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Systemic IGF-1 administration prevents traumatic brain injury induced gut permeability, dysmorphia, dysbiosis, and the increased number of immature dentate granule cells

Acta Neuropathologica Communications volume 13, Article number: 90 (2025) Cite this article

Abstract

Traumatic brain injury (TBI) occurs in 2–3 million Americans each year and is a leading cause of death and disability. Among the many physiological consequences of TBI, the hypothalamic pituitary axis (HPA) is particularly vulnerable, including a reduction in growth hormone (GH) and insulin-like growth factor (IGF-1). Clinical and preclinical supplementation of IGF-1 after TBI has exhibited beneficial effects. IGF-1 receptors are prominently observed in many tissues, including in the brain and in the gastrointestinal (GI) system. In addition to causing damage in the brain, TBI also induces GI system damage, including inflammation and alterations to intestinal permeability and the gut microbiome. The goal of this study was to assess the effects of systemic IGF-1 treatment in a rat model of TBI on GI outcomes. Because GI dysfunction has been linked to hippocampal dysfunction, we also examined proliferation and immature granule cells in the hippocampal dentate gyrus. 10-week-old male rats were treated with an intraperitoneal (i.p.) dose of IGF-1 at 4 and 24 h after lateral fluid percussion injury (FPI). At 3- and 35-days post-injury (DPI), gut permeability, gut dysmorphia, the fecal microbiome, and the hippocampus were assessed. FPI-induced permeability of the blood-gut-barrier, as measured by elevated gut metabolites in the blood, and this was prevented by the IGF-1 treatment. Gut dysmorphia and alterations to the microbiome were also observed after FPI and these effects were ameliorated by IGF-1, as was the increase in immature granule cells in the hippocampus. These findings suggest that IGF-1 can target gut dysfunction and damage after TBI, in addition to its role in influencing adult hippocampal neurogenesis.

Background

Traumatic brain injury (TBI) occurs in 2–3 million Americans each year, and as many as 50 million people worldwide [1, 2]. TBI is a leading cause of death and disability [3, 4], and suffering a TBI is associated with an approximately 2.2–2.8-fold increase in 30-year mortality rate [5]. TBI is also associated with a number of chronic post-traumatic syndromes, including depression, cognitive impairment, and an increased susceptibility to chronic neurodegenerative disorders, such as post-traumatic epilepsy, Parkinson’s disease (PD), and Alzheimer’s disease (AD) [3, 6]. There are currently no effective treatments for mitigating post-traumatic syndromes, and identifying therapeutic mechanisms is of the utmost importance to improve health outcomes for the millions of people who experience a TBI each year, and are living with the consequences [5].

Among the myriad of physiological consequences to a TBI, the hypothalamic–pituitary–adrenal axis (HPA) is particularly vulnerable. The HPA regulates hormonal release and endocrine function, and HPA dysregulation after TBI has been identified in clinical [7,8,9,10,11,12,13] and preclinical studies [14,15,16]. This pathology can manifest as abnormal hormone production [17,18,19,20], including disruption in growth hormone (GH) released from the pituitary gland [21,22,23] and reduced insulin-like growth factor-1 (IGF-1) that is primarily released by the liver in response to endocrine signals. Importantly, these physiological consequences may play a role in TBI pathogenesis [10, 24, 25], and in a Phase II clinical trial, supplementing IGF-1 after TBI alone, or in combination with GH, improved weight gain, nutritional status, and other metabolic parameters in moderate-to-severe TBI patients in the first two weeks after injury [26,27,28].

IGF-1 is a 7.5 kDa peptide hormone that plays a major role in cell growth, differentiation, and repair, including after central nervous system (CNS) trauma [29,30,31,32,33,34]. Reduced serum IGF-1 has been reported in patients during the first week after TBI [35, 36] and more chronically after injury [37, 38]. Reduced levels of IGF binding proteins (IGFBP), which bind to and stabilize IGF-1 for transport in the serum, have also been identified after TBI [39]. Interestingly, higher levels of serum IGF-1 after TBI was predictive of white matter recovery and memory improvement after injury [40], and low serum IGF-1 in children was associated with worse outcomes [41].

Preclinical TBI studies also demonstrate reduced IGF-1 after TBI. Following TBI in adolescent rats, serum IGF-1 was decreased between 1 week and 1 month after injury [42], and this reduction was correlated with impaired cognitive function [43]. In another study, plasma IGF-1 was reduced 3 weeks after controlled cortical impact (CCI) in mice [44]. Thus, IGF-1 deficiency after clinical and preclinical TBI appears to be associated with detrimental neuropathological outcomes. Accordingly, IGF-1 treatment for 14 days elevated serum IGF-1, and the elevations were associated with increased survival and a higher percentage of patients achieving better outcome scores 6 months after injury [26], and this is supported by preclinical studies [45,46,47]. While side effects such as hypoglycemia may limit the therapeutic potential of IGF-1 [48], identification of novel targets could enable studies to overcome this limitation.

After TBI, exogenous IGF-1 may convey benefit in the periphery, as well as in the CNS. In the periphery, the gastrointestinal (GI) tract is damaged after TBI, including altered intestinal permeability [49,50,51], inflammation [51, 52], and alterations to the microbiome [52,53,54,55,56,57,58,59,60,61]. IGF-1 receptors are prominently expressed in the gut where they are involved in regulating intestinal epithelial stem cell (IESC) function [62, 63]. The GI system is increasingly recognized as playing a major role in mediating neuropathology and neurological dysfunction, and IGF-1 may be involved in the GI response to injury [62, 64,65,66,67,68,69,70], including inflammation induced gut permeability [71, 72]. Importantly, gut dysfunction has been shown to worsen the neurological deficits associated with TBI [73]. Therefore, the present study investigated the hypothesis that systemic IGF-1 treatment at 4 and 24 h after FPI would improve GI permeability, dysmorphia, and alterations to gut microbiome. Because TBI is known to alter the number and morphology of immature dentate granule neurons [74,75,76,77], and because IGF-1 has been previously shown to alter hippocampal neurogenesis in the context of TBI [46], this study also examined immature neurons in the hippocampus after FPI.

Results

FPI-induced gut permeability at 3-days post-FPI is attenuated by IGF-1

GI permeability was assessed at 3 days post injury (DPI) by measuring serum levels of LPS, iFABP, and Mucin-2 (Muc-2), elevations of which are indicative of increased intestinal permeability and gut barrier damage [78,79,80]. LPS is an endotoxin released by Gram-negative bacteria, and the concentration of LPS has been reported to be increased in plasma due to an impaired gut barrier after TBI [73, 81]. iFABP and muc-2 are major components of the mucosal layer, and they can be released into circulation when there is damage to the mucosal layer [82, 83]. There was a significant increase in the serum concentrations of LPS (p < 0.0001), iFABP (p < 0.0001), and Muc-2 (p < 0.0001) in the FPI + Veh group compared to sham, all of which were significantly decreased to sham levels in the FPI + IGF1 group (p < 0.0001, p < 0.001, p < 0.001, respectively vs. FPI + Veh) (Fig. 1a–c). These data show intestinal barrier permeability after FPI, and this can be mitigated by IGF-1 treatment.

Fig. 1
figure 1

IGF-1 treatment rescues early FPI-induced gut permeability. Blood-gut barrier permeability was assessed at 3 DPI by measuring serum levels of LPS, iFABP and Muc-2 [78,79,80]. In a, there was a significant increase in the serum concentration of LPS in the FPI + Veh rats (p < 0.0001 vs. Sham + Veh) that was significantly ameliorated by IGF-1 treatment (p < 0.001 vs. TBI + Veh). In b, levels of serum iFABP were significantly elevated in FPI + Veh as compared to the Sham + Veh rats (p < 0.0001), and this increase was significantly attenuated in the FPI + IGF-1 rats (p < 0.001 vs. FPI + Veh). In c, the concentration of Muc-2 (520 kD) was significantly elevated in FPI + Veh rats compared to the Sham + Veh rats (p < 0.0001) and reduced in FPI + IGF-1 rats (p < 0.001 vs. FPI + Veh). These data suggest that the blood-gut barrier and the mucus barrier may deteriorate after FPI and this is prevented by IGF-1. Data are represented as Mean ± SEM; n = 8–10 per group. Note, 3 rats in the FPI + IGF-1 group were omitted from Mucin-2 analysis due to limited serum availability. ***p < 0.001; ****p < 0.0001

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Gut dysmorphia after FPI is diminished by IGF-1

To assess gut morphology, the ileum and proximal colon were analyzed (Fig. 2, Supp. Fig. Q1) using H&E staining at 3 and 35 DPI. Qualitatively, at 3 and 35 DPI the intestines of the FPI + Veh rats exhibited clear disruption relative to sham rats, while the FPI + IGF-1 treated rats resembled the shams. In the FPI + Veh rats, there appeared to be fewer villi in the ileum, and many of the villi appeared short and stubby, and this observation was more pronounced at 35 DPI. (Fig. 2a–f, k–p). Quantitative analysis of the villus length:width ratio and the number of crypts per villus were consistent with the qualitative observations. No significant differences in the ileum were observed at 3 DPI the villus (Fig. 2g, h), but at 35 DPI, FPI significantly reduced the length:width ratio of the ileum villi (p < 0.05) and significantly increased the number of crypts per villus (p < 0.05), compared to sham rats (Fig. 2o, p). Compared to FPI + Veh, IGF-1 treatment after FPI resulted in a significant increase in the length:width ratio (p < 0.05), and a significant decrease in the number of crypts per villus (p < 0.05), such that the appearance was very similar to the Sham + Veh rats (Fig. 2o, p). The average lengths and widths of the villi are also provided (Table 1). Similar to the ileum, in the proximal colon there were no significant differences identified at 3 DPI (Supp. Fig. 1a,b), but at 35 DPI, FPI significantly reduced inter-crypt mucosal length:width ratio (p < 0.01) and increased the number of crypts per inter-crypt mucosa (p < 0.01). As with the ileum, IGF-1 significantly prevented this FPI-induced gut dysmorphia, such that they appeared more like shams (p < 0.01, p < 0.01, respectively) (Supp. Fig. 1c, d).

Fig. 2
figure 2

IGF-1 treatment reduces FPI-induced chronic gut dysmorphia. To assess gut morphology, villi and crypts were analyzed in the ileum using H&E staining at 3 (a–f) and 35 (j–o) DPI. Note the normal appearance of the villi and crypts in sham rats (black arrowhead; a,b). Also note that at the 3 DPI timepoint, the villi are beginning to show a rounded stumpy appearance (green arrowhead; c,d), but the quantitative results are not significant at this time point (g, h). These morphological differences evolve over time so that they appear more pronounced at 35 DPI, such that they have a significantly reduced length:width ratio (p < 0.01 vs. Sham + Veh), and this was significantly increased by IGF-1 treatment (p < 0.01) (o). Importantly, the villi from the IGF-1 treated rats appears much more sham-like (e,f). In p, the number of crypts per villus in the ileum was increased after FPI (p < 0.05 vs. Sham + Veh), and IGF-1 treatment after FPI significantly reduced this effect (p < 0.05). For all rats, 3 slides were assessed, with 3 sections per slide measured. Scale bar in e,n = 10 µm for A,C,E,J,L,N; scale bar in f,o = 5 µm for B,D,F,L,M,O. Data are represented as Mean ± SEM. N for 3 DPI: 4 Sham + Veh, 5 FPI + Veh, 5 FPI + IGF1. N for 35 DPI: 3 Sham + Veh, 3 FPI + Veh, 4 FPI + IGF1. *p < 0.05; **p < 0.01

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Table 1 Average villus length and width at 3 and 35 DPI
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Goblet cells in the gut epithelium produce the intestinal mucus, of which muc-2 is a major structural component [83, 84]. Quantitative analysis of the number goblet cells from PAS-stained tissue in the ileum at 3 and 35 DPI (Fig. 3a–c) revealed that FPI caused a significant decrease in the number of goblet cells at 3 DPI (p < 0.05 vs. Sham + Veh), and this was ameliorated by the IGF-1 treatment (p < 0.01 vs. FPI + Veh; Fig. 3d). At 35 DPI a significant increase in the number of goblet cells per crypt following IGF-1 treatment was also observed (p < 0.05 vs. Sham + Veh, p < 0.01 vs. FPI + Veh; Fig. 3e), suggesting an influence of IGF-1 on goblet cells and mucus production. To determine the influence of FPI on proliferating cells in the ileum, Ki67-labeled cells were quantified. (Fig. 3f–h). Although no significant differences were observed at 3 DPI, IGF-1 treatment after FPI did result in a significant decrease in Ki67 + cells in the ileum (p < 0.01 vs. Sham + Veh; Fig. 3i). At 35 DPI, a significant increase in Ki67 + cells was observed in FPI + Veh rats (p < 0.05 vs. Sham + Veh), and this was significantly reduced by IGF-1 treatment (p < 0.05 vs. FPI + Veh; Fig. 3j). These data suggest that IGF-1 may have a protective effect on the intestinal mucosa, specifically the goblet cells, whereas it had the opposite effect on progenitor cells in the crypt after FPI.

Fig. 3
figure 3

Influence of FPI and IGF-1 on goblet cells and intestinal epithelial stem cells (IESC). PAS staining was used to assess the number of goblet cells per crypt in the ileum at 3 (a–c) and 35 DPI. Quantitative analysis revealed that FPI significantly reduced the number of goblet cells per crypt at 3 DPI (d) and 35 DPI (e) and this was increased by IGF-1 treatment. Proliferating IESCs in the crypts were determined by quantifying Ki67 + labeled cells at 3 (i) and 35 (j) DPI. In f–h, representative micrographs of Ki67 + staining in the crypts of the ileum at 35 DPI, with areas designated by the white arrow enlarged in the corresponding inset. At 3 DPI (i), the FPI + Veh showed a non-significant reduction (p = 0.2152, NS) in the number of Ki67 + cells in the crypts. The FPI + IGF-1 group exhibited a significant reduction (p < 0.01 vs. to Sham + Veh) in the Ki67 + cells in the crypts. Conversely at 35 DPI (j), FPI significantly increased the number of Ki67 + cells, and this was significantly reduced by IGF-1 treatment. This suggests that FPI resulted in a delayed increase in IESC proliferation, whereas IGF-1 reduced the number of Ki67 + cells at both timepoints examined. For all rats, 3 slides were assessed, with 3 sections per slide measured. Data are represented as Mean ± SEM; N for 3 DPI: 4 Sham + Veh, 5 FPI + Veh, 5 FPI + IGF1. N for 35 DPI: 3 Sham + Veh, 3 FPI + Veh, 4 FPI + IGF1. *p < 0.05; **p < 0.01. Scale bar in a = 5 µm; scale bar in b,c = 10 µm; scale bar in h = 10 µm for f–h

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Influence of IGF-1 on immature neurons and proliferative cells in the hippocampus after FPI

Because of the known effects of IGF-1 on the hippocampus, including adult hippocampal neurogenesis [46], this study examined immature neurons and Ki67 cells in the hippocampus at 3 DPI. Consistent with previous studies indicating that FPI induces early increases in adult hippocampal neurogenesis [74, 85], the results show that FPI resulted in a strong trend towards an increased number of DCX-labeled immature neurons in the dentate gyrus (p = 0.051, NS). This increase was not observed in the IGF-1-treated FPI group (Fig. 4a–c). It is pertinent to note that increased neurogenesis after precipitating brain injuries can include aberrant growth and integration of the newborn neurons [77, 86], resulting in dysfunctional hippocampal circuitry [77]. Thus, it is possible that the increased number of immature neurons in the dentate gyrus might contribute to the impaired hippocampal-dependent cognitive dysfunction that has been reported after FPI [87]. Examination of proliferating Ki67 + cells at 3 DPI yielded no significant differences in the dentate gyrus (Fig. 4e–h). These results suggest that FPI might be enhancing immature neuron survival, or increasing the rate of neurogenesis, rather than increasing the number of progenitor cells in the hippocampus at this timepoint.

Fig. 4
figure 4

IGF-1 ameliorates the FPI-induced increase in immature neurons in the adult hippocampus. Immature neurons in the hippocampal dentate gyrus were assessed by stereological quantification of the number of DCX-labeled cells at 3 DPI (a–c). The results show that FPI increased the number of DCX + cells (p = 0.051), and this was mitigated by IGF-1 treatment (d). The number of proliferative cells in the dentate gyrus (DG) was assessed by quantifying the number of Ki67-labeled cells (e–g) in the hilus (h), granule cell layer (GCL), and subgranular zone (SGZ). No significant differences in the number of Ki67 + cells in the hippocampus were identified at 3 DPI (h). Scale bar in c = 20 µm for (a–c). Data are represented as Mean ± SEM; n = 3–4 per group

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Altered gut microbiome composition after TBI is normalized by IGF-1 treatment

Gut microbiome alterations have been observed acutely and chronically in clinical [54, 57] and preclinical models [59] of TBI, and have been linked to cognitive dysfunction [88, 89]. Therefore, fecal samples were collected at pre- and at 35 DPI, and analyzed via 16S sequencing. Changes to the Firmicutes to Bacteroidetes ratio (F:B) is an indicator of gut health [90], and changes to the abundance of major phyla can shift the F:B ratio [54, 56]. Here, the F:B ratio was significantly increased in the IGF-1 treated rats compared to the FPI + Veh (p < 0.05) (Fig. 5a). Further examination of Bacteroidetes levels after injury revealed a trend towards decreased Bacteroidetes in FPI + Veh rats compared to Sham + Veh (p = 0.057, NS) and a significant increase in Bacteroidetes after IGF-1 treatment (p < 0.05 vs. FPI + Veh) (Fig. 5b). Importantly, variations in bacterial phyla such as Bacteroidetes and Firmicutes have been associated with cognitive dysfunction [91,92,93,94,95,96], and the results from the current study show that FPI increased the relative abundance of Bacteroidetes. While there were no significant changes in Firmicutes (Fig. 5c), Firmicutes includes Lactobacillus species that are probiotic. At the species level, the abundance of Lactobacillus was significantly decreased in the FPI + Veh rats 35 DPI compared to baseline (p < 0.05), while there was no difference identified in either the Sham + Veh or IGF-1 treated groups when compared to baseline (Fig. 5d). Furthermore, using the partial Least-Squares Discriminant Analysis (PLS-DA), a multivariate dimensionality-reduction, to assess the major phyla present, the FPI + IGF rats were found to cluster more closely with the Sham + Veh, while the FPI + Veh exhibited greater variability (Fig. 5e). Thus, FPI shifts the gut microbiome population, and IGF-1 mitigates these effects.

Fig. 5
figure 5

Gut dysbiosis after FPI is improved by IGF-1. Gut bacterial composition was assessed from fecal samples at 35 DPI. The ratio of Firmicutes to Bacteroidetes (F:B), an estimate of gut health, was significantly increased in the FPI + IGF-1 treated rats compared to the FPI + Veh rats (p < 0.05) (a). The relative count of Bacteriodetes was increased in FPI + Veh rats (p = 0.057, NS vs. Sham + Veh), and this was significantly reduced with IGF-1 treatment (p < 0.05 vs. FPI + Veh) (b). There were no significant changes identified in Firmicutes (c). In d, the abundance of Lactobacillus was significantly decreased in the FPI + Veh rats at 35 DPI compared to baseline (p < 0.05), while there were no significant differences identified at 35 DPI in either the Sham + Veh or FPI + IGF-1 groups. In e, principal component analysis (PCA) using the partial Least-Squares Discriminant Analysis (PLS-DA shows that the major phyla for Sham + Veh and FPI + IGF-1 rats cluster more closely together than do the FPI + Veh. In f, heat map expression levels further demonstrate that FPI + Veh rats have an altered gut bacterial repertoire, compared to Sham + Veh, and that the FPI + IGF-1 rats are more similar to sham rats. Data are represented as Mean ± SEM; n = 4–5 per group. *p < 0.05; **p < 0.01

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Discussion

The results from this study demonstrate early and chronic changes to gut permeability, morphology, and the fecal microbiome after FPI, and an increase in the number of immature dentate granule cells. Clinical and preclinical TBI studies have demonstrated alterations to gut structure, function, and microbiome composition [53,54,55,56,57,58,59, 97,98,99,100,101,102,103,104,105]. GI dysfunction has been linked to neurobehavioral impairment, neuropsychiatric conditions, and neurodegenerative disease [106], and improving gut structure and function may underlie functional CNS improvements [107]. Increased gut permeability and elevated plasma LPS have been shown to be associated with cognitive decline [108, 109]. That IGF-1 treatment after FPI ameliorated the elevated plasma iFABP, LPS, and Muc-2, suggests that IGF-1 may be acting on the blood-gut-barrier, as has been previously described [71, 110,111,112]. The IGF-1 treatment may have also acted on the protective mucous barrier [113] because the FPI-induced decrease in goblet cells after injury was mitigated by IGF-1 treatment. It was surprising that IGF-1 reduced the number of Ki67 + progenitor cells in the intestinal crypts, despite its positive influence on permeability, the goblet cells, and dysmorphia. It is possible that FPI altered enterocyte survival or influenced the types of cellular offspring being produced by the progenitor cells, accounting for the goblet cell loss and dysmorphia. Future studies are needed to more fully examine the cellular make-up, turnover rates, and function of the intestines in response to injury and treatments. Considering the fact that TBI results in dysmotility and gastroparesis in the clinic [99, 100, 114] and animal models [115], the effects of IGF-1 on gut motility also need to be explored.

Numerous clinical and preclinical studies support the notion that gut dysmorphia can be targeted to improve neurological function. In multiple sclerosis, treating the gut improved neurobehavioral performance and prevented the loss of myelin [116,117,118]. In a mouse model of obesity, β-glucan administered into the lower GI tract attenuates colonic barrier dysfunction, inflammation, and cognitive and affective impairment [119]. In animal models of PD and AD, restoring gut structure and function mitigated the genetically induced neurodegeneration and neurobehavioral impairment [120,121,122]. Furthermore, targeting stroke-induced intestinal dysfunction using IESCs was beneficial to post-stroke outcomes [123]. Therefore, the gut appears to be an important therapeutic target in TBI and other neurological disorders.

Increased neurogenesis after brain insults has been shown to result in aberrant growth and integration into hippocampal circuitry, resulting in impaired hippocampal function [74, 77, 85, 124]. In the current study, FPI resulted in an increased number of DCX-labeled immature neurons in the hippocampus at 3 DPI, and this increase was partially ameliorated by IGF-1 treatment. This is consistent with previous studies in different models of TBI that have demonstrated elevated adult hippocampal neurogenesis after TBI [125, 126]. While FPI did increase immature neurons at 3 DPI, no such change in Ki67 proliferating cells were observed in the dentate gyrus at 3 DPI. There are several possible explanations for this observation. Although the number of proliferating cells was not increased by FPI, it is possible that the rate of proliferation was increased, or that the generation of immature neurons as opposed to astrocytes is increased, as has been previously described [76, 126]. Consistent with this possibility, enhanced proliferation after TBI has been recorded within 1 and 14 DPI [76, 127,128,129]. It is possible that had earlier or later post-FPI timepoints been examined, the results may have been different. Another possibility is that FPI promotes survival of immature neurons, rather than increased proliferation, yielding a net increase in the number of DCX-labeled immature neurons, but not in Ki67 + cells. Consistent with this possibility, TBI has been previously shown to enhance both the survival and dendritic outgrowth of immature neurons in the adult hippocampus [74, 75, 85, 125]. Importantly, IGF-1has been previously shown to normalize TBI-induced alterations to adult hippocampal neurogenesis [46], consistent with the current study.

While the current findings have intriguing therapeutic implications for TBI, there are several limitations. In addition to obvious endocrine differences, there are documented sex differences in the response to TBI, in both clinical studies [130,131,132,133,134,135] and animal models [136,137,138,139,140]. This includes sex differences in the effects on the gut and the influence of gut microbiota on recovery after injury [141]. Because this study only looked at male rats, it is unclear what the differences would be in female rats. Furthermore, the use of IGF-1 in humans is limited clinically as it can cause hypoglycemia in non-diabetic individuals [48, 142], and such metabolic effects of IGF-1 treatment after FPI may have influenced the observed results. Nevertheless, this and other preclinical and clinical studies support the benefit of IGF-1 after FPI, and the current study establishes the possibility that IGF-1 signaling in the gut can be targeted to treat post-traumatic outcomes. Future studies can more selectively target IGF-1 signaling components to achieve therapeutic effects without toxic side effects.

In conclusion, the current findings highlight the benefit of systemic IGF-1 treatment after FPI in rats for improving gut permeability, dysmorphia, altered microbiome, and normalizing the FPI-induced increase in adult hippocampal neurogenesis. Considering the growing recognition of the importance of gut function on neurological outcomes, as well as the multitude of studies indicating gut dysfunction after TBI, these findings support further interrogation of IGF-1 signaling after TBI. The results also suggest the exciting possibility that gut dysmorphia and dysfunction may be novel therapeutic targets for improving TBI outcomes. Future studies are needed to more fully explore these possibilities.

Methods

Animals

10-week-old male Sprague–Dawley rats (Total = 36 rats) were used for this study. At one week prior to FPI or sham, rats were housed in individual cages under controlled environment with a 12-h light dark cycle (light on at 6:00 and light off at 18:00), with food and water continuously available and maintained on a standard diet (Envigo # 8604) for the duration of the experiment. Rats were randomly assigned into three groups: Sham + Veh, FPI + Veh, and FPI + IGF-1. Rats were administered with vehicle (Veh) or recombinant human (rh)IGF-1 (R&D Systems #291-G1-01 M) via i.p. injection (200 µg in 500 µL Phosphate Buffered Saline (PBS)) at 4 h and 24 h post-FPI. This dose was selected based on reports showing that it improved intestinal and neurobehavioral outcomes in a rat stroke model [110]. All Veh rats were given equal volume PBS in place of IGF-1. A subset of rats from each treatment group (n = 7–10 per group) were sacrificed at 3 DPI for assessment of gut pathology and permeability. Additional rats (n = 3–4 per group) were sacrificed at 35 DPI for assessment of gut morphology. All rat experimental protocols were approved by the Institutional Animal Care and Use Committee (IACUC) of Texas A&M Health Science Center (AUP #2010–0140) (Fig. 6).

Fig. 6
figure 6

Experimental Design for the study. Schematic diagram depicting the experimental design showing that rats received either sham or FPI at 10-weeks-of age, followed by IGF-1 or vehicle at 4 and 24 hours after surgery. Tissue was then collected for analysis at either 3 or 35 days post injury (DPI)

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Fluid percussion injury (FPI)

A mild-to-moderate lateral FPI was used as a model of TBI, as previously described [74, 86, 143]. Rats were initially anesthetized in an induction chamber (pre-filled with 4% isoflurane in 100% O2) and later the level of the isoflurane was reduced to 2% for maintenance. Under anesthesia, the hair on the top of the rat’s head was trimmed as close to the skin as possible. Rats were placed in a stereotaxic instrument (Stoelting, Illinois) and a 2-mm burr hole was drilled on the skull using drill bits (Stoelting, Illinois) over the left parietal cortex, at -2 mm antero-posterior to bregma and 3 mm medio-lateral to midline [144], ensuring that dura remained intact. A female Luer-Lok cannula was secured to the skull with dental cement (PlasticOne), then rats were connected to the fluid percussion instrument (Custom Design and Fabrication, Richmond, VA; Model 01-B) via male Luer-Lok attachment. The rat was placed on its side and breathing was monitored. Once a normal breathing pattern resumed, but prior to the rat regaining complete consciousness, the pendulum of the FPI device was released to cause a single ~ 2 atm pressure pulse injury, as measured by a digital Oscilloscope (Tenma model # 728395), connected to a signal transducer hooked in-line between the fluid percussion cylinder and the syringe. Sham animals all underwent the same procedures, but the pendulum was not released so no fluid pulse was delivered to the intact dura. Rats were monitored closely after injury, no death or loss of consciousness were observed, consistent with a mild-to-moderate injury.

Gut permeability ELISA assays

Serum was collected via saphenous draw at 3 days post-FPI from 26 rats (7 Sham + Veh, 9 FPI + Veh, 10 FPI + IGF1). ELISA assays were used to determine levels of surrogate measures of gut permeability: lipopolysaccharide (LPS) (Mybiosources, MBS268498; Detection range: 15.6 ng/mL–1000 ng/mL), mucin-2 (Muc-2) (Mybiosources, MBS2019254; Detection range: 0.312–20 ng/mL), and intestinal fatty acid binding protein (iFABP) (Mybiosources, MBS3807789; Detection range: 1–3200 pg/mL). The procedure was performed according to the manufacturer’s directions. Plates were read on a microplate reader (450 nm; TECAN, VT) and the concentration of the samples was obtained by interpolation from the standard curve.

Gut histology

At 3 or 35 DPI, a portion of the distal ileum and proximal colon were dissected, fixed in 4% PFA, and embedded in paraffin. Paraffin sections (10 μm) were collected on glass slides and analyzed for immunohistochemistry, hematoxylin and eosin (H&E), and Periodic acid-Schiff (PAS) staining [145]. For H&E and PAS staining, sections were photographed at 20 × magnification with the VS200 slide scanner (Olympus) and scored by a rater blind to the subject’s condition. The length was measured from the tip of the villi to the base at the crypt, and the width was measured at the midpoint of the height [146]. The number of crypts at the base of each villus was also counted, as previously described [110]. A total of three slides, with 3 ileum or colon slices per slide were used for each rat. Four positions were selected for each image and 3 villi were measured from each position. All analysis was done on the OlyVia software using the line measurement tool. The data presented are an average of these measurements. At 3 DPI, measurements were done for 14 rats (4 Sham + Veh, 5 FPI + Veh, 5 FPI + IGF1). At 35 DPI, assessments were taken from 10 rats (3 Sham + Veh, 3 FPI + Veh, 4 FPI + IGF1).

Gut immunohistochemistry

Immunofluorescence for KI67 was performed as previously described [123]. Briefly, a portion of the ileum was embedded in paraffin (Leica Microsystems, Buffalo Grove, IL, USA) and stored at room temperature until use. Paraffin sections (10 µm) were collected on glass slides and incubated in blocking buffer (5%BSA + 0.1% Triton X-100 in PBS, pH 7.4) for 20 min at room temperature. Sections were incubated overnight at 4 °C with primary rabbit anti-Ki67 (1:250, Abcam, ab16667). Secondary antibody (Alexa Fluor 555 goat anti-rabbit, Invitrogen) was used at 1:1000 dilution for 1 h at room temperature. Sections were washed three times in PBS, and cover slipped with mounting media containing the nuclear dye DAPI (Fluoroshield, Abcam, ab228549). Sections were imaged using a fluorescent microscope (Olympus, Bethlehem, PA). Gut sections probed for Ki67 immunohistochemistry were imaged and coded and then scored by a rater blinded to the experimental condition. Slides were scored using a predefined scale from 1 to 5 according to staining localization and brightness along the crypt cells. A minimum of 3 sections were scored for each rat, and the data presented are an average of these 3 sections. At 3 DPI, measurements were done for 14 rats (4 Sham + Veh, 5 FPI + Veh, 5 FPI + IGF1). At 35 DPI, assessments were taken from 10 rats (3 Sham + Veh, 3 FPI + Veh, 4 FPI + IGF1).

Microbiome analysis

Microbiome analysis was conducted using fecal samples collected at baseline (pre-FPI) and 35 days after FPI from 12 rats (3 Sham + Veh, 3 FPI + Veh, 6 FPI + IGF1). The fecal samples were frozen immediately after collection and stored at − 80 °C until shipping to Diversigen (New Brighton, MN). Briefly, DNA was extracted with Qiagen’s DNeasy PowerSoil Pro Kit (Qiagen, Germantown, MD) automated for high throughput on QiaCube HT (Qiagen, Germantown, MD), with bead beating in Qiagen Powerbead Pro plates (Qiagen, Germantown, MD) and quantified with Qiant-iT Picogreen dsDNA Assay (Invitrogen, Carlsbad, CA). Libraries were prepared with a procedure adapted from the Nextera Library Prep kit (Illumina, San Diego, CA) and sequenced on an Illumina NovaSeq using single-end 1 × 100 reads (Illumina, San Diego, CA). DNA sequences were filtered for low quality (Q-Score < 30) and length (< 50), and adapter sequences were trimmed using cutadapt. Fastq files were converted into a single fasta using shi7. Sequences were trimmed to a maximum length of 100 bp prior to alignment. DNA sequences were aligned to a curated database containing all representative genomes in RefSeq for bacteria with additional manually curated strains. Alignments were made at 97% identity against all reference genomes (Diversigen’s Venti database) using fully gapped alignment with BURST. Ties were broken by minimizing the overall number of unique Operational Taxonomic Units (OTUs). For taxonomy assignment, each input sequence was assigned to the lowest common ancestor that was consistent across at least 80% of all reference sequences tied for best hit. The number of counts for each out was normalized to the average genome length. OTUs accounting for less than one millionth of all species-level markers and those with less than 0.01% of their unique genome regions covered (and < 1% of the whole genome) were discarded. Absolute count data was then used to calculate Firmicutes: Bacteroidetes ratio, and abundance of specific bacterial groups was evaluated.

Immunohistochemistry for hippocampal proliferation and neurogenesis

Because IGF-1 is known to influence numerous cell types, it is possible that the i.p. injections could have passed through the blood–brain barrier and influenced dividing cells in the central nervous system. Therefore, this study also examined the hippocampus, a region of the adult rat brain in which ongoing neurogenesis is observed. Proliferating cells in the dentate gyrus were examined as 3 DPI, as were the number of immature neurons in the dentate gyrus using doublecortin (DCX), a marker of immature neurons. Immunohistochemistry for DCX and Ki67 were performed as previously described [74, 143, 147, 148]. Briefly, rats were anesthetized with Fatal Plus (Sodium Pentobarbital; 52 mg/kg, administered i.p.) and transcardially perfused with phosphate buffered saline (PBS) through the left ventricle until the blood ran clear. This was followed by 4% paraformaldehyde (PFA) through the left ventricle. All brains were allowed to postfix in the skull for 24 h in PFA, after which they were extracted and fixed for an additional 24 h in 4% PFA. Fixed brains were cut into 44-µm thick serial sections with a freezing microtome (American Optical Corp; Model #860). Slices were first incubated in a 1X Citrate Buffer (Millipore Sigma) for 1 h at 45 °C. Slices were then washed and stained with goat anti-DCX antibody (Santa Cruz Inc. USA) or rabbit anti-Ki67 (1:250, Abcam, ab16667) overnight at room temperature, rotating. After overnight incubation, slices were washed and stained with a secondary biotinylated goat anti-Rabbit IgG (Alexaflour-555; 1:200) (Ki67) or secondary donkey anti-Goat IgG (AlexFlour-555; 1:200) (DCX). Slices were mounted and cover-slipped with antifade reagent containing DAPI (Vector Laboratories #H-1200-10).

Imaging for all immunohistochemistry was done on a fluorescent microscope (Olympus, Bethlehem, PA). Unbiased stereology-based analysis was used to quantify cells positive for DCX in the hippocampus, as previously described [74, 147, 148]. Sections (~ every 260–350 μm apart) containing the dorsal hippocampus (Bregma − 1.34 through − 2.80) were selected for analysis. Analysis of DCX + cells was performed in the ipsilateral infra- and supra-pyramidal blades of the dentate gyrus granule cell layer/subgranular zone. Total Ki67 + cells in the entire dentate gyrus were manually counted, and all counts were conducted by raters blind to experimental conditions. A minimum of 3 left (ipsilateral to injury) hippocampi were counted per animal, per antibody, within the stereological coordinates indicated above. Analysis was completed for 14 rats (4 Sham + Veh, 5 FPI + Veh, 5 FPI + IGF1).

Statistical analysis

Prior to statistical analysis, data were analyzed for outliers using the ROUT algorithm in GraphPad Prism, Q = 1% [147, 149], and outliers were removed from all associated measurements. Data for all groups were analyzed by one-way analysis of variance (ANOVA) with comparisons between groups performed using post-hoc Tukey test. All statistical analysis was performed using GraphPad Prism (Version 9.0; GraphPad). Significance for all tests was set at p < 0.05 and a trend was considered at 0.10 ≥ p > 0.05.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

CCI:

Controlled cortical impact

DPI:

Days post-injury

FPI:

Fluid percussion injury

GH:

Growth hormone

GI:

Gastrointestinal

HPA:

Hypothalamic pituitary axis

iFABP:

Intestinal fatty acid binding protein

IGF-1:

Insulin-like growth factor

IGFBP:

Insulin-like growth factor binding protein

i.p.:

Intraperitoneal

LPS:

Lipopolysaccharide

Muc-2:

Mucin-2

TBI:

Traumatic brain injury

Veh:

Vehicle

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Acknowledgements

The authors acknowledge Reuben Gelin and Carla Furbeck for their assistance in scoring gut pathology, and Samantha Beevers and Brooke Heckel for their assistance collecting tissue samples. The authors would also like to acknowledge Dr. Malea Murphy and the Integrated Microscopy & Imaging Laboratory (IMIL) at the Texas A&M College of Medicine. The schematic diagram was created using biorender.com.

Funding

This work was supported by funding from Texas A&M Neural-Gut Immune Axis group and the WoodNext Foundation.

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Author notes

  1. Lavanya Venkatasamy, Jaclyn Iannucci, and Aleksandr Pereverzev have contributed equally to this work.

Authors and Affiliations

  1. Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A and M University, 8447 Riverside Pkwy, Bryan, TX, 77807-3260, USA

    Lavanya Venkatasamy, Jaclyn Iannucci, Aleksandr Pereverzev, Jonathan Hoar, Emily Huber, Angel Ifegbo, Reagan Dominy, Yumna El-Hakim, Kathiresh Kumar Mani, Farida Sohrabji & Lee A. Shapiro

  2. Department of Statistics, College of Arts and Sciences, Texas A and M University, College Station, TX, USA

    Alan Dabney

  3. Gastrointestinal Laboratory, College of Veterinary Medicine and Biomedical Sciences, Texas A and M University, College Station, TX, USA

    Rachel Pilla

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Contributions

LV: investigation, Writing—Original Draft, project administration. JI: methodology, formal analysis, Writing—Original Draft, Writing—Editing & Review. AP: formal analysis, investigation, data curation, Writing—Original Draft, visualization. JH: investigation, visualization. EH: investigation. AI: investigation. RD: investigation. YE: methodology. KKM: methodology. AD: formal analysis. RP: methodology, formal analysis. FS: conceptualization, resources, Writing—Editing & Review, funding acquisition. LAS: conceptualization, resources, Writing—Original Draft, Writing—Editing & Review, supervision, funding acquisition. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Lee A. Shapiro.

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All the animal experimental protocols were approved by the Institutional Animal Care Committee (IACUC) of Texas A&M Health Science Center (AUP #2010-0140).

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The authors declare no competing interests.

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Venkatasamy, L., Iannucci, J., Pereverzev, A. et al. Systemic IGF-1 administration prevents traumatic brain injury induced gut permeability, dysmorphia, dysbiosis, and the increased number of immature dentate granule cells. acta neuropathol commun 13, 90 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40478-025-01998-x

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Acta Neuropathologica Communications

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