Researchers from Tongji University highlight small intestine’s role in immune and metabolic diseases

The small intestine is not only essential for digestion and nutrient absorption but also for immune regulation and maintaining a balanced microbial population. The small intestine is lined with specialized epithelial cells and populated by diverse immune cells, which serve as a dynamic barrier between the body and the external environment. Among these specialized cells, Paneth cells and tuft cells are crucial for intestinal homeostasis. They work alongside immune cells such as intraepithelial lymphocytes, innate lymphoid cells, macrophages, and T cells to maintain mucosal integrity and prevent pathogen invasion. Dysfunction in these cell populations is associated with inflammatory bowel disease (IBD), celiac disease, metabolic syndrome, and autoimmune disorders.

Although the individual roles of both cells have been studied, most research has focused on individual cell types or disease-specific contexts. However, an integrated overview of how these epithelial cells, along with immune cells, work together to maintain gut integrity and regulate immune responses across both local and systemic levels, is lacking.

To address this lacuna, researchers from the Shanghai Tenth People's Hospital (Tongji University), Ruijin Hospital, and Wuhu First People’s Hospital, led by Prof. Zhanju Liu, conducted a comprehensive review. The review was published in the Chinese Medical Journal and made available online on May 20, 2025.

“In this review, we delve into the structural and functional characteristics of the small intestinal epithelia and immune cells and pinpoint the roles in intestinal homeostasis and the implications of the dysfunction in disease states,” explains Prof. Liu. “Moreover, we also explore emerging therapeutic strategies aiming at harnessing the unique properties of these cells and managing the intestinal and systemic diseases.”

Paneth cells, found at the base of intestinal crypts, are regulators of the gut's innate immunity. They secrete antimicrobial peptides, such as defensins and lysozyme, that control microbial populations and prevent the overgrowth of harmful bacteria. In addition, Paneth cells support the function of intestinal stem cells by secreting growth factors like Wnt and EGF, ensuring epithelial regeneration and barrier integrity. Mutations in genes related to Paneth cell functions, such as NOD2 and ATG16L1, are associated with Crohn’s disease and result in impaired barrier function and chronic inflammation.
Tuft cells function as chemosensors, detecting environmental cues like microbial metabolites and parasitic infections. When the cells detect an infection, they secrete cytokines such as IL-25, which activate type 2 immune responses via innate lymphoid cells. Tuft cells also contribute to tissue regeneration and act as reserve stem cells under certain conditions. Recent studies have shown that tuft cells proliferate and restore damaged intestinal epithelium after injury, making them promising targets for regenerative therapies.

Immune cells in the small intestine, such as intraepithelial lymphocytes (IELs), innate lymphoid cells (ILCs), dendritic cells, macrophages, and B cells, work in tandem with the epithelial cells to provide defense and tolerance. IELs promote epithelial repair and homeostasis, while ILCs regulate immune responses during infection. Macrophages eliminate pathogens and apoptotic cells, secrete anti-inflammatory cytokines, and aid in tissue regeneration. Dendritic cells sample antigens from the lumen and activate T cells, linking innate and adaptive immunity. In parallel, B cells in the intestinal lamina propria produce secretory immunoglobulin A (IgA), which coats the gut microbiota and neutralizes pathogens. Together, these cells regulate barrier integrity and shape the composition of the gut microbiota.

Dysfunction in these cellular networks is linked to systemic diseases. Altered Paneth or tuft cell activity can lead to microbial imbalance and increased intestinal permeability, allowing bacterial metabolites to enter circulation and trigger systemic inflammation. This mechanism is believed to contribute to obesity, insulin resistance, and autoimmune conditions such as rheumatoid arthritis and type 1 diabetes.

The review also highlights emerging therapeutic strategies that target intestinal epithelial and immune cells. These include enhancing antimicrobial peptide production, modulating the gut microbiome with probiotics or dietary interventions, and employing gene-editing technologies to correct mutations in Paneth cell-related genes. Tuft cells and their signaling pathways may also serve as novel therapeutic targets for inflammatory and allergic diseases. “The small intestine, often overshadowed by other organs, emerges as a cornerstone of human health, offering profound opportunities for scientific discovery and therapeutic innovation,” notes Prof. Liu

Taken together, the study provides a detailed map of the cellular players in the small intestine and underscores their importance in health and disease. “This knowledge will not only improve our ability to treat existing conditions but also pave the way for preventive strategies that enhance gut health and systemic well-being,” concludes Prof. Liu.

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Reference

Titles of original papers: The signature of the small intestinal epithelial and immune cells in health and diseases

Journal: Chinese Medical Journal

DOI: 10.1097/CM9.0000000000003615