory diseases of the gastrointestinal tract (IMID-GI). The workshop was responsive to language in the Departments of Labor, Health and Human Services, and Education, and Related Agencies Appropriation Bill of 2024, which encouraged NIH to convene a scientific workshop focused on better understanding “the impact of food and diet on the development of mucosal immunity and the relevance of this topic to Crohn’s disease and ulcerative colitis and to other digestive and autoimmune or immune-mediated diseases”.¹ Beyond Office of Nutrition Research and National Institute of Allergy and Infectious Diseases, workshop sponsors and participants included the National Institute of Diabetes and Digestive and Kidney Diseases, National Cancer Institute, National Institute on Aging, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH Office of Dietary Supplements, and NIH Office of Autoimmune Disease Research, Office of Research on Women’s Health. This broad engagement reflects a strategic refocusing on the importance of nutrition in the development and function of intestinal mucosal immunity and its relevance to the work of virtually every component of NIH. The workshop brought together NIH staff, research scientists, clinicians, people living with digestive diseases, and advocacy groups, with the goals of understanding the current state of the science, identifying knowledge gaps, and discussing avenues to close these gaps (Table).

Table.

High-Level Overview of Key Themes That Emerged During the Workshop, Including Gaps Impacting the Patient Experience in Immune-Mediated Inflammatory Diseases of the Gastrointestinal System, Gaps Impacting Translation of Basic Research Findings Into Clinical Care, and Gaps in Research That Limit Advancement in the Fields of Nutrition and Mucosal Immunity

	Gap	Bridge	Target
Patient experience	Allergens are not reliably labeled on packaged foods.	•Prioritize listing food allergens on packaged foods. •Follow international recommendations on food labeling.2	Ubiquitous food allergy labeling.
	The cost of safe (allergen-free) food can be a barrier to health.	•Consideration of nutrition as a social determinant of health. •Food as medicine (coverage by Payors). •Increase market options for safe foods.	Affordable and accessible nutritious, nonallergenic food
	Translation disconnection in nutrition research.	•Collaboration between clinical and translational research teams. •Refocus mechanistic research aims with patient experience in mind.	Synergistic approaches to nutrition science focused on patient-relevant outcomes.
	Limited practical information available to patients on specific diet-based interventions for disease management.	•Include registered dietitians in interdisciplinary care teams to provide guidance on food selections and interpretation of scientific literature. •Engage patient advocacy groups to provide emotional support in the form of a patient community and help disseminate information. •Communicate research using patient-friendly and culturally competent language.	Individualized dietary interventions targeting patient symptoms and goals
Clinical translation	Data from well-designed dietary intervention studies in human populations are limited.	•Resource generation and availability, including biorepositories and clinical data. •Increase financial support for longitudinal cohort studies. •Implement policy consistent with a focus on dietary interventions.	Publicly available data from well-designed dietary intervention studies in human populations.
	No “control” diet is defined for clinical or animal studies.	•Evaluate how common animal diets may be relevant to human diets. •Collaboration between investigators working in animal and human populations. •Identify specific aspects of dietary content that impact clinically relevant outcomes.	Consensus on what constitutes a “control” diet, with respect to micro- and macronutrient content.
	Ambiguity in diet-related terms (eg, “high-fat,” “low-fat,” “ketogenic,” “Mediterranean,” “diet diversity,” and “fasting”) constrains research.	•Generate consensus on key diet-related terms in basic and clinical settings. •Use of objective biomarkers for specific diets (eg, serum beta hydroxy butyrate levels to quantify ketogenic diets).	Unification of terms in research contexts and clear dissemination of specific features of each diet to clinical populations.
Research Gaps	Mechanisms through which nutritional and human milk components regulate establishment and maintenance of mucosal immunity are not fully characterized.	•Expand research to identify and characterize human milk oligosaccharides (HMOs), food antigens, and immunoglobulins (Igs) that impact infant gut microbiome and metabolism. •Characterize the role of regulatory T cells and natural killer T cells and related signaling pathways in the establishment of mucosal immunity. •Characterize the interplay between the microbiota and IgA in the development of T cell-mediated inflammation. •Develop of interventions that can modify the microbiota to favor a noninflammatory environment in the gut.	Identification of human milk components’ role in short and long-term infant health, and application of this information for therapeutic or preventative intervention.
	Individual components of human milk conferring protection from necrotizing enterocolitis are not established.	•Clinical studies aimed at identifying the pathogenesis resulting from exaggerated pro-inflammatory immune response to bacterial dysbiosis in NEC. •Mechanistic studies aimed at understanding the interaction of antibiotic treatment, human milk, and NEC. •Due to the rarity of NEC, multisite studies and collaborations are needed to move human research forward.	Identification and isolation of protective compounds in human milk for therapeutic use and development of novel preventive strategies such as precision nutrition-based approaches.
	Specific maternal health variables that impact infant health are incompletely understood.	•Conduct longitudinal studies of mothers and infants that are adequately powered to model the complexity of human experience. •Evaluate wide-ranging variables including maternal hormones, genetic variations, diet, age, nutrition, immunization, and environmental exposures on maternal milk, infant gut, and health outcomes. •Expand research into possible association between dietary antigens in human milk and subsequent food allergies.	Characterization of specific intrinsic and extrinsic maternal health variables that impact short- and long-term infant health, with the goal of modifying these variables for optimal health outcomes.
	Crosstalk between the microbiota, immune system, and other systems such as nervous and respiratory systems is not fully characterized.	•Identify molecular mechanisms and bioactive compounds from the microbiota that warrant additional research. •Characterize specific microbial changes and related molecular pathways and cellular responses that confer health benefits. •Evaluate differences in dietary requirements and microbiota composition across the lifespan and disease states. •Expand understanding of how group 3 innate lymphoid cells help to establish tolerance.	Development of microbiota-targeted therapeutic interventions for diseases within and outside of the primary digestive tract.
	Lack of biomarkers of mucosal immune function limits research progress and translation into clinical care.	•Microbiome endotyping to predict diet response. •Prospective analysis of microbiome shifts before disease onset. •Multi-omic analyses for predictive modeling of future disease onset. •Availability of biological samples from the GI tract linked to clinical and molecular data.	Robust, clinically relevant, validated biomarkers of mucosal immune function are available to inform diagnosis, prognosis, and treatment response.
	Mechanisms of T cell-dependent IgA induction, which are critical in shaping the microbiota, are not fully characterized.	•Identify specific intestinal bacteria or their metabolites that induce Th17 responses. •Characterize Th17/IgA/microbiota axis in mediating inflammation.	Harness the interaction of T cells, IgA, and microbiota for therapeutic intervention in inflammatory diseases.
	The breadth and complexity of the microbiota and its impact on health is rapidly expanding.	•Characterize mechanisms by which microbial metabolites regulate the function of intestinal stem cells, reprogramming of epithelial mucosa, and the onset of pathogenesis. •Consider the role of combining factors and coordinated responses from the microbiota or the diet on outcomes. •Include viral, fungal, and other microbiological triggers and their commensal counterparts in conceptualizing the microbiota.	Continued growth in collective understanding of the microbiota and development of novel approaches to harness the therapeutic potential of these systems.

In Addition, Suggested Approaches to Bridge These Gaps and Ultimate Targets Discussed at the Workshop Are Summarized.

The scientific sessions across the 2-day workshop incorporated presentations, question and answer sessions, and panel discussions that facilitated engagement from in-person and virtual attendees. Overarching topics encompassed the role of nutrition in maintaining intestinal homeostasis and the potential of precision nutrition to alter intestinal disequilibrium during disease states across the lifespan. Key gastrointestinal conditions discussed included celiac disease, inflammatory bowel disease (IBD)—including Crohn’s disease and ulcerative colitis, necrotizing enterocolitis (NEC), colorectal cancer, eosinophilic esophagitis, and food allergies. Bringing together a broad set of stakeholders provided a uniquely collaborative approach to move the field forward in a holistic fashion that would inform policy, programs, and practices.

Critical Commentary

The perspective of patients living with IMID-GI was an essential element of the workshop. Two patient participants, a rising sixth grader and an adult, related their personal experiences with IMID-GI. Both shared the profound impact on daily activities, noting the burden of finding safe foods and the practical and emotional effects of constant fear that consuming food could lead to physical incapacitation or death. The financial impact of living with the disease also was emphasized. These testimonies served as a reminder that the United States is not a leader in food labeling regulations and falls short of international standards. As there is no medical cure for many IMID-GIs, safe food is often the only form of treatment for patients. Thus, improving food labeling standards that include ingredient listing and composition information would be expected to have an immediate impact on public health.

Factors such as the gut microbiome, host immune system, and nutritional status that determine the body’s response to diet-based interventions and related clinical observations were explored. Participants agreed that studying these factors both mechanistically and at the population level can reveal drivers of autoimmunity and inform the development of novel therapeutics. However, a concentrated focus on laboratory-based research in isolation can lead to critical knowledge gaps and bottlenecks in translation of research to patients. Findings from basic science or modeling studies must be validated with interventional studies in clinical populations to inform personalized dietary recommendations.

The need for high quality dietary intervention studies in research and clinical settings emerged as a strong theme throughout the workshop. A “control” diet has not been defined for animal or clinical studies, and there is a lack of consensus on definitions of diet-related terms such as “high-fat,” “low-fat,” “ketogenic,” “Mediterranean,” “diet diversity,” and “fasting.” Unifying terms was noted as an important step toward a collective understanding of diet-based interventions and translation of research findings to clinical care. Dietary interventions used in animal studies often do not recapitulate the complexity of human experience with respect to diet diversity, environmental exposures, circadian cycles, or adherence to highly restrictive diets. A recently published summary of primarily observational studies reinforced the dearth of available data from carefully controlled dietary intervention studies in human populations.³ Such data are needed to understand the effects of specific diets on human health. Specifically, discussion focused on the need to characterize the optimal “dose” of these diets, the populations for which they are most helpful, and the potential risks and benefits of each. Participants encouraged refocusing correlative dietary intervention studies in animal models with the long-term goal of translation into humans and conducting clinical studies using clear and validated metrics and outcomes.

Key Takeaways

The Role of Nutrition in Mucosal Immunity Across the Lifespan

The impact of nutrition on mucosal immunity and health across all life stages, from the prenatal period to advanced age, was a theme throughout the workshop. The state of the science and gaps in knowledge, as well as approaches to close these gaps and advance the field were discussed.

Prenatal and perinatal infant health

The largest microbial transfer to an infant generally happens during birth; however, prenatal events and exposures can impact immune system development. There can be dramatic compositional shifts in the gut microbiome during the first 2–3 years of life during which host–microbe symbiosis is established. Disrupting this process through antibiotic exposure or other environmental, lifestyle, and diet changes can have long-lasting clinical consequences.

Human milk contains components that can facilitate the transition of the infant to extrauterine life, including human milk oligosaccharides, food antigens, and immunoglobulins. These components can impact mucosal and systemic immune systems by altering the gut microbiome and metabolism and by directly modulating immune and intestinal epithelial barrier functions. For example, human milk is known to be effective at reducing the incidence of NEC in very low birth weight neonates.⁴ Intrinsic and extrinsic factors including maternal hormones, genetic variations, diet, age, nutrition status, and the environment influence the contents of maternal milk.^5,6 However, the specific impact of these factors on infant health is not completely understood. Further, human milk components have been shown to increase tight junctions in intestinal epithelial cells and promote immune system homeostasis by regulating proinflammatory and anti-inflammatory immune system responses.⁷ Additional research is needed to gain deeper insight into the mechanisms by which components of human milk regulate the establishment and maintenance of microbiota-host crosstalk, improve neonatal outcomes, and promote immune development in the infant gut.

Age-associated changes

Although advancing age is a primary risk factor for many diseases, aging alone is not sufficient to cause age-associated diseases; intermediary triggers are also important. The gut microbiome changes with age, becoming more inflammatory which can promote gut permeability.^8,9 A decline in adaptive immunity and a chronic state of innate immune activation during aging lead to chronic inflammation, termed “inflammaging,” which result in functional decline or chronic disease.¹⁰ In addition, microbiome shifts in postmenopausal women correlate with systemic inflammation and associated risk for cardiovascular disease, breast cancer, obesity, diabetes, and dyslipidemia.¹¹ Inflammation may be controlled by blocking mechanisms upstream of the NLRP3 inflammasome, which senses damage-associated molecular patterns related to adenosine triphosphate, cholesterol, reactive oxygen species, ceramides, fatty acids, uric acid, pathogens, and pathogen-associated molecular patterns. Blocking these mechanisms has been shown to protect from conditions associated with aging such as bone loss, cognitive decline, and glucose intolerance, and to increase lifespan in animal studies. In addition, the negative energy balance resulting from caloric restriction has been shown across species to drive immunometabolic responses that promote longevity and lower disease burden.¹² Reduced inflammation, enhanced thymopoiesis, and induction of transcriptional reprogramming were recently demonstrated in a cohort of healthy humans undergoing a 14% caloric reduction for 2 years.¹³ Workshop participants noted the need for additional dietary intervention studies in human populations aimed at understanding how caloric intake and dietary composition impact the tissue-resident immune system and the control of inflammation across the lifespan.

Gaps Limiting Clinical Care Advancement

Workshop participants reached consensus in several areas across sessions that touched on current barriers to translation of scientific findings into clinical care and scientific gaps in the fields of nutrition, mucosal immunity, and IMID-GI. The workshop format enabled collaborative discussion of approaches to fill identified gaps.

Clinical translation gaps

Collaboration between clinical and basic science researchers, as well as among researchers, patients, clinical care teams, and funding organizations, is needed for research efforts to improve patient-centered outcomes that impact clinical care. For example, identification of key aspects of maternal health that impact long-term infant outcomes is considered crucial. Accomplishing this will require close partnership between clinical scientists conducting carefully designed longitudinal cohort studies of the mother and baby, basic scientists conducting studies on the mechanistic underpinnings of these observational studies, and collaborative teams conducting randomized controlled trials using clear and validated methods with the goal of clinical translation.

Limited practical information is available to patients on specific diet-based interventions. Inclusion of registered dietitians in interdisciplinary care teams is needed to provide guidance on food selections and interpretation of scientific literature for patients. Without access to a multispecialty care team, patients do not have adequate information on symptom management or disease prognosis. IMID-GI, such as celiac disease and IBD, may also be diagnosed and managed by medical specialists outside of gastrointestinal and nutrition specialties, including endocrinology, allergy/immunology, and rheumatology. In addition, bidirectional interactions have been observed between the gut microbiome and multiple body systems, including innate and adaptive immune, nervous, and endocrine systems. Collectively, these observations highlight the breadth of the impact of diet on mucosal immunity and reinforce the need for interdisciplinary approaches to research and clinical care. Advocacy groups are another critical piece of the infrastructure needed to advance patient care. They can provide resources and emotional support in the form of a patient community, communication to the public, and funds for critical research on understudied diseases.

Workshop participants also discussed emerging data on clinical biomarkers of mucosal immune function. Potential approaches to quantify mucosal immune function or outcomes in interventions include microbiome endotyping to predict diet response, prospective analysis of microbiome shifts before disease onset, and multiomic analyses (metagenomic, genomic, epigenomic, metabolomic, etc.) for predictive modeling of future disease onset across the lifespan.

The development of novel research tools and availability of resources are critically needed to drive innovation toward these goals. Specifically, biological samples from the GI tract that are linked to clinical and molecular data are needed for identification of biomarkers of mucosal immune function. The Crohn’s and Colitis Foundation Precision Nutrition Initiative and IBD Plexus resources may serve as a starting point for such collaborative approaches.^14,15

Mechanistic considerations and research gaps

Alteration of the gut microbiome is a contributor to IMID-GI as well as colorectal cancer and conditions impacting nondigestive systems such as multiple sclerosis (MS). Nutritional components and dietary patterns influence mucosal homeostasis by affecting the intestinal immune system and gut permeability. Though T cell-dependent IgA induction is critical in shaping the microbiota, mechanisms underlying T helper 17 cell induction by specific intestinal bacteria and their interaction with IgA are not fully understood. Additional research is needed to characterize how the T helper 17–IgA–microbiota axis mediates inflammation and how these processes may be modulated to combat inflammatory disease.

Type III innate lymphoid cells play a critical role for the maintenance of intestinal barrier integrity, host-microbiota homeostasis, and may influence the development of immune response to antigens in the central nervous system. The gastrointestinal tract is densely innervated by the peripheral nervous system and populated by immune cells and microbiota; intestinal immune responses are also mediated via the gut–brain axis. Dietary mediators can directly and quickly affect intestinal immune and metabolic responses via enteric neurons that integrate rapid intestinal immune changes in response to the diet. Type III innate lymphoid cells play an important role in establishing tolerance, particularly in the small intestine. These cells are enriched in the gut and orchestrate lymphoid organogenesis, promote tissue repair, facilitate host defense, and maintain gut commensal bacteria.^16,17 Future research should focus on how neuroimmune signaling coordinates adaptations to dietary and microbial signals.

Additional knowledge gaps include the mechanisms by which microbial metabolites regulate the function of intestinal stem cells, reprogramming of epithelial mucosa, and onset of pathogenesis. Although presentations focused on the bacterial component of the microbiome, workshop participants noted that a complete definition of microbiota should consider viral triggers for conditions including MS, diabetes, and, possibly, celiac disease as well as fungal and other microbiological triggers and their commensal counterparts.

Conclusion

During the workshop, a wide scope of diseases and conditions was discussed including IBD, celiac disease, NEC, eosinophilic esophagitis, colorectal cancer, food allergies, metabolic endotoxemia, and age-associated conditions including chronic inflammation, menopause, and cardiovascular disease. The research gaps and opportunities that were identified ranged the entire translational research enterprise. Converging lines of evidence suggest that, in response to diet, the gut microbiome can undergo rapid changes to mediate pathogenic host immune responses; indicating these interactions may be particularly fruitful targets for mechanistic and therapeutic studies. Novel tools and analytic techniques are now available that, for the first time, allow integration of information on the genome, metabolome, microbiome, and environment. Additional research is needed to characterize interactions between the gut and other body systems, such as the respiratory and central nervous systems. This work will lead to a more comprehensive understanding of the pleiotropic effects of nutrition on human health and inform the development of diet-based interventions for prevention and treatment of IMID.

A prominent workshop theme was a sense of disconnect between patient experience and research targets in IMID-GI–related fields. Studies aimed at mechanistic aspects of IMID-GI may not necessarily be aligned to outcomes that improve quality of life for patients living with these conditions (Figure). Interpretation and translation of scientific findings into actionable plans, such as diet-based interventions, is needed. Workshop participants called for collective engagement between clinical and translational research teams, such as expanding availability of clinical data and biological samples from IMID-GI cohorts, refocusing laboratory-based studies to be more representative of human disease, and broadening clinical care teams to include nutrition specialists. This integrated approach is critical to improving care, quality of life, and outcomes for people with IMID-GI and advancing the fields of nutrition and mucosal immunity.

Figure.

Current and ideal relationships between key partners in immune-mediated inflammatory disease research and clinical care. Across the 2-day workshop, research scientists, patients, advocacy group representatives, nutrition specialists, and clinicians noted the need for cross-discipline collaboration. An integrated, patient-centered approach was considered necessary to improve care, quality of life, and outcomes for patients and critical to advance research and clinical care in the fields of nutrition, mucosal immunity, and inflammatory diseases. The upper part of this figure represents the current relationship between key partners and clinical care providers that is not patient-centric. The lower part of the figure demonstrates a proposed strategy by workshop participants towards an “integrated, patient-centered approach to improve care, quality of life, and outcomes for patients and to advance research and clinical care in the fields of nutrition, mucosal immunity, and inflammatory diseases.”

Workshop organizers expressed their appreciation for the thoughtful contributions of the participants (in-person and virtual) and the opportunity for the insights shared to inform a research agenda that aims to fill critical scientific gaps, advance the nutrition field, and improve public health.¹⁸