Functional Gastrointestinal Disorders and the Microbiome-What Is the Best Strategy for Moving Microbiome-based Therapies for Functional Gastrointestinal Disorders into the Clinic?

There have been numerous human studies reporting associations between the intestinal microbiome and functional gastrointestinal disorders (FGIDs), and independently animal studies have explored microbiome-driven mechanisms underlying FGIDs. However, there is often a disconnect between human and animal studies, which hampers translation of microbiome findings to the clinic. Changes in the microbiota composition of patients with FGIDs are generally subtle, whereas changes in microbial function, reflected in the fecal metabolome, appear to be more precise indicators of disease subtype-specific mechanisms. Although we have made significant progress in characterizing the microbiome, to effectively translate microbiome science in a timely manner, we need concurrent and iterative longitudinal studies in humans and animals to determine the precise microbial functions that can be targeted to address specific pathophysiological processes in FGIDs. A systems approach integrating multiple data layers rather than evaluating individual data layers of symptoms, physiological changes, or -omics data in isolation will allow for validation of mechanistic insights from animal studies while also allowing new discovery. Patient stratification for clinical trials based on functional microbiome alterations and/or pathophysiological measurements may allow for more accurate determination of efficacy of individual microbiome-targeted interventions designed to correct an underlying abnormality. In this review, we outline current approaches and knowledge, and identify gaps, to provide a potential roadmap for accelerating translation of microbiome science toward microbiome-targeted personalized treatments for FGIDs.

Microbiota-dependent early life programming of gastrointestinal motility.

Gastrointestinal microbes modulate peristalsis and stimulate the enteric nervous system (ENS), whose development, as in the central nervous system (CNS), continues into the murine postweaning period. Given that adult CNS function depends on stimuli received during critical periods of postnatal development, we hypothesized that adult ENS function, namely motility, depends on microbial stimuli during similar critical periods. We gave fecal microbiota transplantation (FMT) to germ-free mice at weaning or as adults and found that only the mice given FMT at weaning recovered normal transit, while those given FMT as adults showed limited improvements. RNAseq of colonic muscularis propria revealed enrichments in neuron developmental pathways in mice exposed to gut microbes earlier in life, while mice exposed later - or not at all - showed exaggerated expression of inflammatory pathways. These findings highlight a microbiota-dependent sensitive period in ENS development, pointing to potential roles of the early life microbiome in later life dysmotility.

Metagenomic Alterations in Gut Microbiota Precede and Predict Onset of Colitis in the IL10 Gene-Deficient Murine Model.

BACKGROUND & AIMS: Inflammatory bowel diseases (IBD) are chronic inflammatory disorders where predictive biomarkers for the disease development and clinical course are sorely needed for development of prevention and early intervention strategies that can be implemented to improve clinical outcomes. Since gut microbiome alterations can reflect and/or contribute to impending host health changes, we examined whether gut microbiota metagenomic profiles would provide more robust measures for predicting disease outcomes in colitis-prone hosts. METHODS: Using the interleukin (IL) 10 gene-deficient (IL10 KO) murine model where early life dysbiosis from antibiotic (cefoperozone [CPZ]) treated dams vertically transferred to pups increases risk for colitis later in life, we investigated temporal metagenomic profiles in the gut microbiota of post-weaning offspring and determined their relationship to eventual clinical outcomes. RESULTS: Compared to controls, offspring acquiring maternal CPZ-induced dysbiosis exhibited a restructuring of intestinal microbial membership in both bacteriome and mycobiome that was associated with alterations in specific functional subsystems. Furthermore, among IL10 KO offspring from CPZ-treated dams, several functional subsystems, particularly nitrogen metabolism, diverged between mice that developed spontaneous colitis (CPZ-colitis) versus those that did not (CPZ-no-colitis) at a time point prior to eventual clinical outcome. CONCLUSIONS: Our findings provide support that functional metagenomic profiling of gut microbes has potential and promise meriting further study for development of tools to assess risk and manage human IBD.

Mediators of Host-Microbe Circadian Rhythms in Immunity and Metabolism.

Circadian rhythms are essential for nearly all life forms, mediated by a core molecular gene network that drives downstream molecular processes involved in immune function and metabolic regulation. These biological rhythms serve as the body's metronome in response to the 24-hour light:dark cycle and other timed stimuli. Disrupted circadian rhythms due to drastic lifestyle and environmental shifts appear to contribute to the pathogenesis of metabolic diseases, although the mechanisms remain elusive. Gut microbiota membership and function are also key mediators of metabolism and are highly sensitive to environmental perturbations. Recent evidence suggests rhythmicity of gut microbes is essential for host metabolic health. The key molecular mediators that transmit rhythmic signals between microbes and host metabolic networks remain unclear, but studies suggest the host immune system may serve as a conduit between these two systems, providing homeostatic signals to maintain overall metabolic health. Despite this knowledge, the precise mechanism and communication modalities that drive these rhythms remain unclear, especially in humans. Here, we review the current literature examining circadian dynamics of gut microbes, the immune system, and metabolism in the context of metabolic dysregulation and provide insights into gaps and challenges that remain.

Synergistic depletion of gut microbial consortia, but not individual antibiotics, reduces amyloidosis in APPPS1-21 Alzheimer's transgenic mice.

In preceding efforts, we demonstrated that antibiotic (ABX) cocktail-mediated perturbations of the gut microbiome in two independent transgenic lines, termed APPSWE/PS1ΔE9 and APPPS1-21, leads to a reduction in Aß deposition in male mice. To determine whether these observed reductions of cerebral Aß amyloidosis are specific to any individual antibiotic or require the synergistic effects of several antibiotics, we treated male APPPS1-21 transgenic mice with either individual ABX or an ABX cocktail and assessed amyloid deposition. Specifically, mice were subject to oral gavage with high dose kanamycin, gentamicin, colistin, metronidazole, vancomycin, individually or in a combination (ABX cocktail) from postnatal days (PND) 14 to 21, followed by ad libitum, low-dose individual ABX or ABX cocktail in the drinking water until the time of sacrifice. A control group was subject to gavage with water from PND 14 to 21 and received drinking water till the time of sacrifice. At the time of sacrifice, all groups showed distinct cecal microbiota profiles with the highest differences between control and ABX cocktail-treated animals. Surprisingly, only the ABX cocktail significantly reduced brain Aß amyloidosis compared to vehicle-treated animals. In parallel studies, and to assess the potential exposure of ABX to the brain, we quantified the levels of each ABX in the brain by liquid chromatography-mass spectrometry (LC-MS) at PND 22 or at 7 weeks of age. With the exception of metronidazole (which was observed at less than 3% relative to the spiked control brains), we were unable to detect the other individual ABX in brain homogenates. Our findings suggest that synergistic alterations of gut microbial consortia, rather than individual antimicrobial agents, underlie the observed reductions in brain amyloidosis.