Fight Aging!

There is a growing interest in the role of microbial populations of the gut in aging and health, with evidence from recent years suggesting that their level of influence might approach that of exercise. Some fraction of the benefits to health and longevity that occur due to the practice of either calorie restriction or intermittent fasting are thought to be mediated by resulting changes in gut microbe populations. This seems a safe assumption, given the evidence to hand, but the still open question is just how large or small that fraction might be. The consensus view remains that benefits largely result from increased cellular housekeeping, and the fact that calorie restriction fails to work in animals with disabled autophagy is telling.

Complicating the matter, however, calorie restriction and intermittent fasting are not just two ways of achieving exactly the same result. They produce significantly different patterns of gene expression in animal studies. Intermittent fasting without reducing calorie intake still produces health and longevity benefits in rodents. Calorie restriction lasting for less than three days in humans fails to produce the significant benefits to immune cell populations that fasting for four or longer days achieves. One could argue that the point is time spent in a state of hunger, but that seems overly simplistic given what is known. A mammalian body and its microbial fellow travelers are collectively a complicated system, and that system has correspondingly complicated responses to environmental circumstances.

In the open access paper here, researchers focus on one specific set of interactions between gut microbes and the immune system. Age-related (and other) changes to the microbiome can contribute to chronic inflammation and autoimmunity - here, the autoimmune condition in question is multiple sclerosis, in which immune cells attack the myelin sheathing of nerves, with catastrophic consequences. Intermittent fasting can help in this situation by reducing the influence of problematic microbial populations.

As is the case in all such investigations, the highly varied and dynamic nature of the gut microbiome makes it hard to settle on definitive results that are true for everyone at all times. Even for a given individual, what turns out to be a beneficial influence one year might be more or less beneficial the next year, because the state of the gut mitobiome shifts over time. Of all the presently available ways to manipulate gut bacteria, forms of calorie restriction appear the most reliable, but the degree to which they work in this matter is greatly obscured by the other reliable benefits they achieve in the operation of cellular metabolism.

Intermittent Fasting Confers Protection in CNS Autoimmunity by Altering the Gut Microbiota

Multiple sclerosis (MS) is more common in western countries. Dietary habits have been considered as a potential factor contributing to MS epidemiology. Different diets and dietary supplements have been implicated in MS risk, but the field is lacking robust scientific data to support this risk. Indeed, many studies highlight the importance of the complex interplay between nutrition, metabolic state, and immune-inflammatory responses in MS. Obesity during childhood/young adulthood is a risk factor for MS development as shown in several recent studies. This might be related to a low-grade chronic inflammatory state in obesity that could promote autoimmunity through altered adipokine production. An additional link between nutrition and immune-inflammatory responses is the gut microbiome. Diet is a critical determinant of the gut microbial composition. Gut commensal bacteria and their metabolites have the potential to exert both pro- and anti-inflammatory responses by regulating T cell differentiation and immune responses in the gut. Ultimately, this can have systemic effects and either drive or protect from autoimmune diseases.

Recently it has been reported that the gut microbiome in relapsing-remitting multiple sclerosis (RRMS) patients is altered compared with healthy controls. Further, calorie restriction (CR) has potent anti-inflammatory effects. Studies, including our own, demonstrated that chronic CR significantly inhibited progression of the MS model, experimental autoimmune encephalomyelitis (EAE). However, chronic CR is not likely to be feasible for most people. Intermittent fasting (IF) induces many of the same changes observed by chronic CR and would possibly be more acceptable. We therefore undertook studies of IF in the EAE model and in MS patients experiencing a relapse and showed that IF ameliorated EAE through effects at least in part mediated by changes in the gut flora.

IF induced protective changes in gut microbiome metabolic pathways and lamina propria lymphocytes as demonstrated by the fact that gut microbiome transplantation from mice on IF ameliorated EAE in recipient mice after immunization. To translate our findings in patients, we performed a small pilot randomized controlled trial. IF in MS patients having a relapse was a safe and feasible intervention associated with short-term metabolic and gut microbiome changes that recapitulated what was observed in the animal model.

IF had a striking effect on gut microbiota composition with enrichment of the Bacteroidaceae, Lactobacillaceae, and Prevotellaceae families. In EAE, alteration of the gut microbiota or their metabolites can modulate inflammation and demyelination. Of particular interest was the IF-induced enrichment in Lactobacilli, which are commonly used in probiotics because of their positive effects, including reduction of inflammatory immune responses. In the present studies, Lactobacillus species that were over-represented in the setting of IF included L. johnsonii and L. reuteri, which are well known to have immunomodulatory properties. In addition, enrichment in Prevotella family members with IF may be beneficial because of its enhancement of production of protective short chain fatty acids (SCFAs), such as butyrate. This is important because SCFAs are bacterial metabolites derived from indigestible carbohydrates that have been reported to inhibit EAE by expanding gut regulatory T cells.