Tradeoffs in milk immunity affect infant infectious disease risk

Abstract

Background and objectives The human immune system has evolved to balance protection against infection with control of immune-mediated damage and tolerance of commensal microbes. Such tradeoffs between protection and harm almost certainly extend to the immune system of milk. Methodology Among breastfeeding mother-infant dyads in Kilimanjaro, Tanzania, we characterized in vitro proinflammatory milk immune responses to Salmonella enterica (an infectious agent) and Escherichia coli (a benign target) as the increase in interleukin-6 after 24 hours of incubation with each bacterium. We characterized incident infectious diseases among infants through passive monitoring. We used Cox proportional hazards models to describe associations between milk immune activity and infant infectious disease. Results Among infants, risk for respiratory infections declined with increasing milk in vitro proinflammatory response to S. enterica (HR: 0.68; 95% CI: 0.54, 0.86; p: 0.001), while risk for gastrointestinal infections increased with increasing milk in vitro proinflammatory response to E. coli (HR: 1.44; 95% CI: 1.05, 1.99; p: 0.022). Milk proinflammatory responses to S. enterica and E. coli were positively correlated (Spearman’s rho: 0.60; p: 0.000). Conclusions and implications These findings demonstrate a tradeoff in milk immune activity: the benefits of appropriate proinflammatory activity come at the hazard of misdirected proinflammatory activity. This tradeoff is likely to affect infant health in complex ways, depending on prevailing infectious disease conditions. How mother-infant dyads optimize proinflammatory milk immune activity should be a central question in future ecological-evolutionary studies of the immune system of milk. Lay Summary While vital to infant health, the immune system of milk (ISOM), like all immune activity, comes with potential for both protection and harm. We described the ISOM’s capacity to respond to bacteria among mother-infant pairs, and found that milk immune activity may both lower and increase infants’ infectious disease risk.

Does the immune system of milk increase activity for infants experiencing infectious disease episodes in Kilimanjaro, Tanzania?

“…expectation, we find no evidence that milk sIgA or ISOM capacity for pro-inflammatory activity change to meet elevated infant need during an ID episode among mother-infant dyads in Kilimanjaro, Tanzania. These measures of milk immune activity clearly capture an important component of the ISOM's capacity to protect infants against ID: sIgA and the IL-6 response to S. enterica are associated with lower risk for ID, particularly respiratory ID, while IL-6 response to E. coli is associated with higher risk for gastrointestinal ID (Wander et al, 2022). If the ISOM were dynamically meeting infant needs with enhanced protection against ID, we would expect sIgA and/or IL-6 response to S. enterica to increase and IL-6 response to E. coli to decrease at infant sick visits.…”

“…The in vitro environment is dissimilar to the infant gut in important ways (e.g., the absence of gut‐associated lymphoid tissue) that limit our ability to characterize immune activity beyond pro‐inflammatory responses; we could not capture adaptive immune responses or anti‐inflammatory immunoregulation (Wander et al, 2021). However, the clear connection these variables have to ID risk among infants recommends them for testing our hypotheses (Wander et al, 2022).…”

“…Although the value of milk immune factors is often inferred from their presence in milk and their role in immune activity in general, remarkably few studies have explored the impact of variation in ISOM characteristics (e.g., milk immune content) on infants' risk for ID. We previously assessed the impact of milk immune factor content (secretory immunoglobulin A and the pro‐inflammatory cytokine interleukin‐6, IL‐6) and milk immune reactivity measured in vitro (IL‐6 responses to Salmonella enterica and Escherichia coli ) on infant ID risk and found that milk IL‐6 responses to S. enterica , and to a lesser extent, milk sIgA concentration, were associated with decreased risk for respiratory infections, while milk IL‐6 responses to E. coli , a benign stimulus, were associated with higher risk for gastrointestinal infections (Wander et al, 2022). We thus interpret the in vitro IL‐6 response to S. enterica as a biomarker of the ISOM's capacity for protective pro‐inflammatory activity and the in vitro IL‐6 response to E. coli as a biomarker of the ISOM's capacity for misdirected pro‐inflammatory activity.…”

Associations between milk cortisol and activity of the immune system of milk

“…We focus here on sIgA and in vitro IL‐6 responses to bacteria as components of the ISOM that are connected with infant infectious disease risk (Agarwal et al, 2011; Ballard & Morrow, 2013; Breakey et al, 2015; Field, 2005; Fujita et al, 2019; Palkowetz et al, 1994; Wander et al, 2021). Higher milk sIgA is associated with decreased risk for gastrointestinal (Breakey et al, 2015) and respiratory infections (Wander et al, 2022) among infants. Additionally, in vitro milk IL‐6 responses to Salmonella enterica are protective against infant respiratory infectious diseases (Wander et al, 2022).…”

“…Higher milk sIgA is associated with decreased risk for gastrointestinal (Breakey et al, 2015) and respiratory infections (Wander et al, 2022) among infants. Additionally, in vitro milk IL‐6 responses to Salmonella enterica are protective against infant respiratory infectious diseases (Wander et al, 2022).…”