The intestinal microbiota is critical in the ontology of early-life immunity. The intestinal microbiota stimulates immune development through microbial-associated molecular patterns which bind and activate pattern recognition receptors (1). Meanwhile there is codevelopment of numerous antiinflammatory mechanisms that prevent excessive immune responses. Intestinal dysbiosis has been associated with metabolic diseases that occur in adult life. In their elegant study, Leonard et al. (2) report that intestinal dysbiosis is associated with celiac disease (CD) in infants. The mechanism elucidated was linked to adverse shifts of many bacterial metabolites, with a propensity for increased proinflammation over decreased antiinflammatory factors. We posit that the dysregulated interaction between the genus Bifidobacteria and butyrate-producing bacteria Faecalibacterium prausnitzii and Clostridium clostridioforme is critical in the development of CD indicated by this study.
The intestinal microbiota is composed of trillions of bacteria cells. The interactions among the microbes are complex and important. It has been demonstrated that the cross-feeding that occurs between Bifidobacteria and butyrate-producing bacteria such as F. prausnitzii, Anaerostipes, Eubacterium, and Roseburia species enhances butyrate production (3, 4). The production of butyrate in the intestines of infants is sophisticatedly programmed. A study has reported that butyrate shows a marked increase in concentration from 3- to 6- to 12-mo-old infants (5). From 6- to 12-mo-old infants, there was a fourfold increase in butyrate levels, reaching levels comparable to the infant mothers. The butyrate levels were correlated with abundance of butyrate-producing bacteria, namely, F. prausnitzii and Eubacterium rectale. Increased butyrate-producing bacteria are critical for the transition from an infant to an adult-like intestinal microbiota. As such, Bifidobacteria and Faecalibacteria among others (3) are important coexisting participants in butyrate-associated programming of the developing infant immune system.
Leonard et al. (2) characterize the dysbiosis before CD onset in their longitudinal study and find that proinflammatory bacteria such as Dialister invisus, Parabacteroides sp., and Lachnospiraceae were increased, while butyrate-producing bacteria F. prausnitzii and C. clostridioforme as well as the antiinflammatory Streptococcus thermophilus were decreased (2). This may indicate insufficient production of butyrate in these patients. A recent study also reported that decreased abundance of Bifidobacteria was a causal factor in inflammatory diseases in infants, including CD (6). Deficits in Bifidobacteria resulted in increased populations of neutrophils, basophils, plasmablasts, and memory CD8+ T cells, and increased blood levels of TNF-α, IL-6, and IL-17 with reduced antigen experienced regulatory T cells and nonclassical monocytes. The mechanism was associated with decreased levels of human mild oligosaccharides (HMO) utilization genes, indicating decreased production of HMO metabolites. These abutyrogenic effects could lead to decreased production of butyrate, disrupting the intestinal inflammatory tone. Butyrate stimulates antiinflammatory immune cells such as regulatory T cells and increases production of antiinflammatory cytokines (7, 8). Butyrate also decreases intestinal barrier permeability with increased mucus production to decrease inflammation caused by endotoxin and bacterial translocation (9). It is plausible that low butyrate production before the onset of CD may predicate an inflammatory tone skewed toward low antiinflammatory mechanisms, facilitating the initiation of CD.
Footnotes
The authors declare no competing interest.
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