NIH - Role of Gut Microbiome in Regulating Reproduction and Its Impact on Fertility Status in Women Living with and Without HIV (R01, R21 Clinical Trial Optional)

The following description was taken from the R01 version of this FOA.

Alterations in the gut microbiome have been associated with reproductive, developmental and metabolic disorders. Gut microbes process the food, synthesize vitamins, and produce numerous chemicals of hormonal nature that are released into the blood. These include small chain fatty acids (SCFAs), neurotransmitters (serotonin, dopamine, GABA), precursors of neuroactive compounds such as tryptophan, kynurenine and L-Dopa, and trimethylamine, a choline metabolite. By virtue of entering the bloodstream, these microbial products could influence the function of the hypothalamo-pituitary-gonadal (HPG), hypothalamo-pituitary-adrenal (HPA), and hypothalamo-pituitary-thyroid (HPT) axes, thereby affecting reproduction, stress management, and metabolism, respectively. Indeed, studies conducted in germ-free animals have shown that the gut microbiome influences stress activity and anxiety-like behavior through the HPA axis. However, there is no information on the influence of the gut microbiome over the HPG and HPT axes which control reproductive and metabolic function.

In 2007, the NIH established a Common Fund Human Microbiome Project (HMP) with the mission of generating research resources for comprehensive characterization of the human microbiota and analysis of their role in human health and disease. The studies under this project have helped determine variations in the microbiome in different tissues and its function in large human populations, as well as established associations between altered microbial content and disease states. However, there are no studies to define precise biological or molecular pathways by which gut or any other organ-specific microbiota influences the host health or disease. This initiative is an attempt to stimulate research in the mechanistic understanding of how gut microbiome composition influences host metabolism and reproduction.

Reproductive success is tightly linked to the metabolic state of an individual. Metabolism, in turn, is exquisitely influenced by nutritional status with both under-nutrition and over-nutrition being associated with compromised fertility in both females and males. The gut is the portal for absorption of digested food, which along with the quantity of food consumed, dictates to a large degree nutritional status. The gut consists of trillions of microorganisms collectively called the microbiome which perform essential protective, structural, and metabolic functions for host health. For example, the gut microbiome produces numerous chemical entities of hormonal nature from food such as small chain fatty acids, neurotransmitters and other precursors of neuroactive compounds. These products may act locally in the gut or get absorbed into the blood stream and act at distal sites. Thus, these “metabolomes” of the gut microbiome may act at the level of gut to reduce or increase appetite or alternatively act at the level of the central nervous system to regulate food intake, metabolism, reproduction, and/or stress management.

Research has shown that the gut microbiome is dysregulated in humans during malnourishment, obesity, chronic infections such as HIV and type 2 diabetes. Studies have also shown that transplantation of gut microbiome from obese humans to germ-free lean mice results in an obese phenotype. There is also evidence to suggest that the gut microbiome is altered in animal models of polycystic ovarian syndrome and that such alterations may be correlated with high circulating androgen levels seen in women with the syndrome. A reduction in fertility in women who are living with HIV compared to uninfected women as well the increased rates of preterm and adverse outcomes such as stillbirth in women living with HIV has been reported. The etiology is unclear and understudied and investigating the role of the microbiome in contributing to these outcomes would add new knowledge for the care and management of women living with HIV. Further, studies conducted in germ-free animals have shown that the gut microbiome influences neural pathways involved in stress activity and anxiety-like behavior and is altered in patients exhibiting mood disorders in the human. Despite these provocative associations, there is a gap in our understanding of pathways linking the gut microbiome, metabolic dysfunction and infertility. Thus, it is imperative that studies be conducted to elucidate the pathways by which the gut microbiome could influence metabolism thereby influencing reproductive competence.

This initiative focused on the gut microbiome seeks to stimulate the receipt of applications in this area the results of which could bring about a new perspective to the diagnosis of infertility, and may lead to development of novel therapeutic approaches to treat both metabolic disorders and infertility.

Research Objectives

Possible research topics that may be addressed in response to this FOA include, but are not limited to, the following:

Examine the effect of altered gut microbiome and metabolome of the microbiome on hypothalamic neuroendocrine function, i.e. GnRH, TRH and CRH secretion.
Elucidate the role of altered microbiome and metabolome of the microbiome on pituitary gland function, i.e., LH, FSH, ACTH, TSH and prolactin.
Examine the impact of altered gut microbiome and metabolome of the microbiome on normal ovarian function and dysfunction, particularly for conditions that impact fertility such as anorexia nervosa, polycystic ovarian syndrome and obesity.
Study the impact of altered gut microbiome and metabolome of the microbiome on normal testicular function and dysfunction from azoospermia/ oligospermia to lack of libido.
Decipher dietary influences on the gut microbiome and metabolome of the microbiome in the development of metabolic dysfunction leading to infertility or subfertility.
Investigate the role of the gut microbiome on the stress responsiveness and its impact on reproduction in both male and females.
Investigate the role of gut microbiome on fertility in women living with HIV.
Investigate the relationship of the gut microbiome and maternal HIV infection on early pregnancy loss and fertility.
Investigate the relationship of the microbiome and maternal HIV infection on adverse pregnancy outcomes such as preterm birth and stillbirth.

Deadline: standard dates and standard AIDS dates apply

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Filed Under: Funding Opportunities

NIH – Role of Gut Microbiome in Regulating Reproduction and Its Impact on Fertility Status in Women Living with and Without HIV (R01, R21 Clinical Trial Optional)