Let’s face it: as it is often presented, the microbiome seems terribly confusing. This is not news to anyone who has scrutinised a microbial profile like the 16s sequencing reports now common in the literature and the industry. However, looking at the all-important metagenome makes it decidedly simpler.
Microbial profiles characterise taxonomic composition. That is, they tell us the types and amounts of the various micro-organisms present in the gut. And they make one thing exceptionally clear: gut composition varies wildly from bird to bird, even when healthy and grown under identical conditions. This is not surprising. As a bird develops from hatch, the micro-organisms that take hold in its gut are subject to a natural degree of randomness. It begs the question: How can something as variable as microbial composition serve an industry where consistency is everything?
Spoiler alert: the key to unlocking robustness and consistency in the microbiome is not microbial profiling. We must look deeper, to the metagenome (the collection of all genes from across the microbiota). Your first reaction might be that this sounds even more complicated than microbial profiles. No, it is decidedly simpler and exceptionally powerful.
Put simply, analysis of the metagenome can be used to understand the functions the microbiome can perform when it works in concert, as a unit. An analogy helps: if you think of the microbiome like an orchestra, the microbiota are the musicians, while the metagenome is the music they play.
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Following this logic, we recently discussed the merits of rethinking the gut microbiome as a unit rather than a collection of bugs. Figure 1 illustrates this thinking. Rather than focusing on organism identities, we consider the biochemical metabolites that run through them.
The circles in Figure 1 represent these metabolites while the lines denote the chemical reactions (microbial genes) that perform them. Via its pathways, the gut microbiome converts undigested feed into thousands of metabolites. Many are nutritional to the host; others are excreted in the litter, runoff or are released into the atmosphere. Some gut metabolites are potent biomolecules that modulate systemic host functions, like inflammation, immunity, muscle growth, colour, flavour and potentially even behavioural factors, like stress, activity level and appetite.
We learn early on in animal biology that certain metabolic functions, like glycolysis and the TCA cycle, are highly conserved across different species. These conserved pathways provide the foundation for basic biological functions, such as growth and homeostasis. The key insight we gain from studying metagenomics is that the same principle holds for micro-organisms.
Often the genes to make a given metabolite are redundant across many different microbes. This redundancy is the recipe for consistency: 2 microbiomes can be functionally equivalent even when they have vastly different microbial profiles. Returning to our analogy: you can swap various musicians in and out of the orchestra, but the ensemble can still play the same music.
In our own work with whole-genome sequencing, we observe repeatedly that many metabolic functions of the microbiome remain conserved between birds with wildly different microbial profiles. Broadly speaking, these core microbiome pathways tend to involve central carbon and nitrogen utilisation, such as carbohydrate, lipid, amino acid and nucleotide metabolism. Certainly aspects of microbial carbon metabolism, such as short-chain fatty acid (SCFA) production, have been recognised for decades. Propionate is upgraded by host gluconeogenesis to create additional metabolic energy. Butyrate directly nourishes the gut epithelium, among many other roles. SCFAs may interface with host regulatory functions, such as immune signalling and the pancreatic hormone regulatory network.
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Nitrogen utilisation pathways control the degradation and biosynthesis of peptides. Amino acids synthesised by the microbiome can be absorbed by the bird to increase effective protein availability. In animal production, adverse protein fermentation may generate excess ammonia, biogenic amines, and nitrogenous toxins that degrade barrier function, trigger inflammation, reduce welfare and increase environmental impact.
Poultry science has long targeted the microbiota with gut health products: direct fed microbials (DFMs), essential oils, organic acids, prebiotics and NSPases, to name a few. These products have their merits but they all suffer from a key weakness. Their modes of action are fundamentally grounded in microbial taxonomy, tying them to the inherent variability of microbial composition. Prebiotics and/or fibre-digesting enzymes provide additional fermentable carbon to the microbiota.
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But do the microbiota use that carbon wisely? Probiotics add bacteria with anticipated benefits. But what if the existing ecology or chemical environment prevents those organisms from acting as intended?
Returning to our analogy: you can hire great musicians, give them a nice venue and even feed them a healthy lunch. But without a conductor, the quality and consistency of the music will vary considerably.
The same is true of the microbiome. If we want consistency, we must provide a conductor to direct function, and modern microbiome science tells us how. There is potential to influence microbial gene expression for targeted pathways, or activate/deactivate microbial enzyme pathways, to name only 2. This idea of microbiome metabolic modulation is, at the same time, simple and a radically new framework for mode of action (Figure 2).
Our goal is a new category of precision feed additives that act on core metagenomic functions to induce targeted effects with unprecedented consistency. Imagine if we could reliably modulate microbiome pathways to improve the health, performance, welfare and sustainability of poultry production. Hold that thought and stay tuned.
References available on request.
Authors: Dr J.M. Geremia, Midori Animal Health and Dr Maria Walsh, DSM