Gut-Brain Mechanisms of Improving Health in an Animal Model of SCI Following Weight Loss Surgery

Background: Approximately two-thirds of spinal cord injured (SCI) individuals become overweight or obese. The likelihood of an individual with SCI developing obesity and metabolic syndrome (cardiopulmonary disease, stroke and type 2 diabetes) is 16%-44% greater than a similar-aged individual without SCI. Given the risk factors for developing obesity following SCI, weight loss surgery (WLS), including vertical sleeve gastrectomy (VSG) and the Roux-en-Y gastric bypass, offers an attractive intervention for SCI-induced obesity and metabolic syndrome. A growing body of evidence suggests that factors such as changes in food preferences and alterations in gut microbiota contribute to the beneficial effects of WLS. Specifically, intestinal microbes produce precursors to hormones and neurotransmitters as well as active metabolites, which in turn, may influence gut-brain signals mediated through the vagus nerve to improve metabolism. We have verified that obese rats with an SCI can tolerate the increasingly preferred VSG procedure and experience better weight loss outcomes than control (non-SCI) rats. Additionally, we found that SCI, together with an obesogenic high fat diet (HFD) changed taste preferences, particularly for sweet taste, more detrimentally in the SCI rats than the same diet did in non-SCI rats. VSG then was more efficient to rescue taste functions in SCI than in non-SCI rats. Among several possible mechanisms, gut microbiota can affect CNS activity through the production of short chain fatty acids (SCFAs). SCFAs reduce food intake through a mechanism that includes intracellular Ca^(2+) signaling within the gastrointestinal vagal afferents, which have been shown to exhibit altered gene expression in response to microbiota-derived stimuli. Furthermore, our preliminary data demonstrate that gastric vagal afferent Ca^(2+) currents are reduced in SCI rats. These findings collectively suggest that alterations in the microbiome in SCI rats following VSG may involve similar mechanism for rescuing blunted vagal sensitivity to hormonal and neural signals regulating eating and metabolism._x000D_ _x000D_ Research Idea and Strategy: The proposed project will use a combination of behavioral, molecular, chemistry methods combined with fecal microbiota transplantation (FMT) to address the overall hypothesis that altered microbiota following VSG is critical to the improved eating behavior (taste and food choices), body weight and metabolic outcomes in SCI rats. Regarding the underlying mechanisms, we propose that VSG results in improved neural and hormonal gut-brain signaling to rescue the effects of SCI - aggravated by HFD-induced pathologies - from blunted vagal signaling, and in turn, resulting in improved taste functions as well as improved sensitivity to satiety hormones critical to maintain healthy body weight._x000D_ _x000D_ Specific Aim 1 will test the hypothesis that improved taste preferences, sustained weight loss and metabolic improvements following VSG in SCI rats are secondary to postoperative changes in the gut microbiota and SCFA signaling pathways are contributory. We will use FMT in male and female Wistar rats (Sub-Aim 1.1) followed by behavioral and physiological tests to examine the capacity of gut microbiota to transfer the taste functions and preferences, weight loss and metabolic improvements from VSG-operated SCI (SCI-VSG) to SCI rats with no VSG (SCI-Sham). Microbiota 16S rRNA sequencing will be used to confirm efficacy of interventions, and to characterize microbiome. Sub-Aim 1.2 will be identical to Sub-Aim 1.1, except it will use diet enriched with SCFAs instead of FMT. In both Sub-Aims, fecal and plasma SCFAs will be assessed._x000D_ _x000D_ Specific Aim 2 will test the hypothesis that improved vagal functions represent a major mechanism by which VSG-induced gut microbiota changes post-SCI improve eating behavior and metabolism. As in Aim 1, we will use FMT (Sub-Aim 2.1) or diet enriched with SCFAs (Sub-Aim 2.2) followed with a two-pronged approach to assess underlying mechanisms: (a) test effectiveness of systemic administration of satiety hormone cholecystokinin to reduce food intake and taste preferences for higher concentrations of sweet and fatty foods and (b) directly assess peripheral vagal afferent neurons in the nodose ganglia, collected from rats used in Aim 1, for their excitability using ex vitro whole-cell electrophysiology with a focus on CaV2.2 channels as a potential target mediating the effects of FMT or SCFAs._x000D_ _x000D_ Impact: There is un-met medical need for novel treatment options for prevention and treatment of obesity and metabolic syndrome in SCI individuals, particularly members of the military who have almost a 10-fold greater risk than the general U.S. population. Knowing which factors are critical (i.e., microbiota or its specific metabolite products, the SCFAs) we anticipate those could offer novel interventions providing the same benefits without the need for the surgery. Identifying specific underlying neuronal and molecular targets could further help with development of novel pharmacological interventions.