The Role of Human Leukocyte Antigen Genes in Shaping the Microbial Ecosystem of the Newborn Intestine

Introduction

The human gut is a dynamic ecosystem that hosts a vast and diverse array of microorganisms, collectively known as the microbiota. In early life, particularly during the neonatal period, the colonization of the gut microbiota is a crucial developmental process. The establishment of a stable and healthy microbiota has profound implications for the infant's immune system, metabolic health, and overall well-being. Among the many factors influencing the development of the gut microbiota, genetic determinantsâ??specifically, the genes encoding Human Leukocyte Antigens (HLAs)â??play an important role in modulating the immune system and, by extension, microbial colonization. Human Leukocyte Antigens (HLAs) are proteins encoded by the Major Histocompatibility Complex (MHC) genes. These proteins are involved in the immune response by presenting peptides to immune cells, allowing the body to recognize and respond to pathogens and other foreign molecules. The HLA system is highly polymorphic, and variations in these genes can influence an individualâ??s immune response to microbial organisms. In the context of the newborn intestine, HLA genes may not only affect the development of the immune system but may also influence how the gut microbiota is established and interacts with the developing immune system.

Description

The HLA system is part of the larger major histocompatibility complex (MHC) on chromosome 6, which plays a critical role in the immune response. The two primary classes of HLA molecules are Class I and Class II:

• HLA class I molecules(e.g., HLA-A, HLA-B, HLA-C) are expressed on almost all nucleated cells and present endogenous peptides to cytotoxic T cells (CD8+).
• HLA class II molecules(e.g., HLA-DR, HLA-DQ, HLA-DP) are expressed on antigen-presenting cells (APCs), such as dendritic cells and macrophages, and present exogenous peptides to helper T cells (CD4+).

The diversity of the HLA system is vast, with thousands of different alleles at each locus. This genetic diversity contributes to individual variations in immune responses to infections, vaccinations, and, notably, microbial colonization. The HLA systemâ??s role in immune regulation extends to the intestinal microbiota, which is a key player in immune system development, especially in the early stages of life.

At birth, the human gut is initially sterile but quickly becomes populated with microorganisms, primarily bacteria. The process of microbial colonization begins at birth, with the mode of delivery (vaginal versus cesarean section) significantly influencing the early microbiota. Other factors, such as diet (breastfeeding versus formula feeding), antibiotic exposure, and environmental factors, also play pivotal roles in shaping the microbiome during infancy. The colonization of the newborn gut is not random. It is influenced by a combination of environmental and host-related factors, including genetics. One key genetic determinant is the HLA system. By influencing immune responses, HLAs can impact how the newbornâ??s immune system interacts with the gut microbiota, influencing both the composition and function of the microbial community [1].

The immune system of the newborn is immature at birth and undergoes a process of development during the early months of life. During this period, the immune system needs to distinguish between harmless commensal microorganisms and potential pathogens. The microbiota plays a critical role in this process, as the developing immune system learns to tolerate beneficial microbes while defending against harmful ones. HLA molecules are central to this immune tolerance and activation process, influencing the balance between immune tolerance and immune activation. In the gut, immune cells constantly interact with microorganisms, using Pattern Recognition Receptors (PRRs) to recognize Pathogen-Associated Molecular Patterns (PAMPs) and Microbe-Associated Molecular Patterns (MAMPs). The HLA system, through the antigen presentation process, is key in shaping these immune responses. Variations in HLA genes can result in different patterns of immune responses, influencing the newborn's ability to regulate and respond to gut microbes. Some HLA alleles may predispose the individual to immune tolerance, supporting the establishment of a stable microbiota, while others might enhance the immune systemâ??s ability to recognize and eliminate foreign microbes, which can impact microbial diversity [2].

Several studies suggest that the HLA genotype may influence the composition of the gut microbiota in infants. HLA alleles that predispose the immune system to a particular immune response may impact the type and abundance of microbes that are able to colonize the infantâ??s gut. For example, certain HLA variants may be associated with a greater abundance of specific bacterial groups, such as Bifidobacterium or Lactobacillus, which are commonly found in the healthy infant gut. On the other hand, certain HLA alleles may be linked to an increased susceptibility to gut dysbiosis, which is an imbalance in the gut microbiota often characterized by a reduction in microbial diversity and an overgrowth of pathogenic microorganisms. The relationship between HLA genes and microbial colonization is complex and bidirectional. Not only can HLA genes influence the types of bacteria that colonize the newborn gut, but the gut microbiota itself can influence the expression of certain HLA genes. The presence of specific gut bacteria can activate immune responses in the gut-associated lymphoid tissue (GALT), which may, in turn, affect the expression of certain HLA molecules. This dynamic interaction shapes the developing immune system and microbial ecosystem in the infant gut [3,4].

One of the critical roles of the developing immune system in the newborn gut is to establish immune tolerance to commensal microbes, ensuring that beneficial bacteria can thrive without eliciting harmful immune responses. The presence of certain HLA alleles may facilitate the development of immune tolerance, while other alleles may make the immune system more prone to activation. For instance, individuals with certain HLA alleles may have a higher propensity for developing autoimmune responses or allergic diseases, which can be influenced by early-life microbial exposures. A balanced immune response, facilitated by the proper functioning of HLA molecules, is essential for maintaining a healthy microbiota. If the immune system is overly reactive, it may lead to the development of inflammatory conditions such as allergies, inflammatory bowel disease, or other autoimmune disorders. In contrast, impaired immune responses can lead to chronic infections or an inability to clear pathogenic microbes, resulting in dysbiosis [5].

Conclusion

Understanding the relationship between HLA genes and microbial colonization in the newborn offers exciting possibilities for therapeutic interventions. For instance, targeted probiotic treatments or dietary interventions could be used to manipulate the microbiota in ways that support healthy immune development, particularly for infants with HLA profiles that predispose them to immune-related diseases. Additionally, personalized medicine approaches based on an individualâ??s HLA genotype and microbiome profile may offer new strategies for preventing or managing diseases that emerge from early microbial colonization. As we continue to explore the complex interactions between genetics, the microbiome, and immune system development, we may uncover novel avenues for promoting long-term health from the very beginning of life. Human leukocyte antigen genes play a pivotal role in shaping the immune response and, by extension, the microbial ecosystem of the newborn intestine. The interplay between HLA genes and the developing gut microbiota is essential for establishing immune tolerance and promoting a balanced microbial community. Variations in HLA genes can influence microbial colonization patterns, immune responses, and susceptibility to disease. As research in this field progresses, understanding the impact of HLA genes on the early-life microbiome will be crucial for developing personalized strategies to promote infant health and prevent future disease.

Acknowledgement

None.

Conflict of Interest

There are no conflicts of interest by author.

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