INNATE IMMUNITY

Innate immunity in birds serves as the initial defense against various infectious agents and plays a crucial role in maintaining physiological stability [93]. Various immune cells, such as macrophages, heterophils, dendritic cells, and natural killer (NK) cells, work together to recognize, phagocytose, and eliminate pathogens through rapid and nonspecific mechanisms. In recent years, probiotics, such as Lactobacillus spp., Bifidobacterium spp., and Bacillus spp., have been shown to enhance innate immune responses through both direct and indirect pathways [94]. However, these immunomodulatory effects are strain-specific and should not be generalized across all probiotic species or formulations.

Immune system component | Specific structures/cells | Main immunological function | Role of probiotics in immune modulation | References
Mucosal immunity (GALT) | Peyer’s patches | Luminal antigen surveillance, M cell-mediated antigen sampling, antigen presentation, and differentiation of B cells into IgA-secreting plasma cells | Enhance mucosal IgA production, promote dendritic cell-mediated antigen presentation, inhibit pathogen adhesion, and strengthen epithelial barrier integrity | [84–86]
 | Bursa of Fabricius | Primary site of B cell maturation, differentiation, and antibody repertoire development in birds | Promote B cell maturation and enhance systemic and mucosal humoral immune responses | [87–89]
 | Pharyngeal tonsils and cecal tonsils | Antigen recognition in the proximal and distal intestinal tract, regulation of inflammatory responses, and maintenance of immune tolerance to commensal microbiota | Enhance T- and B cell activation, modulate local cytokine responses, and improve vaccine-induced mucosal and systemic immunity | [90–92]
Innate immunity | Macrophages | Phagocytosis and production of inflammatory mediators, including IL-1β and TNF-α | Enhance phagocytic activity and early cytokine production through pattern recognition receptor-mediated signaling | [93–97]
 | Heterophils | Rapid degranulation, respiratory burst, and nonspecific elimination of pathogens | Enhance degranulation and respiratory burst activity, although responses are strain-dependent | [98]
 | Dendritic cells | Antigen presentation and activation of T and B lymphocytes | Increase expression of co-stimulatory molecules and enhance lymphocyte activation and adaptive immune responses | [99–100]
 | Natural killer (NK) cells | Cytotoxic elimination of virus-infected and abnormal cells | Enhance cytotoxic activity through probiotic-derived metabolites and microbiota-mediated immunomodulatory signaling | [101–104]
Adaptive immunity | B cells (humoral immunity) | Production of IgA, IgM, and IgY antibodies and establishment of immunological memory | Promote B cell proliferation, increase mucosal IgA secretion, and enhance post-vaccination antibody responses (e.g., NDV and IBDV) | [105–108]
 | T lymphocytes (cellular immunity) | CD4⁺ T cells coordinate immune responses and regulate cytokine production; CD8⁺ T cells eliminate infected cells | Promote T cell proliferation and maintain balanced cytokine responses, particularly IL-10 and IFN-γ | [109–116]
Gut–immune axis | Intestinal epithelium, gut microbiota, and GALT | Maintenance of immune homeostasis, epithelial barrier integrity, microbial tolerance, and coordinated responses to pathogens | Maintain microbiota balance, promote short-chain fatty acid production, reinforce epithelial barrier function, and modulate innate and adaptive immunity | [117–129]
Gut–immune–climate axis (proposed concept) | Gut microbiota, intestinal epithelium, immune cells, and environmental stressors | Integration of thermal stress, immune resilience, microbial homeostasis, and host adaptation under climate-related challenges | Heat-stable probiotics may preserve microbiota balance, maintain mucosal immunity, and reduce physiological stress biomarkers during heat stress | [130–135]

Direct effects occur via interaction of probiotic-associated molecular patterns (e.g., peptidoglycan, lipoteichoic acid) with host PRRs, such as Toll-like receptors (TLRs), expressed on epithelial cells and innate immune cells. The magnitude and direction of PRR-mediated signaling vary depending on the specific strain and its structural components. This interaction activates intracellular signaling pathways that modulate cytokine production and immune cell activation [95].

Macrophages play a key role in phagocytosis and in the production of inflammatory mediators [96]. Probiotic administration has been shown to enhance macrophage phagocytic capacity and increase early-stage cytokine expression, such as interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α), primarily through PRR-mediated signaling [97]. However, these effects are strain-specific and dose-dependent, and not all probiotic candidates produce uniform activation across studies. Notably, these responses have been documented for selected strains under controlled experimental conditions and may differ with other strains or dosages. Heterophils may exhibit increased degranulation and respiratory burst activity following supplementation, although such effects are not uniformly observed across all probiotic candidates [98].

Indirect effects are mediated through modulation of gut microbiota composition and the production of microbial metabolites, such as SCFAs, which influence immune cell differentiation and inflammatory balance. Again, the extent of microbiota-driven immune modulation depends on the colonization ability and metabolic profile of the specific probiotic strain used [99]. Dendritic cells, which function to bridge innate and adaptive immunity, exhibit increased expression of costimulatory molecules and antigen-presenting capacity when the gut microbiota is modulated by probiotics. This activation contributes to optimal lymphocyte stimulation and a more effective adaptive immune response [100]. NK cell cytotoxic activity may also increase, partly driven by metabolite-mediated immunomodulatory signals rather than direct microbial contact alone [101].