INTRODUCTION

The poultry immune system plays a central role in determining resistance to bacterial, viral, and parasitic infections while maintaining physiological stability and production efficiency [1]. It comprises coordinated innate defenses, such as macrophages, heterophils, and dendritic cells, and adaptive components involving B and T lymphocytes [2, 3]. These systems interact closely with gastrointestinal health and microbial composition, forming the gut–immune axis, which is now recognized as a key regulatory network in modern poultry production [4]. Increasing evidence indicates that immune competence is not merely a defensive mechanism but a major determinant of resilience, productivity, and sustainability in intensive farming systems [5].

The poultry industry faces persistent challenges that compromise immune stability, including pathogen pressure, environmental stress, and management constraints [6, 7]. Historically, antibiotic growth promoters (AGPs) have been used to sustain productivity. However, their extensive application has raised global concerns regarding antimicrobial resistance (AMR), drug residues in animal products, and public health risks [8]. As regulatory restrictions on AGPs intensify, the development of safe and sustainable alternatives has become imperative [9]. In this context, strengthening immune regulation, rather than simply accelerating growth rate, has emerged as a strategic priority for long-term productivity and disease control [10].

Probiotics have gained considerable attention as functional feed additives that modulate gut microbial ecology and host physiology [11, 12]. Strains such as Lactobacillus spp., Bifidobacterium spp., and Bacillus spp. have been associated with enhanced innate immune activity, lymphocyte proliferation, improved mucosal (IgA) and systemic (IgY) antibody responses, and reinforced intestinal barrier integrity [13, 14]. Through competitive exclusion, antimicrobial metabolite production, and stimulation of mucosal immunity, probiotics contribute to inhibiting pathogens and maintaining intestinal homeostasis [15]. These multifaceted interactions highlight their potential to reinforce the gut–immune axis.

Although numerous reviews have discussed probiotic supplementation in poultry, most have primarily emphasized growth performance, feed conversion efficiency, or general health indicators. Such approaches often treat immune responses as secondary observations rather than central mechanistic drivers. In contrast, this review positions immune modulation as the principal analytical framework. Growth enhancement is interpreted as a downstream outcome of optimized immune–microbiota interactions, rather than the primary endpoint [8]. By integrating molecular, cellular, and organ-level evidence, this review synthesizes mechanistic insights into cytokine regulation, immune cell activation, gut-associated lymphoid tissue (GALT) dynamics, lymphoid organ development, oxidative stress modulation, and post-vaccination immune responsiveness.

Despite promising findings, significant inconsistencies persist in the literature due to strain-specific variability, differences in dosage and supplementation duration, heterogeneity in experimental designs, and limited long-term commercial validation [16–18]. Most existing reviews address probiotics from a performance-oriented perspective, with limited integration of detailed immunological mechanisms, including effects on GALT, lymphoid organ development, cytokine networks, oxidative stress pathways, and vaccine responsiveness. There is a clear need for a focused, mechanism-driven synthesis that bridges molecular and cellular insights with practical translational outcomes in commercial poultry systems. Such a synthesis is essential for resolving conflicting results and providing evidence-based guidance for probiotic applications as sustainable AGP alternatives [19, 20].

Accordingly, this review aims to elucidate the mechanistic pathways through which probiotics regulate innate and adaptive immune responses in poultry; analyze their effects on GALT and lymphoid organ modulation; evaluate their influence on post-vaccination immunity and pathogen resistance; examine molecular signaling interactions within the gut–immune axis, including cytokine networks and oxidative stress regulation; and assess their role as sustainable alternatives to AGPs from an immunological and translational perspective. By synthesizing current evidence and highlighting knowledge gaps, this review aims to provide a comprehensive framework to support the development of targeted, immune-centric probiotic strategies to improve poultry health, productivity, and sustainability.