Whole body vibration (WBV) is an exercise mimetic; it decreases the inflammatory response and can reverse many symptoms of type II diabetes mellitus (T2DM), such as polyuria and polydipsia. It also significantly improves glucose metabolism measured by a glucose tolerance test and Hb A1C [1
]. Recent reports also reveal marked improvement in hepatic lipid content, decreasing it three-fold [2
]. However, how WBV achieves these beneficial changes remains unclear. Glucose transport in myeloid cells mediated by IL-3 appeared as early as the mid-1990s [3
]. Clinical investigations have also confirmed that perturbation in glucose metabolism is present in acute myeloid leukemia [4
]. Importantly, it has become clear that a complex regulatory network exists, linking glucose metabolism to both myeloid and lymphoid homeostasis. Increased glucose availability to macrophages might initiate a feed forward loop that fosters inflammation and exacerbates insulin resistance and hyperglycemia [6
]. Within this complex network, macrophages display great functional plasticity and the M1/M2 nomenclature now classifies macrophages into cells with pro-inflammatory (M1) or anti-inflammatory (M2) properties [7
]. In mammals, this polarization and other innate immune functions link closely to the largest microbial load: The microbiota of the alimentary canal, with an intimate and reciprocal relationship, in that microbiota affects innate immunity and vice versa [8
]. The impact and importance of this relationship between microbiota and innate immunity is indisputable [9
]. Therefore, there are two objectives to this study. The first is to investigate the changes in macrophage type in blood and adipose tissues by characterizing the macrophage profiles in these tissues before and after WBV, using a well-established murine T2DM model. The second objective, as an initial step towards a proximate mechanistic exploration in trying to establish casual links between WBV and downstream effects, we seek to document fecal microbiome changes related to WBV.
The three hypotheses tested are as follows:
M1 predominates in the abdominal and blood macrophages in T2DM mice;
WBV can cause macrophage polarization from M1 towards M2, decreasing pro-inflammatory cytokines and increasing anti-inflammatory cytokines;
WBV causes alterations in both the alpha and beta diversity of fecal microbiome.
As the prevalence and incidence of T2DM and obesity continue to increase in the US population, effective adjuncts to standard therapy such as WBV are gaining momentum. It is critically important that we explore the mechanism underpinning this promising potential therapeutic modality.
The prospect of WBV as an adjunct to improve musculoskeletal health and its potential benefits on several metabolic diseases, such as diabetes and hypertension, have recently attracted substantial interest [11
]. Despite a certain level of controversy, all studies generally support the notion that WBV may improve the inflammatory indices and help to re-establish the immune balance and homeostasis [12
]. In fact, our recent findings showed that WBV may be capable of de-escalating inflammation by reducing IL-17+
helper T cells and elevating Fox P3+
regulatory T cells [1
]. While the biochemical and physiological improvements from WBV as an exercise mimetic are indisputable, how WBV achieves such effects is likely multi-faceted and largely unknown. Furthermore, our recent data have pointed to potential alterations in the chemical composition of the portal blood after WBV, evidenced by the beneficial effects seen in the liver [2
]. The current experiments seek to answer if WBV can alter fecal microbiome and whether it causes polarization of omental macrophages from M1 to M2.
Macrophages are essential components of the innate immune system, playing a crucial role in the activation and regulation of immune responses. Macrophages apply their regulatory effects through three major mechanisms, including phagocytosis, antigen presentation, and cytokine production [13
]. Among all these three macrophage functions, the cytokine signaling is directly downstream of macrophage polarization. Macrophages are classified based on their phenotype and function in pro-inflammatory M1 and counter-inflammatory M2 types. Several factors including host microenvironment and metabolic interaction can affect the polarization process of macrophages [14
Our data showed that WBV not only could skew the macrophage polarization towards M2, the counter-inflammatory macrophages, it also altered the microbiome in the digestive tract. In fact, this is the first study to report a documented potential cross talk between microbiome and innate immunity through macrophage polarization mediated by WBV. The remodeling of microbiome was in both the alpha and beta diversity of the gut microbiome following WBV, with a massive increase in alistipes. Alistipes
belong to the Rikenellaceae family of class Bacteroidia and are present in very small qualities in the typical intestinal microbiome of C57/B6 mice after weaning [15
]. They are non-alcoholic fermenters and produce short-chain fatty acids (SCFA), such as acetoacetate and butyrate, known to be fuel for the gut flora, highly anti-inflammatory, and capable of reversing adverse effects of a high-fat diet [16
]. Of great interest is the recent observation that alistipes increased when mice were fed beta-glucans, which induces higher levels of SCFA [17
]. Their presence has also been detected in hibernating mammals that undergo extensive nutritional and microbiological adaptations during the winter months [18
]. It is very likely that the gut microbiome change is the proximate cause of improved hepatic steatosis in T2DM mice after WBV. This is in agreement with the anatomy and clinical observations [19
]. However further investigations are required to confirm this in the case of WBV.
The current studies tested if WBV could alter the polarization of omental macrophages. Macrophages are the principle component of innate immunity through their resident antigen-presenting function. The sequencing of the WBV effects is still unclear: Is M2 polarization antecedent to intestinal microbiome changes or vice versa? In this complex network of regulatory and counter-regulatory nodes, there is much still to be worked out at multiple levels from changes in gene expression to cell, tissue, and organ level remodeling.
In summary, it is noteworthy to emphasize that inflammatory responses resulting from a variety of diseases, including diabetes and obesity, are integral to the pathogenesis of these diseases. There is a self-perpetuating, vicious cycle: Metabolic dysregulation and tissue damage cause inflammation, and inflammation causes more tissue destruction and metabolic dysregulation. Sustained inflammation underpins a wide range of diseases from cardiovascular and metabolic dysfunction (e.g., cardiorenal diseases, diabetes), cognitive impairment (e.g., dementia) to several levels of neoplastic-dysplastic transformations (e.g., cancer). These current findings support the notion that WBV has the potential to alter the microbiota in a way that triggers innate and mucosal immunity to produce anti-inflammatory responses, down-regulating the hyper-inflammatory state and reversing the adverse consequences. More studies are required to solidify this novel approach, which can be a very affordable and an effective therapeutic modality in the prevention and treatment of many diseases, including diabetes and obesity.