Extracellular Metabolism Sets the Table for Microbial Cross-Feeding

Abstract

The transfer of nutrients between cells, or cross-feeding, is a ubiquitous feature of microbial communities with emergent properties that influence our health and orchestrate global biogeochemical cycles. Cross-feeding inevitably involves the externalization of molecules. Some of these molecules directly serve as cross-fed nutrients, while others can facilitate cross-feeding. Altogether, externalized molecules that promote cross-feeding are diverse in structure, ranging from small molecules to macromolecules. The functions of these molecules are equally diverse, encompassing waste products, enzymes, toxins, signaling molecules, biofilm components, and nutrients of high value to most microbes, including the producer cell. As diverse as the externalized and transferred molecules are the cross-feeding relationships that can be derived from them. Many cross-feeding relationships can be summarized as cooperative but are also subject to exploitation. Even those relationships that appear to be cooperative exhibit some level of competition between partners. In this review, we summarize the major types of actively secreted, passively excreted, and directly transferred molecules that either form the basis of cross-feeding relationships or facilitate them. Drawing on examples from both natural and synthetic communities, we explore how the interplay between microbial physiology, environmental parameters, and the diverse functional attributes of extracellular molecules can influence cross-feeding dynamics. Though microbial cross-feeding interactions represent a burgeoning field of interest, we may have only begun to scratch the surface.

Keywords: biofilm; coculture; cross-feeding; exoenzymes; microbial ecology; mutualism; nanowires; quorum sensing; siderophores; synthetic ecology.

FIG 1

Microbes release various molecules that promote cross-feeding. Microbially produced extracellular molecules such as quorum sensing signals, exoenzymes, siderophores, toxins, metabolites (e.g., sugars, organic acids, amino acids, etc.), biofilm matrix, nanowires, extracellular vesicles, and nanotubes can be consumed by neighboring microbes or can influence cross-feeding between cells.

FIG 2

Synthetic microbial consortia featuring essential cross-feeding interactions. (A) Bidirectional cross-feeding of CO₂ and NH₄⁺ between Saccharomyces cerevisiae and Chlamydomonas reinhardtii (51). (B) Syntrophic cross-feeding of acetate, CO₂, and H₂ between Desulfovibrio vulgaris and Methanococcus maripaludis (61, 62). (C) Bidirectional cross-feeding of amino acids between Escherichia coli auxotrophs (64, 70). (D) Bidirectional cross-feeding of lysine and adenine between S. cerevisiae auxotrophs (75, 245). (E) Multidirectional cross-feeding of acetate, methionine, and NH₄⁺ between auxotrophic E. coli, Salmonella enterica, and Methylobacterium extorquens (74, 246). (F) Bidirectional cross-feeding of fixed carbon and cobalamin between Lobomonas rostrata and Mesorhizobium loti (78). (G) Bidirectional cross-feeding of organic acids and NH₄⁺ between E. coli and Rhodopseudomonas palustris (207). (H) Syntrophic cross-feeding of electrons between Geobacter metallireducens and Geobacter sulfurreducens (63). The “Δ” symbol indicates an auxotrophy for an incoming metabolite.

FIG 3

Cross-feeding of carbon waste metabolites creates a global carbon cycle. The indicated trophic categories only refer to possible effects on carbon transformation. For example, chemoheterotrophs are primarily responsible for the conversion of macromolecules from both microbes and multicellular organisms into diverse organic compounds that can serve as nutrients for other lifestyles but might also participate in the cycling of other elements. Acetogenesis arrows involve the excretion of acetate from the conversion of two CO₂ to acetyl-CoA via energy-conserving Wood-Ljungdahl pathway activity, rather than referring to every lifestyle possible for a bacterium classified as an acetogen (247). Syntrophy arrows are for fermentative carbon transformations that require consumption by a partner to be thermodynamically feasible (31, 57, 58). The diazotrophy arrow represents one of the carbon transformations known to be carried out by nitrogenase in sufficient quantity to support the growth of a partner (236). In some cases, only certain organisms within a category might generate a given molecule. The figure does not necessarily capture every possible activity within a given lifestyle. The figure also does not include every carbon transformation known to be carried out by microbes.

FIG 4

Cross-feeding and its outcomes are dynamic. (A) A high level of cooperation by one partner can lead to excessive and harmful reciprocation by another. In this case, when production rate exceeds consumption rate (blue arrows), a metabolite (blue dot) can accumulate to toxic levels, for example by acidifying the environment (207). The “conc” triangle illustrates the effect of the metabolite on the recipient, ranging from beneficial (blue) to detrimental (red) as the concentration increases. (B) Growth-independent cross-feeding can rescue partners from starvation. Maintenance metabolism alone can lead to metabolite excretion under nongrowing conditions (left). Consumption of the metabolite by a recipient can stimulate recipient growth and reciprocation, creating a positive feedback loop and lifting both partners out of starvation (30). (C) The level of privatization influences the affinity that each partner must have for a communally valuable metabolite for cooperative coexistence to result (225). (Top) Cross-feeding of an intracellularly generated metabolite (left: high privatization) and an extracellularly generated metabolite liberated by an exoenzyme (right: low privatization). (Bottom) Simulated effect of the relative competition, in this case affinity (inverse of Km, which is the substrate concentration when the growth rate is at half the maximum), for the metabolite on the net growth of each partner under high and low privatization conditions. (Simulated trends are adapted from reference .)