Isoflavone consumption reduces inflammation through modulation of phenylalanine and lipid metabolism.

INTRODUCTION: Phytoestrogens found in soy, fruits, peanuts, and other legumes, have been identified as metabolites capable of providing beneficial effects in multiple pathological conditions due to their ability to mimic endogenous estrogen. Interestingly, the health-promoting effects of some phytoestrogens, such as isoflavones, are dependent on the presence of specific gut bacteria. Specifically, gut bacteria can metabolize isoflavones into equol, which has a higher affinity for endogenous estrogen receptors compared to dietary isoflavones. We have previously shown that patients with multiple sclerosis (MS), a neuroinflammatory disease, lack gut bacteria that are able to metabolize phytoestrogen. Further, we have validated the importance of both isoflavones and phytoestrogen-metabolizing gut bacteria in disease protection utilizing an animal model of MS. Specifically, we have shown that an isoflavone-rich diet can protect from neuroinflammatory diseases, and that protection was dependent on the ability of gut bacteria to metabolize isoflavones into equol. Additionally, mice on a diet with isoflavones showed an anti-inflammatory response compared to the mice on a diet lacking isoflavones. However, it is unknown how isoflavones and/or equol mediates their protective effects, especially their effects on host metabolite levels. OBJECTIVES: In this study, we utilized untargeted metabolomics to identify metabolites found in plasma that were modulated by the presence of dietary isoflavones. RESULTS: We found that the consumption of isoflavones increased anti-inflammatory monounsaturated fatty acids and beneficial polyunsaturated fatty acids while reducing pro-inflammatory glycerophospholipids, sphingolipids, phenylalanine metabolism, and arachidonic acid derivatives. CONCLUSION: Isoflavone consumption alters the systemic metabolic landscape through concurrent increases in monounsaturated fatty acids and beneficial polyunsaturated fatty acids plus reduction in pro-inflammatory metabolites and pathways. This highlights a potential mechanism by which an isoflavone diet may modulate immune-mediated disease.

Multiple sclerosis patients have an altered gut mycobiome and increased fungal to bacterial richness.

Trillions of microbes such as bacteria, fungi, and viruses exist in the healthy human gut microbiome. Although gut bacterial dysbiosis has been extensively studied in multiple sclerosis (MS), the significance of the fungal microbiome (mycobiome) is an understudied and neglected part of the intestinal microbiome in MS. The aim of this study was to characterize the gut mycobiome of patients with relapsing-remitting multiple sclerosis (RRMS), compare it to healthy controls, and examine its association with changes in the bacterial microbiome. We characterized and compared the mycobiome of 20 RRMS patients and 33 healthy controls (HC) using Internal Transcribed Spacer 2 (ITS2) and compared mycobiome interactions with the bacterial microbiome using 16S rRNA sequencing. Our results demonstrate an altered mycobiome in RRMS patients compared with HC. RRMS patients showed an increased abundance of Basidiomycota and decreased Ascomycota at the phylum level with an increased abundance of Candida and Epicoccum genera along with a decreased abundance of Saccharomyces compared to HC. We also observed an increased ITS2/16S ratio, altered fungal and bacterial associations, and altered fungal functional profiles in MS patients compared to HC. This study demonstrates that RRMS patients had a distinct mycobiome with associated changes in the bacterial microbiome compared to HC. There is an increased fungal to bacterial ratio as well as more diverse fungal-bacterial interactions in RRMS patients compared to HC. Our study is the first step towards future studies in delineating the mechanisms through which the fungal microbiome can influence MS disease.

Autoimmunity Increases Susceptibility to and Mortality from Sepsis.

We recently demonstrated how sepsis influences the subsequent development of experimental autoimmune encephalomyelitis (EAE) presented a conceptual advance in understanding the postsepsis chronic immunoparalysis state. However, the reverse scenario (autoimmunity prior to sepsis) defines a high-risk patient population whose susceptibility to sepsis remains poorly defined. In this study, we present a retrospective analysis of University of Iowa Hospital and Clinics patients demonstrating increased sepsis prevalence among multiple sclerosis (MS), relative to non-MS, patients. To interrogate how autoimmune disease influences host susceptibility to sepsis, well-established murine models of MS and sepsis and EAE and cecal ligation and puncture, respectively, were used. EAE, relative to non-EAE, mice were highly susceptible to sepsis-induced mortality with elevated cytokine storms. These results were further recapitulated in LPS and Streptococcus pneumoniae sepsis models. This work highlights both the relevance of identifying highly susceptible patient populations and expands the growing body of literature that host immune status at the time of septic insult is a potent mortality determinant.

Isoflavone diet ameliorates experimental autoimmune encephalomyelitis through modulation of gut bacteria depleted in patients with multiple sclerosis.

The gut microbiota is a potential environmental factor that influences the development of multiple sclerosis (MS). We and others have demonstrated that patients with MS and healthy individuals have distinct gut microbiomes. However, the pathogenic relevance of these differences remains unclear. Previously, we showed that bacteria that metabolize isoflavones are less abundant in patients with MS, suggesting that isoflavone-metabolizing bacteria might provide protection against MS. Here, using a mouse model of MS, we report that an isoflavone diet provides protection against disease, which is dependent on the presence of isoflavone-metabolizing bacteria and their metabolite equol. Notably, the composition of the gut microbiome in mice fed an isoflavone diet exhibited parallels to healthy human donors, whereas the composition in those fed an isoflavone-free diet exhibited parallels to patients with MS. Collectively, our study provides evidence that dietary-induced gut microbial changes alleviate disease severity and may contribute to MS pathogenesis.

Human Commensal Prevotella histicola Ameliorates Disease as Effectively as Interferon-Beta in the Experimental Autoimmune Encephalomyelitis.

Gut microbiota has emerged as an important environmental factor in the pathobiology of multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS). Both genetic and environmental factors have been shown to play an important role in MS. Among genetic factors, the human leukocyte antigen (HLA) class II allele such as HLA-DR2, DR3, DR4, DQ6, and DQ8 show the association with the MS. We have previously used transgenic mice expressing MS susceptible HLA class II allele such as HLA-DR2, DR3, DQ6, and DQ8 to validate significance of HLA alleles in MS. Although environmental factors contribute to 2/3 of MS risk, less is known about them. Gut microbiota is emerging as an imporatnt environmental factor in MS pathogenesis. We and others have shown that MS patients have distinct gut microbiota compared to healthy control (HC) with a lower abundance of Prevotella. Additionally, the abundance of Prevotella increased in patients receiving disease-modifying therapies (DMTs) such as Copaxone and/or Interferon-beta (IFNß). We have previously identified a specific strain of Prevotella (Prevotella histicola), which can suppress experimental autoimmune encephalomyelitis (EAE) disease in HLA-DR3.DQ8 transgenic mice. Since Interferon-ß-1b [IFNß (Betaseron)] is a major DMTs used in MS patients, we hypothesized that treatment with the combination of P. histicola and IFNß would have an additive effect on the disease suppression. We observed that treatment with P. histicola suppressed disease as effectively as IFNß. Surprisingly, the combination of P. histicola and IFNß was not more effective than either treatment alone. P. histicola alone or in combination with IFNß increased the frequency and number of CD4+FoxP3+ regulatory T cells in the gut-associated lymphoid tissue (GALT). Treatment with P. histicola alone, IFNß alone, and in the combination decreased frequency of pro-inflammatory IFN-γ and IL17-producing CD4+ T cells in the CNS. Additionally, P. histicola alone or IFNß alone or the combination treatments decreased CNS pathology, characterized by reduced microglia and astrocytic activation. In conclusion, our study indicates that the human gut commensal P. histicola can suppress disease as effectively as commonly used MS drug IFNß and may provide an alternative treatment option for MS patients.

Sepsis impedes EAE disease development and diminishes autoantigen-specific naive CD4 T cells.

Evaluation of sepsis-induced immunoparalysis has highlighted how decreased lymphocyte number/function contribute to worsened infection/cancer. Yet, an interesting contrast exists with autoimmune disease development, wherein diminishing pathogenic effectors may benefit the post-septic host. Within this framework, the impact of cecal ligation and puncture (CLP)-induced sepsis on the development of experimental autoimmune encephalomyelitis (EAE) was explored. Notably, CLP mice have delayed onset and reduced disease severity, relative to sham mice. Reduction in disease severity was associated with reduced number, but not function, of autoantigen (MOG)-specific pathogenic CD4 T cells in the CNS during disease and draining lymph node during priming. Numerical deficits of CD4 T cell effectors are associated with the loss of MOG-specific naive precursors. Critically, transfer of MOG-TCR transgenic (2D2) CD4 T cells after, but not before, CLP led to EAE disease equivalent to sham mice. Thus, broad impairment of antigenic responses, including autoantigens, is a hallmark of sepsis-induced immunoparalysis.

Sepsis is a life-threatening condition that can happen when the immune system overreacts to an infection and begins to damage tissues and organs in the body. It causes an extreme immune reaction called a cytokine storm, where the body releases uncontrolled levels of cytokines, proteins that are involved in coordinating the body's response to infections. This in turn activates more immune cells, resulting in hyperinflammation. People who survive sepsis may have long-lasing impairments in their immune system that may leave them more vulnerable to infections or cancer. But scientists do not know exactly what causes these lasting immune problems or how to treat them. The fact that people are susceptible to cancer and infection after sepsis may offer a clue. It may suggest that the immune system is not able to attack bacteria or cancer cells. One way to explore this clue would be to test the effects of sepsis on autoimmune diseases, which cause the immune system to attack the body's own cells. For example, in the autoimmune disease multiple sclerosis, the immune system attacks and destroys cells in the nervous system. If autoimmune disease is reduced after sepsis, it would suggest the cell-destroying abilities of the immune system are lessened. Using this approach, Jensen, Jensen et al. show that sepsis reduces the number of certain immune cells, called CD4 T cells, which are are responsible for an autoimmune attack of the central nervous system. In the experiments, mice that survived sepsis were evaluated for their ability to develop a multiple sclerosis-like disease. Mice that survived sepsis developed less severe or no autoimmune disease. After sepsis, these animals also had fewer CD4 T cells. However, when these immune cells were reinstated, the autoimmune disease emerged. The experiments help explain some of the immune system changes that occur after sepsis. Jensen, Jensen et al. suggest that rather than being completely detrimental, these changes may help to block harmful autoimmune responses. The experiments may also hint at new ways to combat autoimmune diseases by trying to replicate some of the immune-suppressing effects of sepsis. Studying the effect of sepsis on other autoimmune diseases in mice might provide more clues.