The distal human intestine represents an anaerobic bioreactor programmed with an enormous population of bacteria, dominated by relatively few divisions that are highly diverse at the strain/subspecies level. This microbiota and its collective genomes (microbiome) provide us with genetic and metabolic attributes we have not been required to evolve on our own, including the ability to harvest otherwise inaccessible nutrients. New studies are revealing how the gut microbiota has coevolved with us and how it manipulates and complements our biology in ways that are mutually beneficial. We are also starting to understand how certain keystone members of the microbiota operate to maintain the stability and functional adaptability of this microbial organ.

It is widely accepted that obesity and associated metabolic diseases, including type 2 diabetes, are intimately linked to diet. However, the gut microbiota has also become a focus for research at the intersection of diet and metabolic health. Mechanisms that link the gut microbiota with obesity are coming to light through a powerful combination of translation-focused animal models and studies in humans. A body of knowledge is accumulating that points to the gut microbiota as a mediator of dietary impact on the host metabolic status. Efforts are focusing on the establishment of causal relationships in people and the prospect of therapeutic interventions such as personalized nutrition.

The gut is home to trillions of microbes that play a fundamental role in many aspects of human biology including immune function and metabolism 1,2. The reduced diversity of the Western microbiota compared to populations living traditional lifestyles presents the question of which factors have driven microbiota change during modernization. Microbiota accessible carbohydrates (MACs) found in dietary fiber, play a key role in shaping this microbial ecosystem, and are strikingly reduced in the Western diet relative to more traditional diets 3. Here we show that changes in the microbiota of mice consuming a low-MAC diet and harboring a human microbiota are largely reversible within a single generation, however over multiple generations a low-MAC diet results in a progressive loss of diversity, which is not recoverable upon the reintroduction of dietary MACs. To restore the microbiota to its original state requires the administration of missing taxa in combination with dietary MAC consumption. Our data illustrate that taxa driven to low abundance when dietary MACs are scarce are inefficiently transferred to the next generation and are at increased risk of becoming extinct within an isolated population. As more diseases are linked to the Western microbiota and the microbiota is targeted therapeutically, microbiota reprogramming may need to involve strategies that incorporate dietary MACs as well as taxa not currently present in the Western gut.

Germ-free mice were maintained on polysaccharide-rich or simple-sugar diets and colonized for 10 days with an organism also found in human guts, Bacteroides thetaiotaomicron, followed by whole-genome transcriptional profiling of bacteria and mass spectrometry of cecal glycans. We found that these bacteria assembled on food particles and mucus, selectively induced outer-membrane polysaccharide-binding proteins and glycoside hydrolases, prioritized the consumption of liberated hexose sugars, and revealed a capacity to turn to host mucus glycans when polysaccharides were absent from the diet. This flexible foraging behavior should contribute to ecosystem stability and functional diversity.

The human intestine, colonized by a dense community of resident microbes, is a frequent target of bacterial pathogens. Undisturbed, this intestinal microbiota provides protection from bacterial infections. Conversely, disruption of the microbiota with oral antibiotics often precedes the emergence of several enteric pathogens1–4. How pathogens capitalize upon the failure of microbiota-afforded protection is largely unknown. Here we show that two antibiotic-associated pathogens, Salmonella typhimurium and Clostridium difficile, employ a common strategy of catabolizing microbiota-liberated mucosal carbohydrates during their expansion within the gut. S. typhimurium accesses fucose and sialic acid within the lumen of the gut in a microbiota-dependent manner, and genetic ablation of the respective catabolic pathways reduces its competitiveness in vivo. Similarly, C. difficile expansion is aided by microbiota-induced elevation of sialic acid levels in vivo. Colonization of gnotobiotic mice with a sialidase-deficient mutant of the model gut symbiont Bacteroides thetaiotaomicron (Bt) reduces free sialic acid levels resulting in a downregulation of C. difficile’s sialic acid catabolic pathway and impaired expansion. These effects are reversed by exogenous dietary administration of free sialic acid. Furthermore, antibiotic treatment of conventional mice induces a spike in free sialic acid and mutants of both Salmonella and C. difficile that are unable to catabolize sialic acid exhibit impaired expansion. These data show that antibiotic-induced disruption of the resident microbiota and subsequent alteration in mucosal carbohydrate availability are exploited by these two distantly related enteric pathogens in a similar manner. This insight suggests new possibilities for therapeutic approaches for preventing diseases caused by antibiotic-associated pathogens.