Many dietary fatty acids (FA) have potent effects on inflammation, which is not only energetically costly, but also contributes to a range of chronic diseases. This presents an evolutionary paradox: Why should the host initiate a costly and damaging response to commonly encountered nutrients? We propose that the immune system has evolved a capacity to modify expenditure on inflammation to compensate for the effects of dietary FA on gut microorganisms. In a comprehensive literature review, we show that the body preferentially upregulates inflammation in response to saturated FA that promote harmful microbes. In contrast, the host opften reduces inflammation in response to the many unsaturated FA with antimicrobial properties. Our model is supported by contrasts involving shorter-chain FA and omega-3 FA, but with less consistent evidence for trans fats, which are a recent addition to the human diet. Our findings support the idea that the vertebrate immune system has evolved a capacity to detect diet-driven shipfts in the composition of gut microbiota from the profile of FA consumed and to calibrate the costs of inflammation in response to these cues. We conclude by extending the nutrient signaling model to other nutrients, and consider implications for drug discovery and public health.