Whispering Inflammation: Sex Shapes Responses to Chronic Low‐Grade Endotoxemia Across Behavior, Brain, and Metabolism

ABSTRACT Chronic low‐grade inflammation is implicated in obesity, type 2 diabetes, affective disorders, and neurodegeneration. Yet, most preclinical studies focused exclusively on males. Here, we conducted a comprehensive study of sex differences in the response to chronic low‐dose lipopolysaccharide (LPS) exposure in male and female rats using telemetric monitoring, behavioral testing, plasma and cecal metabolomics, fecal microbiome profiling, and hippocampal transcriptomics. LPS reduced food intake and slowed body weight gain in males but not females, with depot‐specific adipose tissue loss (inguinal in males, visceral in females) and increased liver weight in females only. Body temperature changes were small and had a distinct temporal and directional pattern in each sex. Males, but not females, displayed reduced locomotion. Plasma amino acids increased in males but decreased in females, while citrate and mannose were affected in both sexes. Cecal metabolomics revealed shifts in TCA cycle intermediates and short‐chain fatty acid precursors independent of sex. Taxon‐level, sex‐specific effects of chronic LPS were detected in the fecal microbiome. While circulating inflammatory factor changes were consistent with endotoxin tolerance in both sexes, hippocampal RNA sequencing revealed increased cytokine signaling and innate immune pathways in both sexes, with more robust changes in males. Anxiety‐like behavior was affected in males only. In females, LPS prolonged the estrous cycle through extended diestrus. These findings demonstrate that intermittent low‐dose LPS exposure produces widespread multi‐system sex‐divergent outcomes, with males showing greater central inflammatory and behavioral vulnerability and females exhibiting distinct peripheral metabolic, thermoregulatory, and reproductive consequences.