The contribution of native microbiota to immunity

Immunologists can give the impression that microbes are a continuous and terrible threat and we would be better off living germ-free. Perhaps this comes from work in vitro where microbes indeed make it difficult to maintain cultured cells. Living animals are different from cultured cells and exist in close association with their microbes. We engage in simply commensal relationships with some microbes and in other cases the relationship is mutually beneficial. In this section we discuss how the native microbiota of a fly might contribute to its immune response.

A simple way in which the native microbiota support the immune response of an insect is by supporting the normal physiology of the host. In cases where there are mutalistic microbes living within an insect the disruption of these microbes can be anticipated to cause physiological changes that would alter the immune response of the animal. For example, in a termite that depends upon its native microbiota for the digestion of cellulose, it might be expected that a gut infection that altered the number and diversity of bacteria could adversely affect both the amount and quality of available nutrients, and thus alter the immune response. Changes in nutrient availability and insulin signalling could be described as a way of monitoring the health of a host's native microbiota.

Native microbes also help protect a host against invading microbes. Early work done by Bakula (1969) in Drosophila showed that flies raised under axenic conditions could be forced to support the growth of E. coli. If the E. coli gnotobiotic flies were exposed to a normal gut flora in a food vial, the E. coli would be quickly replaced with the native flora. This suggests that the native flora can prevent the invasion of foreign bacteria, at least by occupying a niche, but perhaps by more active means. Perhaps this is why oral 'natural infection' models in the fly require that larvae be challenged with bacteria at an optical density of 50 for the rest of the larva's life to generate a phenotype. The insect gut is a resilient reactor that resists colonization by foreign microbes in part because it maintains a natural microbiota that excludes non-adapted competitors (Dillon and Dillon, 2004).

A mechanistic description of this sort of gut microbe effect was published recently by Ryu et al. (2008); they showed that flies carefully regulate the expression of AMPs in their gut and this in turn regulates the indigenous microbes. A simplistic explanation for the role of AMPs in the gut would be that they are present to sterilize the gut and to limit the possibility of infections. Ryu and colleagues found that when AMPs were misregu-lated and over-expressed it led to an alteration in the gut microbiota and that one particular Gluconobacter strain became numerically dominant and caused pathology. They proposed that the normal gut flora prevents the growth of this particular pathogen and the disruption of the native micro-biota through AMP over-expression is the cause of pathogen overgrowth. It appears as though the flies were 'farming' their gut microbes, trying to create an optimal balance of bacteria to maintain health.

The native microbiota can be critical in defining the sensitivity to infections by blocking pathogens but native gut microbes can also be a cause of pathology. Broderick and colleagues (2006) showed that sensitivity of caterpillars to orally administered Bacillus thuringiensis toxin depended upon the presence of indigenous microbiota. Elimination of endogenous bacteria by antibiotic treatment eliminated sensitivity to the toxin. The reason appears to be that the toxin damages the gut, allowing the gut

Energy

Ageing Feeding behaviour

Native microbiota Clotting RNAi

Energy

Ageing Feeding behaviour

Native microbiota Clotting RNAi

Circadian rhythm

Reproduction

Barrier epithelial response

Figure 7.1 Summary of potential interactions between immunity, feeding behaviour, ageing, energy use, circadian rhythm, and reproduction in D. melanogaster. All potential interactions are listed. Below are listed the seven potential immune responses. These are all shown springing from immunity. Presumably, once the entire signalling matrix has been studied, it will be possible to distinguish the individual effects of, say, circadian rhythm on cellular immunity. There are not enough data yet to begin filling in this side of the figure.

Circadian rhythm

Reproduction

Antimicrobial peptides Cellular immunity Melanization

Barrier epithelial response

Figure 7.1 Summary of potential interactions between immunity, feeding behaviour, ageing, energy use, circadian rhythm, and reproduction in D. melanogaster. All potential interactions are listed. Below are listed the seven potential immune responses. These are all shown springing from immunity. Presumably, once the entire signalling matrix has been studied, it will be possible to distinguish the individual effects of, say, circadian rhythm on cellular immunity. There are not enough data yet to begin filling in this side of the figure.

bacteria to cause a fatal septicaemia. In this case, the native microbiota which are normally harmless become pathogenic when the insect is stressed by the toxin.

Ageing can be introduced into this story because Ren and colleagues (2007) demonstrated that as flies age they accumulate bacteria; they recorded as much as a 100 000-fold increase in the number of microbes. Surely this affects immunity; if these microbes act as a barrier to the introduction of pathogens then this aspect of the immune response will increase drastically as flies age. The immune response of aged flies suffering from a natural infection will reflect the sum of all of its defences: senescence of antibacterial responses may be offset by increases in protection from the native microbiota.

Native microbiota are something that simply hasn't been controlled in immunity experiments but we should start; first by learning what the native microbiota of our favorite insects are and then be figuring out how these alter infections.

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