Dietary fibre supplementation enhances radiotherapy tumour control and alleviates intestinal radiation toxicity.

BACKGROUND: Non-toxic approaches to enhance radiotherapy outcomes are beneficial, particularly in ageing populations. Based on preclinical findings showing that high-fibre diets sensitised bladder tumours to irradiation by modifying the gut microbiota, along with clinical evidence of prebiotics enhancing anti-cancer immunity, we hypothesised that dietary fibre and its gut microbiota modification can radiosensitise tumours via secretion of metabolites and/or immunomodulation. We investigated the efficacy of high-fibre diets combined with irradiation in immunoproficient C57BL/6 mice bearing bladder cancer flank allografts. RESULT: Psyllium plus inulin significantly decreased tumour size and delayed tumour growth following irradiation compared to 0.2% cellulose and raised intratumoural CD8+ cells. Post-irradiation, tumour control positively correlated with Lachnospiraceae family abundance. Psyllium plus resistant starch radiosensitised the tumours, positively correlating with Bacteroides genus abundance and increased caecal isoferulic acid levels, associated with a favourable response in terms of tumour control. Psyllium plus inulin mitigated the acute radiation injury caused by 14 Gy. Psyllium plus inulin increased caecal acetate, butyrate and propionate levels, and psyllium alone and psyllium plus resistant starch increased acetate levels. Human gut microbiota profiles at the phylum level were generally more like mouse 0.2% cellulose profiles than high fibre profiles. CONCLUSION: These supplements may be useful in combination with radiotherapy in patients with pelvic malignancy. Video Abstract.

Pleiotropic constraints promote the evolution of cooperation in cellular groups.

The evolution of cooperation in cellular groups is threatened by lineages of cheaters that proliferate at the expense of the group. These cell lineages occur within microbial communities, and multicellular organisms in the form of tumours and cancer. In contrast to an earlier study, here we show how the evolution of pleiotropic genetic architectures-which link the expression of cooperative and private traits-can protect against cheater lineages and allow cooperation to evolve. We develop an age-structured model of cellular groups and show that cooperation breaks down more slowly within groups that tie expression to a private trait than in groups that do not. We then show that this results in group selection for pleiotropy, which strongly promotes cooperation by limiting the emergence of cheater lineages. These results predict that pleiotropy will rapidly evolve, so long as groups persist long enough for cheater lineages to threaten cooperation. Our results hold when pleiotropic links can be undermined by mutations, when pleiotropy is itself costly, and in mixed-genotype groups such as those that occur in microbes. Finally, we consider features of multicellular organisms-a germ line and delayed reproductive maturity-and show that pleiotropy is again predicted to be important for maintaining cooperation. The study of cancer in multicellular organisms provides the best evidence for pleiotropic constraints, where abberant cell proliferation is linked to apoptosis, senescence, and terminal differentiation. Alongside development from a single cell, we propose that the evolution of pleiotropic constraints has been critical for cooperation in many cellular groups.

Enforcement is central to the evolution of cooperation.

Cooperation occurs at all levels of life, from genomes, complex cells and multicellular organisms to societies and mutualisms between species. A major question for evolutionary biology is what these diverse systems have in common. Here, we review the full breadth of cooperative systems and find that they frequently rely on enforcement mechanisms that suppress selfish behaviour. We discuss many examples, including the suppression of transposable elements, uniparental inheritance of mitochondria and plastids, anti-cancer mechanisms, reciprocation and punishment in humans and other vertebrates, policing in eusocial insects and partner choice in mutualisms between species. To address a lack of accompanying theory, we develop a series of evolutionary models that show that the enforcement of cooperation is widely predicted. We argue that enforcement is an underappreciated, and often critical, ingredient for cooperation across all scales of biological organization.

Rapid radiation in bacteria leads to a division of labour.

The division of labour is a central feature of the most sophisticated biological systems, including genomes, multicellular organisms and societies, which took millions of years to evolve. Here we show that a well-organized and robust division of labour can evolve in a matter of days. Mutants emerge within bacterial colonies and work with the parent strain to gain new territory. The two strains self-organize in space: one provides a wetting polymer at the colony edge, whereas the other sits behind and pushes them both along. The emergence of the interaction is repeatable, bidirectional and only requires a single mutation to alter production of the intracellular messenger, cyclic-di-GMP. Our work demonstrates the power of the division of labour to rapidly solve biological problems without the need for long-term evolution or derived sociality. We predict that the division of labour will evolve frequently in microbial populations, where rapid genetic diversification is common.

Mucin biopolymers prevent bacterial aggregation by retaining cells in the free-swimming state.

Many species of bacteria form surface-attached communities known as biofilms. Surrounded in secreted polymers, these aggregates are difficult both to prevent and eradicate, posing problems for medicine and industry. Humans play host to hundreds of trillions of microbes that live adjacent to our epithelia, and we are typically able to prevent harmful colonization. Mucus, the hydrogel overlying all wet epithelia in the body, can prevent bacterial contact with the underlying tissue. The digestive tract, for example, is lined by a firmly adherent mucus layer that is typically devoid of bacteria, followed by a second, loosely adherent layer that contains numerous bacteria. Here, we investigate the role of mucus as a principle arena for host-microbe interactions. Using defined in vitro assays, we found that mucin biopolymers, the main functional constituents of mucus, promote the motility of planktonic bacteria and prevent their adhesion to underlying surfaces. The deletion of motility genes, however, allows Pseudomonas aeruginosa to overcome the dispersive effects of mucus and form suspended antibiotic-resistant flocs, which mirror the clustered morphology of immotile natural isolates found in the cystic fibrosis lung mucus. Mucus may offer new strategies to target bacterial virulence, such as the design of antibiofilm coatings for implants.

The sociobiology of molecular systems.

It is often assumed that molecular systems are designed to maximize the competitive ability of the organism that carries them. In reality, natural selection acts on both cooperative and competitive phenotypes, across multiple scales of biological organization. Here I ask how the potential for social effects in evolution has influenced molecular systems. I discuss a range of phenotypes, from the selfish genetic elements that disrupt genomes, through metabolism, multicellularity and cancer, to behaviour and the organization of animal societies. I argue that the balance between cooperative and competitive evolution has shaped both form and function at the molecular scale.