Composición de la microbiota en pacientes pediátricos con déficit de hormona de crecimiento antes y después de recibir tratamiento con hormona de crecimiento
The microbiota is defined as the community of micro-organisms that inhabit a specific environment. Generally, commensal microorganisms populate all epithelial surfaces of the body, the most numerous and complex being the gut. Alterations in the composition and functionality of the microbiota (dysbiosis) have been associated with various pathologies. Among the different functions of the microbiota, its role in growth is particularly important. Indeed, several studies have shown that germ-free mice lacking gut microbiota have reduced levels of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor transporter protein-3 (IGFBP-3) and poor growth, with decreased linear growth and body weight, suggesting that mammals require the gut microbiota to ensure optimal growth. In this regard, studies in preclinical animal models have shown that physiological levels of growth hormone (GH) maintain gut integrity and improve digestive function. This effect of GH occurs synergistically with IGF-1, as observed in bone growth, metabolic and intestinal homeostasis, suggesting some association between the GH-IGF-1 axis and the gut microbiota. GH deficiency in children has a prevalence of 1:3,480 children, and can occur in isolation or associated to other pituitary deficits. Clinically it is characterised by harmonic and postnatal hypogrowth. They have a decreased response to stimulation tests and reduced levels of IGF-1 and IGFBP-3. The indicated treatment is recombinant human GH. Therefore, and given the analytical characteristics of these patients, with decreased GH and IGF-1 levels, the aim of the present study was to investigate whether these alterations were associated with changes in intestinal physiology/integrity as well as in the intestinal microbiota composition. To achieve this objective, a case-control study was performed in 21 patients with GH deficiency prior to baseline and after 6 months of GH treatment and in 20 healthy controls. Anthropometric data, analytical data, markers of inflammation, bacterial translocation and also the composition of the microbiome was determined by massive sequencing of the 16S rRNA gene, with comparison between cases and controls. The same data were analysed in patients with GH deficiency after treatment with growth hormone. Our results showed that patients with GH deficiency had lower height and lower IGF-1 and IGFBP-3 levels than controls, with a significant increase in both parameters after starting treatment. A disturbance was also observed in the two bacterial translocation markers studied, LBP and sCD14, with statistically significant differences in the latter. Our study shows that after GH treatment there is a significant increase in IGF-1 and IGFBP-3 levels in parallel with the observed reduction in bacterial translocation, underlining the bidirectional association between IGF-1-GH and gut/microbiota functionality. But it is also important to relate this improvement in TB after GH treatment to the significant decrease observed in faecal calprotectin levels after GH treatment, which underlines that GH administration is improving not only gut functionality and architecture but also gut inflammation, at a local level. No significant differences in the composition, α- or β-diversity of the gut microbiota were visualised between cases and controls, and no differences were observed in GH-deficient patients after treatment. To our knowledge, this is one of the first studies to compare the levels of bacterial translocation in children with ‘short stature’ and growth hormone deficiency with healthy controls, and also to study possible changes after GH treatment, which supports the interest of this work. In this regard, the increase observed in bacterial translocation in GH-deficient children, which is restored after GH treatment, is very interesting. In conclusion, our work demonstrates that a growth hormone deficiency (pathological hypocrectile growth and two GH stimulation tests with a low response < 7 ng/mL) in children is not accompanied by changes in the composition of the gut microbiota compared to the microbiota of healthy children, nor is it modified after treatment for 6 months with GH. However, this growth deficit and low levels of IGF-1 and GH were associated with an increase in bacterial translocation, which was reversed after treatment and with a decrease in gut inflammation, underlining the beneficial role of GH and IGF-1, not only at the level of growth, but also of gut integrity and thus of all gut-related axes: gut-brain, gut-liver axis, etc. Further studies (with prolonged periods of treatment, or with more severe GH deficits) are needed to understand in detail the association between GH-IGF-1 and gut and its impact on children's health, both in the short and long term.
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