From Mouse to Man: Translating Findings in Mouse Study Into a Human Cohort (Luxembourgish Fiber Cohort: Lux-FiCo)

Industrialized nations tend to consume less dietary fiber and, in many nations with a Western-style diet, average consumption is half the recommended daily intake of 25-38 g/day. Dietary fiber is an important component of a healthy diet because it increases fecal bulking and laxation, lowers cholesterol and regulates levels of blood glucose. The connection between low fiber-intake and disease may rest with the gut microbiota, the trillions of commensal microorganisms that inhabit the gastrointestinal tract. Bacteria found in the gut are responsible for an array of functions that support human health, including conversion of host-indigestible fibers into short chain fatty acids (SCFAs), which provide energy for colonic cells, support mucus production, and modulate the immune system.

The investigators have recently investigated the effects of a fiber-free diet in a gnotobiotic mouse model with a 14-member synthetic microbial community showing that mucus-degrading bacteria outcompete fiber-degrading bacteria, causing degradation of the colonic mucus layer. One member of this synthetic community, Akkermansia muciniphila, is a commensal bacterium found at 1-4% relative abundance in the human gut and feeds specifically on the host-secreted mucins. However, this bacterium is significantly enriched in the gut of patients with multiple sclerosis and colorectal cancer, suggesting that its mucolytic capabilities may play a role in these diseases. A microbial shift toward enrichment of mucolytic bacteria could be an important precursor to gut-linked diseases. While observational studies have identified a lower risk of irritable bowel diseases (IBD) in people who consume diets high in fiber, fruits, and vegetables, no study has explicitly investigated the effects of fiber on the functional capacity of the human gut microbiome in the context of effects on the mucus-degrading microbiome. Based on our published work in mice, for the current project, the investigators hypothesize that deficiency of dietary fiber in humans promotes increased activities of mucus-degrading bacteria, thereby reducing the mucus lining in the intestine. The investigators request pump priming to initiate this pilot project, as it will generate foundational datasets to inform numerous follow-up studies.

Thus, the current project seeks to translate findings from mouse models to humans, using a crossover study among healthy adults. Participants will be randomly assigned to a first dietary intervention that is low or high in fiber and then, following a washout period intended to reverse any compositional changes, switched to the second diet type. The diets will be evaluated by a nutritionist to ensure that they differ in fiber content, but are comparable in terms of caloric and macronutrient content. The targeted amount of dietary fiber intake from the high-fiber test meals will be around 30 g/d more than the low-fiber diet. In addition to dietary records, the investigators will administer questionnaires, obtain basic clinical measures (blood pressure, weight, height, waist/thigh circumference), collect blood samples for immunological assays and collect stool samples before and at the end of each diet intervention for sequencing and functional profiling of bacterial communities.

The investigators will recruit healthy volunteers to participate in a 2x2 crossover design controlled-diet study. After statistical consultation, the investigators conclude that the investigators require a sample size of n=15 in each sequence group (a total sample size of N=30) to have 87.5% power to detect a -0.5 difference in means for alpha diversity (Shannon index) under the two diet conditions. Volunteers who meet all inclusion and exclusion criteria will be randomly assigned to a high- or low-fiber diet intervention and then, after a week-long washout period, will receive the second diet type. High and low fiber meals containing a variety of fiber types will be served to participants at a designated drop-off site (home or workplace) for one week in order to decrease variance in fiber intake, increase adherence to the diet, and maximize knowledge of the nutritional content in participants' diet. Nutritionally balanced dietary interventions are designed by a qualified dietitian at SERVIOR in conjunction with the LIH study team and delivered by Paul Eischen Traiteur, a partner catering service. Participants on both diet interventions will be given multivitamin supplements in order to further ensure they receive essential vitamins and minerals.

At the baseline visit, our team will work with nurses from the Clinical and Epidemiological Investigation Center (CIEC, headed by Dr. Manon Gantenbein) to collect demographic data, anthropometry, early life history, family medical history, detailed dietary patterns, and biological samples (blood, urine, and stool). Participants will use a Participant Diary to log their diet throughout the study in the form of daily 24 hour food recalls, except for foods or beverages provided during the dietary interventions. After each intervention period, a week-long washout period will be employed to reverse any changes that occurred due to the diet.