Chronic gut inflammation differentially modulates mitochondrial and antioxidant transcriptional programs in limbic brain structures

doi:10.21203/rs.3.rs-4486754/v1

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Chronic gut inflammation differentially modulates mitochondrial and antioxidant transcriptional programs in limbic brain structures

https://doi.org/10.21203/rs.3.rs-4486754/v1

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Chronic inflammatory diseases are frequently comorbid with depression and anxiety, often persisting during periods of inflammatory remission. This suggests functional changes to neural circuits involved in the contextual regulation of motivation and threat processing. Here, we test how chronic gut inflammation evoked by dextran sodium sulfate (DSS) affects gene expression in several limbic brain structures associated with these functions. We assessed post-mortem expression of mRNA transcripts in the anterior cingulate cortex (ACC), CA1 hippocampus, nucleus accumbens (NAc), and primary motor cortex (M1) as a non-limbic control. The levels of mRNA associated with mitochondrial function, inflammation, and synaptic connectivity were altered in DSS-treated animals, but the specific pattern of changes was heterogeneous among brain structures. Chronic gut inflammation affected transcript expression in the CA1 and NAc more so than in the ACC and M1. These differences involved genes related to antioxidant systems and mitochondrial function. For example, expression of the cytochrome oxidase 1 gene mt-co1, which is necessary for oxidative phosphorylation, was reduced in ACC and NAc of DSS animals, suggesting reduced capacity for ATP production in these regions. Markers of gut inflammation correlated with expression of several transcripts in the ACC, including markers of synapses and GABA synthesis. The NAc showed strong correlations of mitochondrial function and measures of mitochondrial fission, inflammation, synaptic connectivity, and GABA synthesis. In sum, these data indicate neuroinflammatory processes in the brain evoked by chronic relapsing gut inflammation are heterogeneous among brain structures, and possess complex relationships between mitochondrial function, antioxidants, neurotransmission and gut inflammation.

neuroinflammation

hippocampus

nucleus accumbens

anterior cingulate cortex

mt-co1

Inflammation appears to promote anxiety and depression, likely by altering neurophysiological processes. This may contribute to the high comorbidity of anxiety and depression in chronic inflammatory diseases such as diabetes (Castellano-Guerrero, Guerrero, and Relimpio 2018), rheumatoid arthritis (Isik et al. 2007), and cardiovascular diseases (Celano et al. 2016). Such comorbidity is particularly high in people with inflammatory bowel disease (IBD). Approximately 57% of people with active IBD experience anxiety, and 39% have symptoms of depression (Barberio et al. 2021). Importantly, these mood disorders persist even during periods of disease remission (Barberio et al. 2021). This suggests that chronic somatic inflammation can produce changes in the brain that persist after peripheral inflammation subsides. Neuroinflammation is a likely intermediary. Even transient inflammation in the gut produces a neuroinflammatory response in the brain, leading to changes in behaviour (Emge et al. 2016; Jain et al. 2015; Chelsea E. Matisz et al. 2020) and an array of changes in neural physiology (Chelsea E. Matisz et al. 2022; Riazi et al. 2015; Zonis et al. 2015). Several of these physiological changes are associated with anxiety and depression, including oxidative stress, mitochondrial dysfunction, changes in neural structure, altered neural activity, and neurotransmitter levels(Salim 2014; Y. Liu, Zhao, and Guo 2018; Guo et al. 2023; Allen et al. 2018; Rezin et al. 2009) The diversity and complexity of neuroinflammatory-evoked changes in neural physiology complicates a straightforward theory for the cellular etiology of anxiety and depression. We and others have proposed that bioenergetics and its regulation by reactive oxygen species in a key brain circuit called the limbic system are a core feature that may account for many phenomena (C. E. Matisz and Gruber 2022; Picard and McEwen 2018).

The brain’s high energy demand is predominantly met by mitochondria, the largest cellular source of ATP. Mitochondria activity influence a variety of processes related to neural structure, function, and circuity, including dendritic and axonal branching (Courchet et al. 2013; Gebara et al. 2021) and neurotransmitter synthesis (Kwon et al. 2018; Sun et al. 2013). The metabolic needs of the brain are both spatially and temporally variable, as evidenced by functional and molecular evidence (Castrillon et al. 2023). For example, the energetic costs of stress and inflammation can deplete metabolic resources in the brain if they reach sufficient magnitude and duration (Lacourt et al. 2018; Straub 2017). It has been proposed that prolonged downregulation of energy production in the brain can promote alterations in neuronal architecture and plasticity that promote anxiety and depression (Morava and Kozicz 2013; Picard et al. 2018). Specific regions of the brain appear to be more liable to this process. For example, clinical and preclinical studies indicate that certain structures within the limbic system, such as the hippocampus (Bagot et al. 2015; Haj-Mirzaian et al. 2017), anterior cingulate cortex (C. E. Matisz and Gruber 2022; J. Wang et al. 2017), and nucleus accumbens (Gebara et al. 2021; Strasser et al. 2019) are associated with changes in brain metabolism that appear to promote anxiety and depressive behaviours (Duman et al. 2016). Moreover, the phenotype of mitochondria varies among brain structures, as does the mitochondrial sensitivity to stressors and endocrines; notably, stress induced changes to identified ‘mitochondrial networks’, which correlated with anxiety-like behaviours in mice (Rosenberg et al. 2023). Whereas structure-specific effects of chronic stress on mitochondrial function have been reported, the consequences of gut inflammation on brain mitochondria have received less attention. We and others hypothesize that chronic neuroinflammation may have a similar effect on mitochondrial function as stress (Zhao et al. 2019; Culmsee et al. 2018).

Much of the previous work on gut inflammation-induced neuroinflammation has employed relatively brief inflammatory treatments. Our previous research has demonstrated that the duration of gut inflammation influences its behavioural effects. Short-term gut inflammation (1 week) produced deficits in learning and memory, and increased motoric response in a forced swim task. These behavioural changes, however, were not observed in mice with chronic gut inflammation (5 weeks) (Chelsea E. Matisz et al. 2020). In other words, it appears that the mnemonic and motoric alterations were transient effects triggered by the onset of inflammation. Conversely, increased contextual fear only emerged in chronic gut inflammation (C. E. Matisz et al. 2022). These data suggest that the neural circuits that encode some behaviours (e.g. contextual fear memory) are only affected by prolonged inflammation, possibly by the accumulated effects of neuroinflammation over many weeks. Here, we test the hypothesis that the accumulated effects of gut inflammation involve decreased mitochondrial function in limbic brain structures more so than in non-limbic structures, and that reduced metabolic function will be associated with changes in cellular physiology and metabolics, such as the management of oxidative stress.

Animals

The study used 16 male C57Bl/6 mice (8 weeks old, Jackson Laboratories, Bar Harbor, ME, USA). Mice were housed in groups of four in standard clear plastic cages in a vivarium with a 12-h light/dark cycle, with free access to standard mouse chow and drinking water. Animals were acclimatized to the facility for 2 weeks prior to the start of experimentation. All experiments were carried out in accordance with the guidelines of the Canadian Council of Animal Care, and were approved by the University of Lethbridge Animal Care Committee (Protocol #2018).

Colitis

For the induction of chronic DSS colitis, mice were exposed to three cycles (3% wt/v) of DSS (MW 40kD; Fischer Scientific, CAT 9011-18-1) each lasting five days, with 9 days of recovery (access to regular drinking water) between cycles. Control mice received regular drinking water for the duration of the experiment (Fig. 1).

Forced Swim Task

The forced swim task was conducted on day 42. Mice were placed in a clear glass cylinder (30cm tall, 15 cm diameter) filled 14cm deep with water (28C) and video recorded for 6 minutes. Mice were monitored continuously. Any animal unable to keep its head above water was immediately removed from the cylinder. After completing the task, mice were removed, dried with a paper towel, and placed in a cage with a heating pad before being returned to the home cage. Immobility time was defined by minimal movements to keep its head above water, recorded by an observer blind to the experimental treatment. Each mouse was euthanized 30 minutes after its completion of the FST, and the brain was quickly snap frozen. The timing of testing, euthanasia, and brain freezing was kept as constant as possible among animals in order to normalize any effects of stress and/or motoring output (swimming) on gene expression.

Colitis Assessment:

Disease activity was assessed on the third cycle of DSS and scored as previously described (Matisz et al. 2020). Briefly, percentage of body weight lost from the start of the cycle on day 28 scored on a 1–4 range based on the percentage of body weight lost (0 = 0%, 1 = < 1 to ≤ 5%, 2 = > 5 to ≤ 10%, 3 = > 10 to ≤ 15%, 4 = > 15%); stool consistency (solid fecal pellets = 0, soft, sticky stools = 2, loose, water stools = 4); and the presence of fecal blood (no blood = 0, fecal blood = 4). The total disease score was computed as a weighted average of each of these three measures. After euthanasia, the length of the colon was measured from anus to ileocecal junction.

Tissue Collection

Mice were euthanized 30 minutes post forced swim task on day 42 by induction into an isoflurane chamber and subsequent injection with ~ 1.6mL/kg euthanyl (Bimeda MTC 00141704). Brains were immediately removed and snap-frozen via immersion into pre-chilled isopentane for 60–120 seconds and subsequently stored at -80°C until downstream processing. Tissue punches were obtained following protocols outlined by Wager-Miller et al.. (Wager-Miller et al. 2020). All tools and surfaces were cleaned using RNaseZap™ RNase Decontamination Solution and UltraPure™ DNase/RNase-Free Distilled Water (Thermofisher scientific).

ELISA

Fecal lipocalin-2 is a biomarker for intestinal inflammation in both humans and rodents. Samples were prepared following previously published protocols (C. E. Matisz et al. 2022). Briefly, frozen fecal samples were reconstituted in PBS with 1% Tween 20 (10mg/100uL), and vortexed for 20 minutes. Samples were centrifuged for 10 minutes at 12,000 rpm, and supernatants were collected and stored at -20◦C until analysis. At baseline, all processed fecal samples were diluted at 1:1 in reagent diluent. Moving forward, all fecal samples from mice exposed to DSS were diluted at 1:1250 in reagent diluent to ensure optical density was within limits of detection of the standard curve. Lipocalin-2 levels were quantified in the supernatants using the DuoSet murine Lcn-2 ELISA Kit (R&D Systems, Minneapolis, MN), following the manufacturer’s instructions.

RNA isolation and RT-PCR

RNA was extracted using the standard Trizol reagent protocol (Cat # 1596026, Invitrogen) and reverse transcribed using Superscript IV (CAT 18090010, Invitrogen) by the following method: 100ng of total RNA was mixed with 100ng Random Primer Mix (S1330S, NEB), and 1 uL of 10mM dNTP mix (CAT N0447S, NEB). The mixture was incubated for 5 min at 65°C and placed immediately on ice for a minimum of 1 minute. The mixture was then incubated with 4uL of 5X Superscript IV buffer, 1uL of 0.1M DTT, and 1uL of Superscript IV (200U/uL) for 10 min at 25°C, 10 min at 55°C and 10 min at 80°C. The produced cDNA was analyzed by qPCR using 2uL of 1:10 diluted cDNA, 0.5uL of each gene-specific primer diluted to 10uM, 5uL of Luna Universal qPCR master Mix (M3003E, NEB), and 2uL of H2O. qPCR was performed using the Bio-Rad CFX384 Real-time detection system, with the following thermocycler conditions: 3 min at 95°C (15 s at 95°C, 30 s at 54°C, 30 s at 66°C) × 40 cycles. Fluorometer readings were taken during the extension phase, while standard curves were prepared for relative expression. The analysis of PCR efficiency was achieved by pooling 2uL of each cDNA sample and the subsequent preparation of standard dilutions SD1: 1:2; SD2: 1:4; SD3: 1:8; SD4: 1:16; SD5: 1:32. All samples were run in triplicate. Quantitative measurements of target gene expression relative to controls followed the 2^−ΔΔCt method. Group differences were expressed as fold changes, normalized to the housekeeping gene hypoxanthine phosphoribosyltransferase (Hprt). Gene-specific primers were ordered from IDT (USA, CO) as custom DNA oligos. The sequences of primers used are shown in Table 1.

Table 1

List of RNA primers used in study.
Gene	Forward primer (5’-3’)	Reverse primer (5’-3’)
DRP1	ATG CCA GCA AGT CCA CAG AA	TGT TCT CGG GCA GAC AGT TT
MFN2	TGC ACC GCC ATA TAG AGG AAG	TCT GCA GTG AAC TGG CAA TG
MtCO1	ACC CAA TCA AAC GCC TAG CA	GGA CTG GAA TGC TGG TTG G
GPX1	CCT CAA GTA CGT CCG ACC TG	CAA TGT CGT TGC GGC ACA CC
NRF2	TAG ATG ACC ATG AGT CGC TTG C	GCC AAA CTT GCT CCA TGT CC
GAD1	TCC TGG TTG ACT GTA GAG ACA C	CAT ATT GGT ATT GGC AGT CGA T
CFOS	TTT TGC GCA GAT CTG TCC GT	GTG GGG AGT CCG TAA GGA TG
SNAP25	GTG CAC TTA GGG TGC GGT AT	ATC TCC TCC AGC TCA TTG CG
PSD95	TCT GTG CGA GAG GTA GCA GA	AAG CAC TCC GTG AAC TCC TG

Statistical analysis

Data are presented as mean ± SEM. Statistical significance was set at p < 0.05. Body weight was analyzed by a two-way repeated measures ANOVA with Sidak post-test, and Lcn-2 expression analyzed by mixed effects analysis with a Tukey’s comparison post-test. Disease activity index was analyzed by One Sample Wilcoxon Signed ranked Test. Comparisons of the mean between groups was analyzed via Student’s t-test or One-Way ANOVA with Tukey’s post-test. Principal component analyses (PCA) were used to generate plots to visualize clustering between treatment groups. Primary and secondary principal components were compared via Mann-Whitney between DSS and control groups. Significant differences between the first or second principal component are reported. Statistical analyses were conducted with GraphPad Prism 10.0.0 (GraphPad Software, La Jolla, CA). Figures created with BioRender.com and Adobe Photoshop.

Exposure to DSS produces signs of gut inflammation and disease

Dextran Sodium Sulfate is widely used to model gut inflammation in rodents, with excellent face validity (Chassaing et al. 2014). In our study, exposure to DSS in the drinking water led to expected signs of disease. Mice exposed to DSS for 3 cycles exhibited significant weight loss relative to controls (Two-way Rm ANOVA F_1,14 = 41.48, p < 0.0001; Fig. 2A). Further, expression of the pro-inflammatory mediator lipocalin-2 (Lcn2) was significantly elevated in the feces among DSS-treated mice throughout the study (Mixed-effects model F_1,14=19.70, p = 0.0006; Fig. 2B). The disease activity index was increased after final cycle of DSS in DSS-treated animals compared to controls (One way Wilcoxon Signed Rank Test, W = 36, p = 0.0078; Fig. 2C). Colon length was reduced, but not significantly, among mice exposed to DSS (Students t-test, t = 1.064; Fig. 2D). Overall, mice chronically exposed to DSS exhibited increased weight loss, disease activity, and increased fecal lipocalin-2 expression relative to controls, indicating that DSS treatment evoked the expected inflammation in the gastrointestinal tract.

Transcript Selection

The objective of the study was to determine if DSS-colitis more strongly affects neurons in brain regions associated with anxiety and depression (e.g. limbic structures) as compared to other structures. Four brain regions were selected, based on their well-recognized role in goal-directed and threat-coping behaviors that are altered in anxiety and depression; the CA1 of the hippocampus, the ACC, and the NAc. The motor cortex (M1) was selected as a control region (Supplementary Fig. 1). A panel of 9 different primers were selected to assess several transcriptional programs in neurons that may be modulated by gut inflammation (Table 2). Three transcripts were selected to assess how gut inflammation may affect mitochondrial function in the brain. Inflammation has been shown to affect mitochondrial network dynamics and mitochondrial function. Mitochondria form dynamic networks that undergo fusion and fission to maintain cellular energetic requirements. These structural changes are mediated by several fusion and fission proteins, including Mfn2, and Drp1, respectively. Mt-Co1 encodes for a subunit of complex IV in the electron transport chain in mitochondria, by which the process of oxidative phosphorylation generates cellular energy in the form of ATP. Thus, its expression regulates energy production in mitochondria. Inflammation can promote oxidative stress. Therefore, we selected two transcripts to assess how gut inflammation affects oxidative stress responses in the brain. Nuclear factor erythroid 2 related factor 2 (Nrf2) regulates antioxidant response elements, while Gpx1 encodes for glutathione peroxidase 1, an enzyme that works with glutathione as a key neuronal antioxidant. Our previous research has revealed that acute DSS alters spine density in CA1, as well as the fraction of neurons activated by the forced swim task (Chelsea E. Matisz et al. 2022). Therefore, to assess how chronic DSS may affect pre- and post-synaptic elements and neuronal activation, we assessed transcript expression of Snap25, Psd95, and cFos. Animals were subjected to a 6-minute forced swim task (FST) prior to euthanization in order to (i) test for changes in active threat coping or depressive endophenotypes, and (ii) provide a stressor to activate neurons in the limbic system and motor cortex. Mice previously given DSS exhibited similar mobility time during the FST relative to controls (t = 0.43; Fig. 2E), in alignment with previous reports (Chelsea E. Matisz et al. 2020). Finally, because GABAergic transmission has been implicated in anxiety and depression, we assessed Gad1 expression. Gad1 mRNA encodes for the rate-limiting enzyme glutamate decarboxylase 67, which is responsible for over 90% of basal GABA synthesis (Asada et al. 1997).

Table 2

List of selected genes examined in the present study and their function
Gene name (transcript)	Function
Mfn2	Mitofusin2; Regulates mitochondrial fusion
Drp1	Dynamin-related protein; Regulates mitochondrial fission
Mt-Co1	Cytochrome C oxidase subunit I; Mitochondria-encoded gene important for oxidative phosphorylation and ATP production
CFos	Early immediate gene, expressed by recently activated cells, inducing neurons
Gad1	Precursor to GABA, inhibitory neurotransmitter
Nrf2	Nuclear factor erythroid 2-related factor 2; Regulates cellular defense against oxidative stress
Gpx1	Glutathione peroxidase; antioxidant enzyme
Psd95	Postsynaptic density 95kda; regulates retention of glutamate receptors
Snap25	Synaptosome associated protein 25kda; participates in synaptic vesicle exocytosis of neurotransmitters

Regional differences in basal transcript expression

We first examined how expression of the selected transcripts varied among brain structures in control animals (Supplementary Fig. 2; Supplementary Table 1). The NAc exhibited an expression profile that most differed from the other structures. The expression of Gad1 (F_3,20) = 29.56, p < 0.001) was significantly highest in the NAc relative to all other structures (Tukey’s test for ACC and Ca1, NAc, and M1 are all p < 0.001). This is not surprising, as GABAergic medium spiny neurons are the dominant neuronal cell in the striatum (Yager et al. 2015). Interestingly, the NAc also possessed highest expression of Gpx1 (F_3,20) = 76.18, p < 0.001) relative to all other structures (p < 0.0001). The NAc expressed significantly higher expression of Mt-Co1 (F_3,20) = 7.554, p = 0.0014) and Psd95 (F_3,20) = 8.062, p = 0.0010) compared to the ACC (Mt-co1, p = 0.0060; Psd95, p = 0.0013) and M1 ( Mt-co1, p = x ; Psd95, p = 0.0033, and significantly lower expression of Snap25 relative to CA1 and M1. The CA1 and NAc displayed lowest expression of cFos relative to the ACC and MA (F_3,20=12.21, p < 0.0001; CA1 vs. ACC p = 0.0004; CA1 vs. M1, p = 0.0026; NAc vs. ACC p = 0.002, NAc vs. M1 p = 0.014), and highest expression of Nrf2, relative to the ACC and M1 (F_3,20=20.30, p < 0.0001; CA1 vs. ACC p < 0.0001; CA1 vs. M1 p < 0.0001; NAc vs ACC p = 0.002; NAc vs. M1 p = 0.0053). No differences in the expression of Mfn2 (F_3,20=0.6606, p = 0.59) and Drp1 (F_3,20=1.070, p = 0.38) were observed among neural structures in control animals.

Gut inflammation alters expression of selected gene transcripts in regional manner

We next compared the structure-specific expression of transcripts between treatment groups. Exposure to DSS altered the expression of several transcripts, in a region-specific manner (Table 3). The CA1 of the HPC was most affected by exposure to DSS; expression of 6 of the 9 transcripts were different (Fig. 3B,C). Specifically, cFos (t = 2.94, p = 0.015), Drp1 (t = 2.64, p = 0.025), Gad1 (t = 2.27, p = 0.046) and Snap25 (t = 2.29, p = 0.045) expression was significantly elevated in the CA1 among DSS-treated mice relative to controls. Conversely, Nrf2 (t = 3.91, p = 0.0029) and Gpx1 (t = 6.707 p = 0.000053) were significantly reduced in the CA1 of DSS-treated mice. Mt-Co1 approached significance (t = 2.092, p = 0.063). The expression of Mt-Co1 was significantly reduced in the NAc (t = 5.19, p = 0.00041) and ACC (t = 2.722, p = 0.021), and Gpx (t = 1 3.29, p = 0.0082) was significantly reduced in the NAc of mice with DSS relative to controls (Fig. 3B,C). Treatment did not significantly affect the expression of any selected transcripts in the M1. These data indicate that chronic gut inflammation promotes heterogenous responses of different transcripts that vary among brain regions.

Table 3

**T-test and p-value for comparisons between control and DSS exposed animals in different regions** N = 6 male mice per treatment group. Data shown in Fig. 3.
Gene	Region	T ratio	P value
Drp1	ACC	1.04	0.32
	CA1	2.64	0.02
	NAc	1.08	0.30
	M1	0.13	0.90
Mfn2	ACC	0.31	0.76
	CA1	1.62	0.14
	NAc	0.29	0.78
	M1	0.26	0.80
Mt-Co1	ACC	2.72	0.02
	CA1	2.09	0.06
	NAc	5.19	0.00
	M1	1.90	0.09
C-fos	ACC	0.31	0.77
	CA1	2.94	0.01
	NAc	0.53	0.60
	M1	0.12	0.90
Gad1	ACC	0.73	0.35
	CA1	0.05	2.27
	NAc	0.97	0.04
	M1	0.22	1.31
Gpx1	ACC	1.02	0.33
	CA1	6.71	0.00
	NAc	3.29	0.01
	M1	1.93	0.08
Nrf2	ACC	0.77	0.46
	CA1	3.91	0.00
	NAc	1.60	0.14
	M1	1.22	0.25
Psd95	ACC	0.26	0.80
	CA1	1.83	0.10
	NAc	0.39	0.71
	M1	0.94	0.37
Snap 25	ACC	0.18	0.86
	CA1	2.29	0.05
	NAc	0.07	0.94
	M1	0.44	0.67

Gut inflammation drives regional changes in transcriptional programs in the brain

To better understand how transcriptional programs were differentially affected by gut inflammation, we conducted principal component analysis (PCA). When all gene transcripts were loaded (Fig. 4A), and transcript expression from all brain regions are included in the PCA, clear clustering among mice with DSS colitis vs control emerged (p = 0.0022). Further, when PCA loadings were restricted to transcript expression within specific brain regions, there were significant differences between control and DSS animals in the CA1 (p = 0.0022) and NAc (p = 0.015). When only transcripts related to mitochondrial function (Drp1, Mfn2, Mt-Co1) were loaded into the PCA analysis, there was a significant difference in PC1 between control and DSS mice among all brain regions; and upon separation of structure in the analysis, there were significant differences between principal components of control and DSS mice in the CA1 (P = 0.015), and PC2 NAc (p = 0.0043) (Fig. 4B). Similarly, PCA of transcripts related to inflammation regulation (Gpx1, Nrf2) revealed significant differences between the PC1 of controls and DSS among all brain regions (p = 0.0022; Fig. 4C). This significance persisted when the PCA only included transcript expression from the CA1 (p = 0.0022) and the NAc (p = 0.026). The expression of transcripts related to pre- and post-synaptic density proteins did not reveal any significant clustering of principal components (Fig. 4D).

All genes include Mfn2, Drp1, Mtco1, CFos, Gad1, Gpx1, Nrf2, Snap25, and Psd95. Genes related to mitochondrial function include Drp1, Mfn2, Mt-Co1. Genes related to antioxidant regulation include Nrf2 and Gpx1. Pre and post-related synapse genes include post-synpatic (Psd95) and pre-synaptic (Snap25) mechanisms. The percentage of variation explained by the principal component is indicated on the axis. N = 6 male mice per treatment group. Ellipses indicate significant differences between the first or second principal component (*p < 0.05) between treatment groups.

Correlations between transcript expression within brain regions among healthy and gut-inflamed animals

We next tested if gut inflammation affects the relationships (i.e. correlations) between expression among transcripts within each brain structure. DSS treatment did have structure-dependent effects on the correlation among transcript levels (Fig. 5).

Pearson correlation analysis of transcript expression within a given brain region, in mice with gut inflammation and healthy controls. N = 6 per treatment group. *p < 0.05.

Animals with gut inflammation displayed significantly different relationships between several transcripts in the NAc relative to healthy controls (Table 4). Interestingly, the expression of MtCo-1 was a common denominator for all these relationships. We observed a significant positive correlation with Mt-Co1 and Drp1 (p = 0.048, r2 = 0.67; Fig. 6A), Mfn2 (p = 0.015, r2 = 0.81; Fig. 6B) and Gad1 (p = 0.030, r2 = 0.73, Fig. 6C), with a similar trend observed with Psd95 (p = 0.067; Fig. 6D). A negative relationship between Mt-co1 and Drp1, Mfn2, Gad1, and Psd95 was observed among controls, with the latter reaching statistical significance (p = 0.016, r2 = 0.80; Fig. 6).

Table 4

**Correlation between Mt-Co1 and Drp1, Mfn2, Gad1, and Psd95 among different treatment groups, within the NAc** Pearson correlation and linear regression; n = 6 per treatment group. Data shown in Fig. 6.
Comparison within NAc	Treatment	Pearson r	Linear Regression r²	P value
Mt-co1 vs. Drp1	Among controls	-0.58	0.33	0.23
Mt-co1 vs. Drp1	Among DSS *	0.67	0.67	0.048
Mt-co1 vs. Mfn2	Among controls	-0.41	0.17	0.42
Mt-co1 vs. Mfn2	Among DSS *	0.90	0.81	0.015
Mt-co1 vs. Gad1	Among controls	-0.12	0.61	0.065
Mt-co1 vs. Gad1	Among DSS *	0.88	0.73	0.030
Mt-co1 vs. Psd95	Among controls*	-0.90	0.80	0.016
Mt-co1 vs. Psd95	Among DSS	0.78	0.61	0.066

Within the CA1, expression of Psd95 was positively correlated with Nrf2 among controls (p = 0.012, r = 0.91), but not DSS animals (p = 0.64, r=-0.24; Fig. 7). No significant relationship between Psd95 and Nrf2 was observed for any other regions, among control of DSS mice. We observed a significant correlation between the expression of Psd95 and Gad1 among control and DSS animals in the M1 and the NAc, among DSS animals in the ACC, and among controls in the CA1 (Supplementary Table 2). However in the CA1, among animals with DSS, the positive relationship between these genes was lost, and trended towards a negative correlation, although this did not reach statistical significance. The expression of Drp and Gad1 were positively correlated with each other among controls, in all limbic regions, but not M1 (Supplementary Table 3). This positive correlation was maintained in mice with DSS in the ACC, with similar trends in the NAc and the M1. Conversely, exposure to DSS was associated with a negative correlation between Drp and Gad1 in CA1 (Supplementary Table 3).

Expression of Psd95 as a function of Nrf2 among control and DSS animals in the CA1 N = 6 animals per group. Transcript expression normalized to expression of Hprt. Pearson R and p values for all comparisons can be found in Supplementary Table 4.

In the motor cortex and the NAc, DSS animals exhibited a significant positive correlation between MtCo1 and Gad (p = 0.030 r = 0.85); this relationship did not exist among controls, trending towards a negative correlation in the NAc (p = 0.065, r=-0.78) (Table 4). No such relationships between transcript expression in the ACC were affected by gut inflammation.

Correlations of transcript expression between brain structures, among control and DSS animals

To examine the possibility that gut inflammation affects the way the expression of a given transcript between two structures are related, we analyzed the relationship between transcript expression among different brain structures. Correlations of the same gene transcript between different regions are listed in Supplementary Table 5. Treatment status affected the correlation of transcripts related to GABA synthesis, mitochondrial function, and synapse function between brain structures. For example, correlations between the expression of Drp1, Gad1, and Psd95 in the ACC and the NAc were only present in healthy controls (Supplementary Table 5). CFos expression in the CA1 and NAc was negatively correlated only among DSS-treated animals. Further, Psd95 expression in the CA1 and ACC were correlated only among mice exposed to DSS. Interestingly, many correlations between gene expression were observed between the M1 and ACC, and the M1 and the Ca1 (Supplementary Table 5).

Correlations between fecal Lcn-2 and transcript expression within DSS animals

To determine if there was a relationship between the severity of disease among mice with DSS and mRNA transcript expression, we produced a correlation matrix between transcript expression and levels of Lcn-2 from fecal samples of DSS exposed mice that were collected the same day as euthanasia.

Pearson correlation coefficients relating levels of fecal Lcn-2 with expression of transcripts in different brain regions reveals that ACC transcript expression was most strongly correlated with fecal Lcn-2 levels, with a positive correlation between 4 transcripts (Fig. 8). Specifically, the expression of Drp1 (p = 0.033, r = 0.0849), Gad1 (p = 0.029, r = 0.858), Psd95 (p = 0.049, r = 0.813), and Snap25 (p = 0.003, r = 0.957) in the ACC were all positively correlated with fecal Lcn-2. Ca1 expression of Psd95 (p = 0.018, and M1 expression of Snap25 (p = 0.019, r = 0.0886) were also positively correlation with fecal Lcn-2. No significant relationships between transcripts in the NAc and fecal Lcn-2 were observed, although Gad1 and Psd95 approached significance (p = 0.062 and p = 0.064, respectively).

Pearson correlation of transcript expression in different brain structures and fecal Lcn-2 levels among mice with gut inflammation. N = 6, *p < 0.05.

In this study we investigated the effects of chronic gut inflammation on transcript expression in four neural structures, using the DSS-colitis model of IBD in mice. We report here that chronic gut inflammation is associated with changes in the expression of several transcripts related to mitochondrial function and antioxidant responses. The CA1 of the hippocampus, and secondarily the nucleus accumbens were most affected. Several interesting relationships between transcript expression emerged in mice with chronic gut inflammation that suggest impaired mitochondrial metabolism in the CA1 and NAc. Reduced transcript expression of Mt-co1, indicative of diminished mitochondrial output, was also observed in the ACC. In contrast to these limbic structures, the expression of transcripts in the primary motor cortex (M1) were not affected by DSS. Combined, these results suggest (i) effects of chronic gut inflammation are heterogeneous among brain structures, and (ii) that limbic structures may be more susceptible to such inflammation.

Chronic gut inflammation is associated with regional changes in mitochondrial transcripts

Mitochondria play a key role in brain health, and their impairment is hypothesized as a key feature of psychiatric diseases including anxiety, depression, and cognitive dysfunction (Giménez-Palomo et al. 2021; L. Liu et al. 2023; Picard and McEwen 2014; Khacho et al. 2017). Inflammation can produce mitochondrial dysfunction through several mechanisms. For example, pro-inflammatory mediators can promote oxidative damage to mitochondrial components, leading to impaired energy production (Brown and Borutaite 2004; Al-Mehdi et al. 2012). Further, inflammation can generate alterations in calcium homeostasis, in turn disrupting mitochondrial dynamics and promoting fragmentation, which can exacerbate inflammation, and reduce energy capacity (Boyapati et al. 2018; Irazoki et al. 2023). Considering the high basal metabolic rate of the brain, neuroinflammation may generate exacerbated metabolic consequences, particularly in neural structures with high metabolic activity.

The bulk of ATP production in the brain is accomplished by mitochondrial oxidative phosphorylation, by which electrons are transported through a series of protein complexes to generate ATP. The final complex of the electron transport chain is cytochrome oxidase c, which is comprised of several subunits, including mt-co1. Thus, Mt-co1 gene expression plays a role in regulating energy production, and can be used as an indicator for ATP production (Nagai et al. 2019). Indeed, previous studies have reported a relationship between low Mt-co1 gene expression and mitochondrial dysfunction and oxidative stress (Holvoet et al. 2017). Our results suggest that chronic gut inflammation is associated with reduced mitochondrial respiration in the NAc and ACC, based on the significant reduction in Mt-Co1 expression relative to control animals. The reduced Mt-Co1 expression was most pronounced in the NAc, with a 30% reduction relative to healthy controls; comparatively, the ACC exhibited a 21% reduction in Mt-Co1 expression. Within the Ca1, there was a trend towards reduced Mt-co1 expression relative to controls, and significantly increased expression of Drp1, which suggests increased mitochondrial fission. Enhanced fission can lead to increased levels of mitochondrial damage associated molecular patterns (DAMPS; e.g. ROS, mtDNA) in the cytoplasm, inducing the production of the proinflammatory cytokine IL-1b via inflammasome activation (Park et al. 2015). Increased expression of IL-1b has been reported in the HPC following gut inflammation (Gadotti et al. 2019). We speculate that the emergence of DAMPS within the brain as a consequence of chronic gut inflammation may be a mechanism by which neuroinflammation persists during periods of disease remission, mirroring the role of systemic mitochondrial DAMPS in promoting inflammation in IBD (Boyapati et al. 2018).

Chronic gut inflammation also transformed the relationship between Mt-Co1 and other transcripts in the NAc. Among control mice, we observed a negative relationship between expression of Mt-Co1 and Drp1, Mfn2, Gad1, and Psd95. These relationships were consistently shifted to the left and inverted to positive correlations among mice with chronic gut inflammation. The physiological significance of this finding is unclear; however, the fact that this transformation was only observed in the NAc, and all correlated with expression with Mt-Co1, suggests chronic gut inflammation may promote changes in mitochondrial function that impact neurotransmitter signaling and neuronal spine structure in this region. In our study, the NAc had significantly highest expression of Mt-Co1 relative to other regions among control animals. This may reflect a higher basal metabolic requirement in the NAc, which could render this region especially vulnerable to the metabolic demands of neuroinflammation. Research indicates that there are regional differences in mitochondrial bioenergetics within the brain (Rosenberg et al. 2023; Andersen et al. 2019) and evidence suggests mitochondria within the striatum may be particularly active. For example, mitochondria from striatal neurons exhibited highest rates of oxygen consumption and ATP production in the presence of some respiratory substrates, relative to mitochondria from cerebral cortex and hippocampal neurons (Andersen et al. 2019). Indeed, striatal mitochondria are more susceptible to calcium-induced activation of the permeability transition pore (leading to cell damage or death) than cortical mitochondria (Brustovetsky et al. 2003), and evidence suggests the striatal mitochondria are particularly sensitive to defects in oxidative phosphorylation relative to mitochondria in the cortex and hippocampus (Pickrell et al. 2011). Combined, these data suggest that chronic gut inflammation impairs the energy transformation capacity of mitochondria in a regionally dependent manner. The effect of colitis-induced neuroinflammation on aspects of mitochondrial metabolism in the brain, and how this influences neural physiology requires further investigation.

The CA1 displays increased sensitivity to chronic gut inflammation

Our study revealed that out of the structures examined, the CA1 of the hippocampus appeared to be the most sensitive to gut inflammation; the expression of 6 out of 9 of the selected transcripts were significantly altered. As well, our PCA revealed that the principal components that included the expression for all transcripts, antioxidant-related transcripts, and mitochondria function related transcripts in the CA1 was consistently different between treatment groups. The apparent sensitivity of the HPC to gut inflammation is supported by the literature, where the reported effects of gut-inflammation in the brain are dominated by the HPC (C. E. Matisz and Gruber 2022). For example, mice administered chemically-induced models of colitis demonstrated increased expression of proinflammatory cytokines (e.g. IL-6, IL-1β, TNF-α) and a variety of markers of oxidative stress in the HPC (Gadotti et al. 2019; Hilel et al. 2018; Haj-Mirzaian et al. 2017). Our previous research has revealed that acute exposure to DSS is associated with increased proportion of immature spines in the apical dendrites of CA1 pyramidal neurons, and reduced neural activation in the CA1, based on reduced immunostaining of cFos (Chelsea E. Matisz et al. 2022). It is tempting to speculate that sensitivity of the CA1 HPC to gut inflammation is associated with activated learning mechanisms, possibly to aid in identification of environmental factors that may be contributing to negative affective states associated with gut inflammation. this may explain the increased Snap25 in the Ca1 of mice with chronic DSS exposure. However, additional testing is needed to substantiate such speculation.

In the present study we also observed that chronic gut inflammation is associated with elevated cFos mRNA expression in the CA1. This contrasts the effects of acute DSS exposure, which is associated with reduced immunostaining of cFos in the CA1 of mice (Chelsea E. Matisz et al. 2022). Interestingly, CA1 hypoactivity was correlated with increased swimming time in the FST in mice exposed to a single 5-day exposure of DSS; here we report increased cFos expression in mice with three cycles of 5-day exposures to DSS, which was accompanied by swimming in the FST equivalent to controls. This suggests neural activity in the CA1 may contribute to mobility in this task. Taken together, the results from these studies suggest that the duration of inflammation differentially modulates neural activity in the CA1 hippocampus.

Chronic Gut Inflammation is associated with reduced expression of antioxidant-related genes

Reactive oxygen species (ROS) play an essential role in normal physiological processes, including cell signaling, immune responses, and mitochondrial function. However, the accumulation of ROS can lead to cellular damage, a pathological state termed oxidative stress. Antioxidant responses play an important role in maintaining the balance between ROS production and its elimination. The brain is a huge consumer of oxygen; estimates suggest 20% of the body’s oxygen supply is consumed by this organ to support the ATP intensive activities of neurons, despite only accounting for 2% of the body weight (Rolfe and Brown 1997). As such, neurons are especially vulnerable to oxidative damage due to their high oxygen demand, combined with their relatively weak antioxidant defense system (Cobley, Fiorello, and Bailey 2018). Inflammation is energy-intensive; it is estimated that chronic inflammatory diseases can increase energy costs by 10-15% (Straub 2017; Lacourt et al. 2018). Inflammation drives a metabolic switch in astrocytes and microglia towards glycolysis, increasing the production of ATP and the consumption of glucose (L. Wang et al. 2019). Further, inflammation can lead to impairments in glutamate clearance, leading to neuronal excitotoxicity and metabolic dysfunction (Haroon, Miller, and Sanacora 2017).Thus, neuroinflammation places an additional metabolic demand on an already highly metabolic organ, leading to increased risk of oxidative stress, both of which are hypothesized to play a role in the pathophysiology of anxiety, depression, and cognitive dysfunction (Black et al. 2015; Bhatt, Nagappa, and Patil 2020; Hovatta, Juhila, and Donner 2010; Guo et al. 2023). Chronic gut inflammation was associated with reduced mRNA expression for Gpx1, the enzyme that contributes to the potent antioxidant activity of glutathione, in the CA1 and the NAc. Reduced expression of the transcription factor Nrf2, which regulates antioxidant expression, was also observed in the CA1. These findings suggest impaired antioxidant responses in the CA1 and NAc of mice with chronic gut inflammation.

Mice with acute DSS colitis has increased levels of reactive oxidant-induced protein and lipid modifications in the HPC and striatum, respectively (Hilel et al. 2018). The effects of chronic gut inflammation on antioxidant systems in the brain has not been reported. However, chronic unpredictable stress, which can produce neuroinflammation and similar behavioural phenotypes as chronic inflammation in animal models, was found to reduce activity of glutathione peroxidase in the brain of rats (Che et al. 2015). Interestingly, we observed a positive correlation between Nrf2 and Psd95 among control mice; chronic gut inflammation decoupled this relationship. This aligns with previous studies which suggest that depletion of antioxidant systems can impair synaptic function and plasticity, as observed in rodent models of traumatic brain injury (Ansari, Roberts, and Scheff 2008). Further, Both Nrf2 and Psd95 were reduced in a mouse model of chronic stress, and treatment with the Nrf2 activator oltipraz restored Psd95 expression in the hippocampus(Zeng et al. 2023).

Research suggests the brain possesses regional vulnerability to oxidative stress. For example, the literature paints the CA1 as a region that is highly vulnerable to insult. Within the hippocampus, the CA1 and CA3 subfields lie adjacent to each other, and both possess a high density of pyramidal neurons. However, despite these similarities, studies conducted in a diversity of mammalian species (rats, gerbils, primates, humans) using a variety of different methods to generate oxidative stress in the brain demonstrate that CA1 neurons are much more sensitive to oxidative stress relative to their CA3 neuronal counterparts (Bartsch et al. 2015; Kirino 1982; Pulsinelli, Brierley, and Plum 1982; Tabuchi et al. 1992). Molecular mechanisms that ascribe such vulnerability are not completely understood; it has been suggested that high baseline levels of ROS-generating activities (e.g. cellular respiration) within neuronal populations render those neurons more vulnerable to insults, such as neuroinflammation (X. Wang and Michaelis 2010). Extending from this, regions with greater basal levels of oxidative stress should also possess higher basal expression of genes involved in antioxidant responses, such as Nrf2. Indeed, Wang et al. report higher basal expression of Nrf2 in the CA1 than that of the CA3 (X. Wang et al. 2005). In the present study, basal levels of Nrf2 in control mice were significantly higher in the CA1 and NAc compared to the ACC and M1. Further, transcript expression of Gpx1 was significantly higher in the NAc relative to other regions in control mice. Combined, these data support previous assertations that the CA1 maybe especially vulnerable to neuroinflammation relative to other structures. Our results extend upon these studies and suggest the NAc may similarly possess intrinsic vulnerability to the costs of neuroinflammation. Both the Ca1 and NAc represent neural substrates involved in anxiodepressive phenotypes, which are well-established comorbidities in preclinical and clinical studies of IBD (C. E. Matisz and Gruber 2022). The relative vulnerability of neural regions involved in threat-coping and motivation behaviours in the face of chronic neuroinflammation may explain why anxiety and depression emerge in such a wide range of chronic inflammatory diseases, despite their diverse etiology. Further studies are necessary to confirm the oxidative stress vulnerability transcript responses to chronic gut inflammation in other regions known to be involved in anxiety and depression, such as the basal ganglia, prefrontal cortex, and amygdala.

Chronic gut inflammation is associated with altered Gad1 expression in the CA1

Disturbed modulation of excitatory circuits by Gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the CNS, is implicated in psychological processes such as anxiety and depression (Möhler 2012; Nuss 2015). GABA synthesis is in part regulated by the rate-limiting enzyme glutamate decarboxylase isoform Gad67, which is encoded by Gad1 mRNA. We report the expression of Gad1 mRNA is significantly increased in the CA1 of mice with chronic DSS exposure. Further, chronic gut inflammation transformed the relationship between the expression of Gad1 and Psd95, and Drp1 in the CA1. The functional significance of these relationships is not clear; however, it suggests an intriguing relationship between post-synaptic density, mitochondrial dynamics, and the GABAergic system in our model. To our knowledge, the effects of gut inflammation on hippocampal GABA expression have not been previously reported. However, research suggests neuroinflammation induced by chronic stress (Lang et al. 2020) and toxin exposure (Nascimento et al. 2022) can alter GABA signaling in the hippocampus by increasing GABA receptor expression and GABA levels, respectively. In vitro studies indicate GABA contributes to neuroinflammation by stimulating the secretion of pro-inflammatory cytokines from microglia (Lang et al. 2020). Using the TNBS model of colitis in rats, Riazi et al. revealed that gut inflammation is associated with increased neuronal excitability in the HPC, and increased susceptibility to seizure that was dependent on microglial activation (Riazi et al. 2008). Specifically microglial activation was increased in the entorhinal cortex, and activation of this region has been shown to promote increased Gad1 mRNA in the CA1 (Falkenberg et al. 1997; Riazi et al. 2008). The entorhinal cortex was not investigated in the present study, but is involved in processing fear responses and anxiety, which we have shown are modulated as a consequence of chronic gut inflammation (C. E. Matisz et al. 2022).

Fecal Lcn2 expression is correlated with transcript expression in the ACC, and other regions

The ACC, positioned at the interface between the ‘emotional’ limbic system, and the ‘cognitive’ prefrontal cortex, is heavily involved in affective processing. Neuroinflammatory remodeling of the ACC is a key driver of anxiety and depression, and this region is among the most consistently altered neural structures in patients with gastrointestinal diseases and disorders, displaying cortical thinning and hyperactivity (C. E. Matisz and Gruber 2022). Despite evidence that suggests the ACC is heavily involved in the neuropathology comorbid with gut inflammation, the only transcriptional change observed in the ACC on mice with chronic gut inflammation was the reduced expression of Mt-co1. Interestingly, we did note that fecal Lcn2 was most frequently associated with shifts in transcript expression in the ACC; the expression of 4 of 9 transcripts positively correlated with fecal Lcn-2. Fecal Lcn-2 is a well-established biomarker for severity of gut disease in preclinical models, and patients with ulcerative colitis (Chassaing et al. 2012; Hsieh et al. 2016; Buisson et al. 2014). The correlation between fecal Lcn-2 and Drp1 may reflect a relationship between the severity of gut inflammation and increased mitochondrial fission, which aligns with reduced Mt-co1 expression in this region. GABAergic neurons regulate neuronal activity, and their activity in the ACC has been shown to attenuate anxiety in a rodent model of inflammatory pain (Shao et al. 2021); the correlation between fecal Lcn2 and Gad1 in the ACC may reflect a greater need for regulating neuronal activity in the ACC among these animals. The physiological significance of changes in pre and postsynaptic protein transcripts in the ACC, CA1 and M1 as they relate to fecal Lcn-2 levels are not clear. The correlation between fecal Lcn-2 and Psd95 mRNA may reflect visceral pain among more severely inflamed animals; DSS-induced colitis promotes visceral hyperalgesia in mice (Lapointe et al. 2015; Defaye et al. 2022; Esquerre et al. 2020), and PSD95 in the ACC has been shown to contribute to neuropathic pain (Li et al. 2022). Stress and inflammation have also been shown to alter spine morphology in both the ACC and CA1 It is important to note that the current study did not assess post transcriptional modifications or protein expression of the transcripts. Further, the phenotype of cell on which these mRNA transcripts are modified is unknown, which limits the interpretations of these findings.

Our results indicate chronic gut inflammation is associated with heterogenous changes in the brain, particularly the limbic system. Changes in transcript expression suggest prolonged colitis promotes reduced oxidative phosphorylation, and impaired antioxidant defense systems in the ACC, CA1, and NAc. Our data suggest chronic gut inflammation may alter mitochondrial function and dynamics in regions of the brain that are known to be affected in patients with symptoms of anxiety and depression. This lends support to the literature that proposes a role of altered bioenergetics and mitochondrial dysfunction in the brain of patients with chronic inflammatory diseases, which may play a role in mood disorders that are comorbid in these illnesses.

Acknowledgements

We are grateful for Natural Sciences and Engineering Research Council (CEM; PDF, AJG and RJS, discovery grant) and Canada Research Chairs program and Genome Canada BioNet grant (AZ) for financial support of this work.

Funding

AJS and RJS received an NSERC Discovery Grant from the National Science and Engineering Research Council. AZ is a recipient of the Canada Research Chairs program and Genome Canada BioNet grant. CEM was supported by an NSERC PDF.

Competing Interests

The authors have no financial or non-financial interests to disclose.

Author Contributions

CEM and AJG conceptualized the study; CEM, VL, KB, and TH collected, curated and analyzed data; CEM and AJG drafted the manuscript; all authors critically revised and approved the final manuscript for submission. AJG, AZ, and RJS obtained funding and provided oversight and supervision of the study.

Ethics Approval

All experiments were carried out in accordance with the guidelines of the Canadian Council of Animal Care and were approved by the University of Lethbridge Animal Care Committee (Protocol #2018).

Data Availability

The datasets generated and analyzed for the current study are included in the supplementary materials.

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No competing interests reported.

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Chronic gut inflammation differentially modulates mitochondrial and antioxidant transcriptional programs in limbic brain structures

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