Credit: S. Bradbrook/NPG

Epidemiological studies have suggested that disruption of the bacterial colonization of mucosal surfaces early in life can influence susceptibility to chronic inflammatory disorders such as allergic asthma and colitis. Now, three studies in mice provide new insights into the mechanistic links between commensal bacteria and disease susceptibility.

In a short study by Russell et al., administration of subclinical doses of the antibiotic vancomycin markedly reduced the diversity of gut commensal microorganisms in neonatal mice, to a greater extent than treatment of adult mice. Furthermore, antibiotic treatment of neonatal mice, but not adult mice, was associated with enhanced severity of allergic lung inflammation.

Hill et al. also used antibiotics to assess the role of commensals in allergic inflammation. In this study, adult mice treated with five clinically relevant antibiotics had increased IgE levels and basophil numbers in the blood compared with conventionally reared mice. Antibiotic-treated mice also had increased airway inflammation following allergen challenge, and this effect was reversed following basophil depletion. These data suggest that commensals limit basophil-mediated allergic inflammation. Of note, patients with hyperimmunoglobulinemia E syndrome — who have an increased susceptibility to allergies and increased levels of serum IgE — were found to also have higher numbers of circulating basophils than control subjects.

But what is the underlying mechanism? The authors showed that B cell-intrinsic MYD88 signalling induced by bacteria-derived signals limits steady-state IgE levels and circulating basophil numbers. In antibiotic-treated mice, the elevated levels of IgE were responsible for the increased frequency and number of basophils in the blood. This effect of IgE on basophils was mediated at the level of bone marrow-resident basophil precursors through increased expression of the interleukin-3 (IL-3) receptor subunit CD123, which increased the responsiveness of these precursors to the basophil-differentiation factor IL-3. So, this study suggests that commensal bacteria can influence disease susceptibility by limiting serum IgE concentrations, thereby regulating basophil haematopoiesis and restricting basophil-associated allergic inflammation.

Olszak et al. found that the numbers of invariant natural killer T (iNKT) cells in the colonic lamina propria and lungs of adult germ-free mice (which lack commensals) were increased compared with specific pathogen-free (SPF) mice. This iNKT cell accumulation in the absence of commensals was associated with increased IL-1β and IL-13 production and with susceptibility to oxazolone-induced colitis and ovalbumin-induced allergic lung inflammation. Microbial colonization of neonatal but not adult germ-free mice restored iNKT cell numbers in mucosal tissues to those observed in SPF mice and protected against colitis-induced mortality and lung inflammation. Therefore, early microbial colonization reduces disease susceptibility in later life by regulating iNKT cell accumulation and function in mucosal tissues.

The expression of CXC-chemokine ligand 16 (CXCL16) was higher in the colon and lungs of germ-free and adult-colonized mice than in these organs in SPF and neonatal-colonized mice. Inhibition of CXCL16 in germ-free mice protected against oxazolone-induced colitis. CpG-rich regions within the Cxcl16 gene were hypermethylated in the colon and lungs of germ-free mice, but not in other tissues, and this hypermethylation was decreased following bacterial colonization of neonatal but not adult mice. Furthermore, inhibition of methylation in newborn germ-free mice resulted in decreased CXCL16 expression and reduced iNKT cell numbers in the intestine and lungs. This study therefore suggests that early (but not late) microbial colonization can prevent Cxcl16 methylation, thereby reducing CXCL16 expression and preventing iNKT cell accumulation in mucosal tissues.

Together, these studies indicate that commensal bacteria have an impact on several different immune pathways, disruption of which can contribute to chronic disease susceptibility.