The hidden cost of antibiotics: microbial dysbiosis-induced SCFA imbalance and its underlying mechanisms

Antibiotics, especially broad-spectrum types, disrupt the gut microbiota by indiscriminately killing both pathogenic and beneficial bacteria, leading to dysbiosis. This dysbiosis directly contributes to an imbalance in metabolites, such as short-chain fatty acids (SCFA) produced by gut bacteria from indigestible carbohydrates. Such shifts promote the selective expansion of facultative anaerobic pathogens, particularly Proteobacteria, thereby exacerbating epithelial oxidative stress and low-grade inflammation. Simultaneously, reduced SCFA availability disrupts tight junction expression, increases intestinal permeability, and impairs immune regulation by limiting Regulatory T cell (Treg) differentiation and attenuating G protein-coupled receptor (GPCR) (e.g., Free fatty acid receptor (FFAR) 2/3) and histone deacetylase (HDAC)-dependent anti-inflammatory pathways. Furthermore, antibiotic-induced SCFA depletion impairs GPCR-mediated signaling and disrupts vagal and enteroendocrine pathways that mediate gut-brain communication. Consequences of this antibiotic-dysbiosis-SCFA imbalance cascade include short-term issues like antibiotic-associated diarrhea (AAD), as well as long-term risks such as obesity, allergies, asthma, inflammatory diseases, and even impacts on brain development in neonates. In this review, we overview the mechanistic insights of how antibiotics reshape microbiota-derived SCFA profiles and highlight the implications for host health and disease, ultimately underscoring the need for targeted strategies such as microbiota restoration and prebiotic supplementation to mitigate these hidden consequences.