Meera K. Shenoy

Maternal antibodies fundamentally regulate gut immunity in the developing infant, yet the mechanisms underlying this process remain elusive. We found that maternal immunoglobulin G (IgG), ingested in the first week of life, restrained microbiota-dependent adaptive immune responses weeks later, after weaning. This activity was linked to maternal antibodies that could bind bacteria in the neonatal gut and the ability of microbe-IgG complexes to engage Fc and complement-dependent effector functions in offspring. Ingestion of microbiota-specific maternal IgG also limited aberrant neonatal responses to dietary antigens encountered at weaning. These discoveries suggest that maternal IgG engages the immune system of offspring in early postnatal life to tune mucosal responses and reinforce intestinal homeostasis in the face of dynamic shifts in food and bacterial antigens during development.

Maternal antibodies fundamentally regulate infant immunity to the developing gut microbiota, yet the mechanisms underlying this process remain elusive. Here, we show that maternal IgG, ingested in the first week of life, functions to restrain microbiota-dependent adaptive immune responses and reduce offspring susceptibility to intestinal inflammation weeks later, following weaning. To exert these functions, efficient binding of IgG to gut bacterial antigens and engagement of Fc and complement dependent effector functions in offspring was required. These discoveries reveal a novel mechanism wherein maternal IgG engages the offspring immune system to calibrate responses to gut microbes. This mode of maternal immune instruction may provide adaptability to developmental shifts in microbiota necessary for establishing host-microbiota mutualism and limiting susceptibility to inflammatory disease. One sentence Ingestion of maternal IgG during a discrete postnatal window calibrates neonatal immunity to the gut microbiota.

Mechanisms for Helicobacter pylori (Hp)-driven stomach cancer are not fully understood. In a transgenic mouse model of gastric preneoplasia, concomitant Hp infection and induction of constitutively active KRAS (Hp+KRAS+) alters metaplasia phenotypes and elicits greater inflammation than either perturbation alone. Gastric single-cell RNA sequencing showed that Hp+KRAS+ mice had a large population of metaplastic pit cells that expressed the intestinal mucin Muc4 and the growth factor amphiregulin. Flow cytometry and IHC-based immune profiling revealed that metaplastic pit cells were associated with macrophage and T-cell inflammation. Accordingly, expansion of metaplastic pit cells was prevented by gastric immunosuppression and reversed by antibiotic eradication of Hp. Finally, MUC4 expression was significantly associated with proliferation in human gastric cancer samples. These studies identify an Hp-associated metaplastic pit cell lineage, also found in human gastric cancer tissues, whose expansion is driven by Hp-dependent inflammation.Significance:Using a mouse model, we have delineated metaplastic pit cells as a precancerous cell type whose expansion requires Hp-driven inflammation. In humans, metaplastic pit cells show enhanced proliferation as well as enrichment in precancer and early cancer tissues, highlighting an early step in the gastric metaplasia to cancer cascade.

Mechanisms for Helicobacter pylori (Hp)-driven stomach cancer are not fully understood. In a transgenic mouse model of gastric preneoplasia, concomitant Hp infection and induction of constitutively active KRAS (Hp+KRAS+) alters metaplasia phenotypes and elicits greater inflammation than either perturbation alone. Gastric single-cell RNA sequencing showed that Hp+KRAS+ mice had a large population of metaplastic pit cells that expressed the intestinal mucin Muc4 and the growth factor amphiregulin. Flow cytometry and IHC-based immune profiling revealed that metaplastic pit cells were associated with macrophage and T-cell inflammation. Accordingly, expansion of metaplastic pit cells was prevented by gastric immunosuppression and reversed by antibiotic eradication of Hp. Finally, MUC4 expression was significantly associated with proliferation in human gastric cancer samples. These studies identify an Hp-associated metaplastic pit cell lineage, also found in human gastric cancer tissues, whose expansion is driven by Hp-dependent inflammation.Significance:Using a mouse model, we have delineated metaplastic pit cells as a precancerous cell type whose expansion requires Hp-driven inflammation. In humans, metaplastic pit cells show enhanced proliferation as well as enrichment in precancer and early cancer tissues, highlighting an early step in the gastric metaplasia to cancer cascade.

Mechanisms for Helicobacter pylori (Hp)-driven stomach cancer are not fully understood. In a transgenic mouse model of gastric preneoplasia, concomitant Hp infection and induction of constitutively active KRAS (Hp+KRAS+) alters metaplasia phenotypes and elicits greater inflammation than either perturbation alone. Gastric single-cell RNA sequencing showed that Hp+KRAS+ mice had a large population of metaplastic pit cells that expressed the intestinal mucin Muc4 and the growth factor amphiregulin. Flow cytometry and IHC-based immune profiling revealed that metaplastic pit cells were associated with macrophage and T-cell inflammation. Accordingly, expansion of metaplastic pit cells was prevented by gastric immunosuppression and reversed by antibiotic eradication of Hp. Finally, MUC4 expression was significantly associated with proliferation in human gastric cancer samples. These studies identify an Hp-associated metaplastic pit cell lineage, also found in human gastric cancer tissues, whose expansion is driven by Hp-dependent inflammation. Significance: Using a mouse model, we have delineated metaplastic pit cells as a precancerous cell type whose expansion requires Hp-driven inflammation. In humans, metaplastic pit cells show enhanced proliferation as well as enrichment in precancer and early cancer tissues, highlighting an early step in the gastric metaplasia to cancer cascade.

Genes driving the subclustering of the major gastric epithelial cell types.

Description of the mouse samples used for single-cell RNA-sequencing.

IFN-γ but not IL-4 is associated with metaplastic pit cell expansion.

The 10 most differentially expressed genes within each cluster of UMAP #2.

Description of the mouse samples used for single-cell RNA-sequencing.