Klebsiella pneumoniae (Kp) is a gram-negative, non-motile rod, endowed with a prominent sugar capsule, that is part of the Enterobacteriaceae family and that can present hypervirulence or multidrug-resistance features. It causes human respiratory, urinary tract, and systemic infections and it is considered as the third cause of deaths associated to and/or attributable with Antimicrobial Resistance (AMR). The intestine is the main reservoir of Kp in humans. Following antibiotic treatment, Kp can bloom in the intestine and translocate to the bloodstream, causing disseminated infections that are hardly difficult to treat. Importantly, Kp can also promote gut inflammation in mouse models and is enriched in the microbiota of Inflammatory Bowel Disease (IBD) patients, suggesting that the interaction between Kp and the immune system in the gut microenvironment could have important implications for distinct medical conditions. Commensal microbes and host immunity are both key modulators of the fitness of Kp in the gut and strongly impact its capacity to thrive and promote disease. In particular, the gut microbiota strongly limits Kp overgrowth, providing colonization resistance through multiple mechanisms, including nutrient competition and production of short-chain fatty acids. Immune responses can rather be seen as a double-edge sword as they can either limit or favour luminal expansion of Kp, in a context-dependent manner. However, despite being relevant to devise strategies to tackle Kp colonization and infection, the impact of disturbances in the intestinal environment on the fitness, survival, expansion, and drug susceptibility of this pathogen is not well-understood. Here, we investigated the adaptation of Kp to the gut lumen microenvironment, in the context of immune activation, competition with the microbiota, and therapeutic approaches, with the aim of identifying approaches to facilitate intestinal clearance of this relevant pathobiont. By using a murine model, ex vivo and in vitro approaches, we report that the intestinal colonization and the luminal changes occurring during inflammation induce a complex transcriptional rewiring possibly orchestrated by the cAMP-receptor protein (CRP). We finely define the transcriptional features acquired by Kp upon acute immune activation in the intestine, providing a roadmap to a deeper understanding of the pathobiont’s biology in inflammatory contexts. We furthermore show that such intestinal immune responses strongly impact on the clearance of Kp achieved through Fecal Microbiota Transplantation (FMT) and phage therapy. We speculate that the transcriptional rewiring of Kp occurring during inflammation may impact this phenomenon. Finally, by leveraging transcriptome data obtained in vivo and comparing them with in vitro cultures, we provide a detailed list of the carbon sources preferentially utilized by Kp in the gut lumen. Thus, this work provides unprecedented understanding of Kp adaptation to the gut lumen environment including utilization of carbon sources and responses to immunity, and exploits these concepts in the context of relevant therapeutic approaches.