Maternal circadian rhythm writes immune fate in offspring.

Abstract

An organism's environment is rarely constant. Light, temperature, humidity, food availability, and microbial exposure often fluctuate rhythmically, creating daily patterns that organisms must anticipate and respond to (Paranjpe and Sharma 2005; van der Linden et al. 2010; Thaiss et al. 2014). The ability of biological systems to align physiology with such environmental cycles has fascinated biologists for decades, and circadian regulation is now known to influence diverse processes, including metabolism, behaviour, development, immunity, and stress responses (Fagiani et al. 2022; Poole and Kitchen 2022). Whether environmental rhythms experienced by the mother can influence offspring physiology has only begun to be explored (Yao et al. 2025). In a recent study, Lalsiamthara et al. (2026) provide compelling evidence that infection vulnerability in offspring can be shaped by maternal circadian rhythms. Using Caenorhabditis elegans, the authors first asked whether genetically similar animals differ in a measurable pre-infection state that anticipates later infection outcomes. They focused on irg-5, a PMK-1/p38 MAPK-regulated infection-response reporter (Peterson et al. 2019), and found that animals with high basal irg-5 expression before infection were more susceptible to subsequent Pseudomonas aeruginosa PA14 challenge. Importantly, this high-irg-5 state was not simply a sign of generally poor health, because these animals did not show obvious differences in baseline lifespan, feeding, movement, or pathogen avoidance. The study then asked whether this pre-infection state could be influenced by maternal circadian rhythms. Mothers were exposed to alternating 12 h light/20 C and 12 h dark/15 C cycles, mimicking daily fluctuations that worms may experience in nature. This entrainment did not increase irg-5 expression in the mothers themselves; instead, it rhythmically altered the proportion of offspring entering the high basal irg-5 state. The transgenerational effect of this state was further supported by the observation that high-irg-5 mothers produced more high-irg-5 offspring than low-irg-5 mothers. Consistent with clock-associated regulation, knockdown of nhr-23, a C. elegans homolog of mammalian ROR clock genes (Hiroki and Yoshitane 2024), disrupted this rhythmic oscillation. Together, these experiments connect maternal environmental timing, offspring immune-marker heterogeneity, and infection vulnerability in a single framework. These observations raise mechanistic and evolutionary questions. Mechanistically, what maternal cues are transmitted to offspring: metabolites, small RNAs, chromatin-associated states, or nutrients, and how do they influence basal immune state? Evolutionarily, why might mothers generate heterogeneous offspring states, especially when the high-irg-5 state increases susceptibility to PA14 in this study? One possibility is that this state is not universally maladaptive. Caenorhabditis elegans inhabits transient microbe-rich substrates such as rotting vegetation and compost, where temperature, humidity, food availability, and microbial communities can fluctuate with daily cycles (Schulenburg and Felix 2017). In such habitats, rhythmic cues are not merely background variables; they may act as reliable signals of changing risk. Temperature cycles can influence worm development, movement, and feeding, while also altering microbial growth and community composition (Felix and Braendle 2010). Light exposure may be indirect in soil or rotting-fruit microenvironments, but together with temperature it can serve as a proxy for day-night transitions (van der Linden et al. 2010). Maternal entrainment to these cues could therefore allow offspring physiology to be adjusted in anticipation of conditions that are likely, but not guaranteed, to follow. A state that is costly against one pathogen may be beneficial under other microbial, thermal, or nutritional conditions. Maternal generation of heterogeneous offspring states could therefore resemble bet-hedging, spreading risk across uncertain environments rather than optimizing all progeny for a single challenge. In a self-fertilizing organism with limited genetic diversity, such non-genetic heterogeneity could increase the chance that at least some individuals are appropriately tuned to future conditions. This idea could be tested further by asking whether natural genetic variation or microbiome context modifies intergenerational circadian immune heterogeneity in C. elegans. Such modifiers are plausible since, in mice, the gut microbiome can influence host circadian gene expression and metabolic rhythms (Thaiss et al. 2014), while in humans, genetic variation has well-established effects on circadian timing and behaviour (Kalmbach et al. 2017). Wild C. elegans isolates and defined natural microbiota (Dirksen et al. 2020) would therefore provide useful context to ask about the general nature and ecological sensitivity of this phenomenon. Beyond circadian regulation of intergenerational immune heterogeneity, the study also raises an important point about how basal immune markers should be interpreted. The irg-5 result is counterintuitive because irg-5 is an established PMK-1-regulated infection-response gene (Peterson et al. 2019), yet animals with high basal irg-5 expression were more susceptible to PA14. This does not mean that immune activation is generally harmful, or that irg-5 alone defines immune status. Instead, the same immune-marker expression may have different implications before and after infection: pathogen-induced expression may participate in defence, whereas high basal expression may mark altered intestinal homeostasis, metabolic imbalance, low-grade stress-pathway activity, or marker-specific transcriptional regulation. Mechanistically, prior ChIP data support binding of UNC-62 (MacNeil et al. 2015), a conserved MEIS/homeobox transcription factor (Van Nostrand et al. 2013), near the irg-5 promoter, and the present study shows that loss of UNC-62 increases basal irg-5 expression in mothers through PMK-1 and ELT-2. Thus, basal irg-5 heterogeneity appears to be a regulated transcriptional state shaped by UNC-62-dependent control. More broadly, this adds to an emerging view in C. elegans immunity that conserved developmental regulators can be redeployed in differentiated tissues to tune adult immune defence (Drury et al. 2023; Liu et al. 2024). The broader relevance of this work lies in connecting two ideas that are often considered separately: circadian regulation of immunity and maternal shaping of offspring physiology. Mammalian studies have shown that immune function is strongly time-of-day dependent, and that disruption of circadian rhythms can alter inflammatory responses and susceptibility to infection (Curtis et al. 2014; Poole and Kitchen 2022). Separately, the maternal environment, for example, nutritional state during pregnancy and lactation, can shape offspring metabolic, developmental, and behavioural physiology (Yao et al. 2025). Lalsiamthara et al. (2026) bring these themes together in a genetically tractable organism by showing that maternal circadian rhythms can shape infection-relevant heterogeneity in the next generation. Although the molecular details may be partly conserved and partly organism- or context-specific, the conceptual message is broad: before the pathogen arrives, vulnerability may already carry the imprint of time, ancestry, and environment.