Gut Microbes and Autoimmunity
A recent report by Janet Markle et al., in Science magazine, identifies a possible causative link between gut microbes and sex hormone production that may drive protection from autoimmunity.
The human gastrointestinal (GI) tract houses an extensive microbial ecosystem, represented by trillions of microorganisms located in our intestines. In fact, there are 10 times more intestinal microbial cells than cells in the human body. Recent research implicates disrupted intestinal equilibrium, termed gut dysbiosis, in the pathogenesis of autoimmune, allergic and metabolic diseases, and colorectal cancer (S. Prakashet al., Biologics: Targets and Therapy, 2011; 5: 71).
The sexual dimorphism in autoimmunity, wherein women, in general, are more frequently affected than men, is a well known phenomenon, but its mechanism remains poorly understood.
In the study by Markle and colleagues, the international team of researchers used the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D) to show that the strong >2:1 female-to-male NOD T1D sex bias and incidence is lost in germ-free (GF) conditions, in contrast to specific pathogen-free (SPF) conditions. Of note, no hygiene-dependent effects were detected in relation to 17β-estradiol, but the authors showed that commensal colonization regulated testosterone production and/or usage.
In a series of experiments the authors demonstrate that the transfer of gut microbiota from adult males to immature females resulted in elevated testosterone and metabolomic changes, reduced islet inflammation and autoantibody production, and T1D protection.
These findings, combined with previous research, as specified by the authors – specifically data of incomplete concordance in monozygotic twins and the recent rise in autoimmune disease incidence in developed countries may overall indicate a causal role of environmental factors in autoimmune disease.
This work seems to support the hygiene hypothesis of autoimmune diseases that may provide the missing immunoregulatory environmental factor that is needed to explain the recent increases in autoimmune disease.
The study also provides further evidence that testosterone is protective against autoimmunity.
After the hunt for genetic factors of the last decades, this study may represent the renaissance of interest towards hormonal and environmental factors that regulate autoimmune disease development and expression.
Source: Science, 2013, 339:1084-8.doi: 10.1126/science.1233521. Epub 2013 Jan 17.
Read more: PubMed
An Update
As per Andres Gomez, David Luckey, and Veena Taneja members of the gut microbiome are reported to interact with steroids, possibly impacting the steroid balance at the intestinal level and the metabolic activity in the colonic ecosystem. As such, some specific taxa have the capacity to metabolize sex steroid hormones and influence their activity.
For instance, the intestinal commensal Clostridium scindens encodes hydroxysteroid dehydrogenases and other enzymes involved in glucocorticoid conversion into androgens. Slackia sp., a common member of the gut microbiome, can exert inter-conversion of beta-estradiol and estrogen. Even though some sterols can be re-absorbed from the colonic ecosystem through enterohepatic circulation, it is unclear whether or how microbiome-derived sex steroids have an impact on host physiology and immunity, analogous to that of host-derived hormones.
Recent reports on the influence of gut microbes on gender-based autoimmunity suggest that both bacteria and sex hormones interact directly to regulate disease fate in genetically susceptible individuals.
Influence of sex-hormones on the gut microbial composition and immune response. From: The gut microbiome in autoimmunity: sex matters. Public domain.
Gender-bias in – gut microbiome profiles is caused, in part, by the sex hormones, estradiol and testosterone. β-estradiol promotes differentiation of conventional dendritic cells (DCs) into IL-12, IFNγ-producing DCs which activates pathways for pro-inflammatory cytokines IL-6 and IL-8 and polarization of T cells into Th1/Th17 (red dots) rather than anti-inflammatory cytokines (green dots).
The pro-inflammatory immune environment compromises gut permeability, causing translocation of gut commensals in to the lamina propria where they can amplify pro- inflammatory responses. In males (right panel), testosterone has a suppressive effect on T cell proliferation, resulting in attenuated immune responses and a balanced immune system. DCs maintain a tolerant environment by generating Th1/Th17 as well as T regulatory cells by production of IL-4, IL-10, IL-22 and CCL20.
The data suggest that a feedback loop between sex-hormones and gut microbes determine the expansion of microbial lineages that can likely influence autoimmunity by triggering an inflammatory or tolerogenic effect. Overall, these studies argue that gut microbes drive testosterone-dependent attenuation of T1D via immune regulation, which could be a mechanism characteristic of other gender-biased autoimmune disorders.
