Periodic Reporting for period 4 - IntraGutSex (Sex differences in intestinal plasticity)
Reporting period: 2023-04-01 to 2024-03-31
Males and females differ in their physiology and disease susceptibility. Research over the past few decades has often neglected the sex of cells/animals, or preferentially used only female or (more commonly) male animals. Such practices may have prevented identification of key sex differences that could inform clinical studies, and ultimately, clinical practice. There is, however, increasing pressure from science-policy stakeholders such as the European Commission and NIH to consider both sexes in both fundamental and clinical research.
In recent years, the gastrointestinal (GI) tract has come to the forefront of metabolic research. The GI tract is now recognised as a major source of signals modulating food intake, insulin secretion and energy balance, with profound effects on whole-body physiology. Using Drosophila, a powerful experimental system to explore the genetic underpinnings of physiological processes, we discovered that there are extensive sex differences in gene expression in the adult Drosophila intestine: an organ not previously known to be sexually dimorphic.
We have explored the nature and significance of these sex differences. Using Drosophila fruit flies as an experimental system, we have discovered how the intestine becomes different between the sexes. We have established that every cell type that makes up the intestine knows whether it is male or female both because of its own genetic make up and the hormones that it is exposed to.
Using flies, we have also been able to establish why the intestine needs to be male or female; this is because it needs to engage in communication with the reproductive organs to sustain reproduction.
Using mice, we have been able to establish that these sex differences are reproductive roles are not a fly peculiarity: they are widely applicable and relevant to mammalian systems, and may even impact our own physiology.
In recent years, the gastrointestinal (GI) tract has come to the forefront of metabolic research. The GI tract is now recognised as a major source of signals modulating food intake, insulin secretion and energy balance, with profound effects on whole-body physiology. Using Drosophila, a powerful experimental system to explore the genetic underpinnings of physiological processes, we discovered that there are extensive sex differences in gene expression in the adult Drosophila intestine: an organ not previously known to be sexually dimorphic.
We have explored the nature and significance of these sex differences. Using Drosophila fruit flies as an experimental system, we have discovered how the intestine becomes different between the sexes. We have established that every cell type that makes up the intestine knows whether it is male or female both because of its own genetic make up and the hormones that it is exposed to.
Using flies, we have also been able to establish why the intestine needs to be male or female; this is because it needs to engage in communication with the reproductive organs to sustain reproduction.
Using mice, we have been able to establish that these sex differences are reproductive roles are not a fly peculiarity: they are widely applicable and relevant to mammalian systems, and may even impact our own physiology.
Our work has revealed extensive sex differences in the intestine, and has discovered new mechanisms accounting for sex differences in two different cell types: the digestive enterocytes and the neurons that reside in the GI tract.
In males, enterocytes are masculinised by signals emanating from the testes. In response to testes-derived signals, male enterocytes produce citrate which is taken up by the testes to produce sperm. Gut-derived citrate also signals to neurons to promote food intake in males. These findings suggest that circulating citrate in our bloodstream (and/or that made in high levels by the prostate) may have important roles in the context of food intake regulation and/or fertility in humans.
More intriguingly, this work also revealed that communication between organs takes place between adjacent organ regions, raising the possibility that the spatial arrangement of internal organs is stereotypical and (patho) physiologically significant. We have now secured new funding to explore this idea.
We also found sexually dimorphic roles for the metal handling machinery in enterocytes. We established that metal interoception plays important roles in dietary choices and growth control during development. The nutrition field does normally only consider the effects of carbohydrates, proteins and fat in (patho)physiology; our findings underscore the need to consider micronutrients such as zinc.
We have also explored sex differences in the female intestine and found that, like that of males, it communicates with the gonad (the ovary in this case), but the mechanisms involved are very different. We found that female (but not male) enteric neurons change their activity after mating. This change is mediated by reproductive hormones and is required to sustain the increased food intake of female flies during reproduction - which is in turn required to maximise fecundity. This finding raises the possibility that neurons residing in our gastrointestinal tract mediate the increased food intake of (female) humans during pregnancy and lactation. We are currently exploring this idea.
Finally, we have established that the mammalian intestine also differs between the sexes and is remodelled in female by reproduction. This suggests that these features may be relevant to humans and might affect our ability to reproduce or the incidence of pathologies known to be modulated by pregnancy. We have begun to explore these ideas.
In males, enterocytes are masculinised by signals emanating from the testes. In response to testes-derived signals, male enterocytes produce citrate which is taken up by the testes to produce sperm. Gut-derived citrate also signals to neurons to promote food intake in males. These findings suggest that circulating citrate in our bloodstream (and/or that made in high levels by the prostate) may have important roles in the context of food intake regulation and/or fertility in humans.
More intriguingly, this work also revealed that communication between organs takes place between adjacent organ regions, raising the possibility that the spatial arrangement of internal organs is stereotypical and (patho) physiologically significant. We have now secured new funding to explore this idea.
We also found sexually dimorphic roles for the metal handling machinery in enterocytes. We established that metal interoception plays important roles in dietary choices and growth control during development. The nutrition field does normally only consider the effects of carbohydrates, proteins and fat in (patho)physiology; our findings underscore the need to consider micronutrients such as zinc.
We have also explored sex differences in the female intestine and found that, like that of males, it communicates with the gonad (the ovary in this case), but the mechanisms involved are very different. We found that female (but not male) enteric neurons change their activity after mating. This change is mediated by reproductive hormones and is required to sustain the increased food intake of female flies during reproduction - which is in turn required to maximise fecundity. This finding raises the possibility that neurons residing in our gastrointestinal tract mediate the increased food intake of (female) humans during pregnancy and lactation. We are currently exploring this idea.
Finally, we have established that the mammalian intestine also differs between the sexes and is remodelled in female by reproduction. This suggests that these features may be relevant to humans and might affect our ability to reproduce or the incidence of pathologies known to be modulated by pregnancy. We have begun to explore these ideas.
Our work has shed light on the mechanisms contributing to sex differences in an organ not previously known to be different between males and females.
In flies, we have established that the sex of the intestine contributes to sex differences in whole body physiology and disease (e.g. tumour susceptibility).
Beyond flies, we have established that these intestinal sex differences are conserved in mice.
Looking ahead, we expect to:
1) continue to shed light on the nature of these differences, within an emphasis on multimodal, multiscale approaches that take into consideration three-dimensional aspects
2) establish which of these differences are relevant to mammalian systems through ongoing work in mice and budding work in humans.
In flies, we have established that the sex of the intestine contributes to sex differences in whole body physiology and disease (e.g. tumour susceptibility).
Beyond flies, we have established that these intestinal sex differences are conserved in mice.
Looking ahead, we expect to:
1) continue to shed light on the nature of these differences, within an emphasis on multimodal, multiscale approaches that take into consideration three-dimensional aspects
2) establish which of these differences are relevant to mammalian systems through ongoing work in mice and budding work in humans.