Worms need microbes too: microbiota, health and aging in Caenorhabditis elegans

Abstract

Many animal species live in close association with commensal and symbiotic microbes (microbiota). Recent studies have revealed that the status of gastrointestinal tract microbiota can influence nutrition-related syndromes such as obesity and type-2 diabetes, and perhaps aging. These morbidities have a profound impact in terms of individual suffering, and are an increasing economic burden to modern societies. Several theories have been proposed for the influence of microbiota on host metabolism, but these largely remain to be proven. In this article we discuss how microbiota may be manipulated (via pharmacology, diet, or gene manipulation) in order to alter metabolism, immunity, health and aging in the host. The nematode Caenorhabditis elegans in combination with one microbial species is an excellent, defined model system to investigate the mechanisms of host-microbiota interactions, particularly given the combined power of worm and microbial genetics. We also discuss the multifaceted nature of the worm-microbe relationship, which likely encompasses predation, commensalism, pathogenicity and necromeny.

Keywords: C. elegans; aging; metformin; microbiota; type-2 diabetes.

Figure 1. From hunter to prey: the changing relationship between C. elegans and E. coli

Different stages in the course of the life of the worm can serve as models to study how humans interact with their microbiota.

1. During development, bacteria mainly serve as a source of food (green), since they are almost entirely crushed by the pharyngeal grinder and live colonies are absent from the lumen of the gut (Kurz et al, 2003).

2. In young adults, bacteria that have escaped the action of the grinder proliferate and establish a community within some sections of the lumen of the gut (Portal-Celhay et al, 2012), and exist as commensals or symbionts (green).

3. As the worm ages, bacteria proliferating within the lumen of the gut become detrimental to the host (McGee et al, 2011) and can cause severe constipation (Garigan et al, 2002). A possibility is that this reflects changes in bacterial metabolism engendering dysbiosis (red). In addition, blockage of the lumen (Garigan et al, 2002), and changes in bacterial metabolism may be detrimental too (Portal-Celhay et al, 2012). Treatments that block bacterial proliferation extend lifespan, likely by preventing microbial dysbiosis (Garigan et al, ; Gems & Riddle, 2000).

Figure 2. Functions of the microbiota in human and nematode hosts

1. Schematic summary of the effects of intestinal microbiota on host fitness. These include protective, structural and metabolic effects.

2. The host confers benefits to the microbiota. In the case of C. elegans, the benefits to the microbiota, as hypothesized here, involve cannibalistic commensalism and necromeny.

Figure 3. How to test host-targeted drugs in worms

Bacterial roles in drug action on host physiology.

1. Biotransformation (activation, inactivation, toxification) by different bacterial strains can alter the efficacy of a host-targeted drug with consequences to host physiology.

2. Impact of host-targeted drugs and antibiotics on bacterial metabolism. Antibiotic and host-targeted drug action in bacterial proliferation and/or metabolism influences host physiology either through reduced pathogenesis or the alteration of bacterially derived metabolites.

3. Host-targeted drugs can alter the physiology of the worm-bug. Effects of drugs on microbe and/or host can positively or negatively modulate the symbiotic relationship established between host and bacteria. For example, metformin action on E. coli can extend worm lifespan, but acting directly on worms metformin shortens lifespan (Cabreiro et al, 2013).