Clostridium difficile, Aging, and the Gut: Can Microbiome Rejuvenation Keep Us Young and Healthy?

One of the most important risk factors for mortality with Clostridium difficile infection (CDI) is age. Elderly patients experience more severe disease, more frequent recurrences and higher mortality rates than younger patients [1]. In addressing possible explanations for this age effect, one might consider the causative agent, as well as attributes of the host. To be clear, neither acts alone; it is the set of complex interactions between microbial disease agent and host that dictates outcome. Aging is associated with a number of intertwined factors, each of which increases the likelihood of CDI. For example, as we age, we accumulate underlying comorbid conditions and visit healthcare facilities more frequently. Such facilities expose patients to C. difficile and other infectious agents. Healthcareand community-associated infections, in general, lead to more frequent antibiotic use. As a net result, C. difficile exposure is more likely, and is more likely to lead to colonization and population expansion (or “blooms”) of C. difficile— and high bacterial load is an independent predictor of poor clinical outcome [2]. The story, however, is more complex: aging in animals involves a set of linked processes, including and in particular, changes in immune system function, sometimes referred to as “immunosenescence” [3], as well as changes in the gut microbiome [4]. In a study in this issue of The Journal of Infectious Diseases, Shin et al [5] investigate the role of the gut microbiome in CDI and discuss a possible relationship between the microbiome and age, as well as a relationship with early innate immune responses. In an earlier study, van Opstal et al [6] showed that disease severity, likelihood of relapse, and mortality were increased, and recovery from infection was delayed, in aged mice compared to young mice in a model of CDI, recapitulating the effects of age in humans with CDI. They also showed that these aged mice generated lower serum levels of anti–C. difficile toxin A immunoglobulin M, immunoglobulin A, and immunoglobulin G, and had altered microbiota composition. In the current work, Shin et al [5] examined additional features of the innate immune response to CDI in aged (18 months) and young (3 weeks) mice and explored the role of the gut microbiota in mediating differential responses and outcome. They report dampened proinflammatory cytokine expression, neutrophil recruitment, and tissue damage in the cecum of aged mice early in the infection (day 2, before peak C. difficile burden) but no differences at day 5, at the peak of infection. Interestingly, when aged and young mice swapped cages and were exposed to each other’s feces, aged mice acquired gut microbiota members from the young mice and displayed more vigorous early innate immune responses and improved survival after subsequent CDI. The reverse did not occur; that is, young mice did not take on features of the aged mouse microbiota, nor did they display increased CDI disease, suggesting either that members of the young mouse microbiota are more invasive or that the aged mouse microbiota loses some capacity for colonization resistance and as a result accommodates new microbes more easily. These findings add to a growing body of work that ties microbiota structure and function to local and systemic immune responses [7] and to host outcome after pathogen encounters [8]. More detailed examination of local immune function will be helpful. Quantitative and qualitative analysis of antigen presenting cells, intraepithelial lymphocytes, T-cell subsets, and B cells, not only in the cecum, but in the gut-associated lymphoid tissue and regional lymph nodes, might shed additional light on potential mechanisms. For example, the gut microbiota seems to induce epigenetic changes in intestinal intraepithelial lymphocytes with consequences for gene expression pathways [9]. From a conceptual perspective, the aging of a host-associated ecosystem can be viewed as the cumulative impact of historical exposures and disturbances, and the intrinsic degradation of host tissue integrity and cellular function, resulting in an altered ecological “fitness landscape” (eg, less stable states) [10] and heightened E D I T O R I A L C O M M E N T A R Y