Stomach microbiota, Helicobacter pylori, and group 2 innate lymphoid cells

Abstract

The stomach has been thought to host few commensal bacteria because of the existence of barriers, such as gastric acid. However, recent culture-independent, sequencing-based microbial analysis has shown that the stomach also harbors a wide diversity of microbiota. Although the stomach immune system, especially innate lymphoid cells (ILCs), has not been well elucidated, recent studies have shown that group 2 ILCs (ILC2s) are the dominant subtype in the stomach of both humans and mice. Stomach ILC2s are unique in that their existence is dependent on stomach microbiota, in sharp contrast to the lack of an impact of commensal microbiota on ILC2s in other tissues. The microbiota dependency of stomach ILC2s is partly explained by their responsiveness to interleukin (IL)-7. Stomach ILC2s express significantly higher IL-7 receptor protein levels on their surface and proliferate more in response to IL-7 stimulation in vitro than small intestinal ILC2s. Consistently, the stomach expresses much higher IL-7 protein levels than the small intestine. IL-5 secreted from stomach ILC2s promotes immunoglobulin (Ig) A production by plasma B cells. In a murine model, stomach ILC2s are important in containing Helicobacter pylori infection, especially in the early phase of infection, by promoting IgA production.

Fig. 1. Characteristics of ILC subsets.

Outline of ILC differentiation pathways with the respective transcription factors required for their differentiation and cytokines produced by ILC subsets. CLP common lymphoid progenitor, NKP NK cell progenitor, CHILP common helper-like innate lymphoid precursor, E4BP4 E4 promoter-binding protein 4 (also known as NFIL3), ROR RAR-related orphan receptor, AHR aryl hydrocarbon receptor, cNK conventional NK cell, LTiP lymphoid tissue inducer projenitors, LTi lymphoid tissue inducer.

Fig. 2. Stomach ILC2s.

In germ-free (GF) mice, there are few ILC2s. Under GF conditions, IL-7 expression in stomach tissue is hardly detectable, and IL-7 receptor expression on stomach ILC2s is lower than that under SPF conditions. In contrast, the expression of the IL-33 receptor on stomach ILC2s is similar and that of IL-33 in the stomach tissue is slightly decreased in GF compared to SPF conditions. Under SPF conditions, the combination of IL-33 and IL-7 signaling leads to IL-5 secretion by ILC2s, which then promotes IgA production from plasma B cells.

Fig. 3. The role of stomach ILC2s in H. pylori infection.

In the early phase of H. pylori infection, the induction of IL-7 and IL-33 in the stomach tissue increases and activates ILC2s to secrete IL-5, which promotes plasma B cells differentiation and IgA production. At this stage, there is no apparent increase in CD4⁺T cells (T-cell-independent pathway). In the later phase of the infection, IL-5 derived from Th2-type CD4⁺ T cells also promotes IgA production (T-cell dependent pathway).