<p>The human gut microbiome is a dynamic and densely populated ecosystem where microbial gene exchange plays a central role in shaping both ecological interactions and host physiology. This review critically examines the mechanisms and implications of horizontal gene transfer (HGT) among natural and engineered probiotics within the human gut, with a specific focus on antibiotic resistance dissemination and metabolic modulation. We provide an in-depth analysis of the molecular pathways of conjugation, transformation, and transduction under anaerobic gut conditions, highlighting their roles in the spread of mobile genetic elements, including antibiotic resistance genes (ARGs) and functional metabolic traits. Special emphasis is placed on the dual nature of gene exchange: while beneficial traits such as vitamin biosynthesis and polysaccharide degradation can be horizontally acquired to enhance probiotic efficacy and host-microbe symbiosis, the uncontrolled dissemination of ARGs or synthetic constructs poses significant clinical and ecological risks. Through a synthesis of recent findings from metagenomics, microbial ecology, and synthetic biology, we explore how natural probiotics may act as reservoirs of ARGs, and how engineered strains—if not properly contained—may contribute to genetic instability in the gut. We also evaluate current containment strategies such as chromosomal integration, kill switches, auxotrophy, and orthogonal circuit design to limit horizontal spread, alongside emerging tools for in situ gene transfer monitoring. Finally, we discuss regulatory challenges and propose a context-dependent risk assessment framework in which the consequences of probiotic gene exchange are determined by cargo properties, host ecological niche, gut inflammatory status, and biocontainment design.</p>