Altered intestinal microbiota in mice consuming high-fat diets influence cognitive function

doi:10.21203/rs.3.rs-2369665/v1

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Altered intestinal microbiota in mice consuming high-fat diets influence cognitive function

https://doi.org/10.21203/rs.3.rs-2369665/v1

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This study was aiming to verify critical role of gut microbiota linking diet-induced obesity and cognitive dysfunction. After antibiotic treatment, male C57BL/6 mice were subjected to fecal microbiota transplantation (FMT) using fecal microbiota isolated from donor mice fed on various high-fat diets and control basic diet. Novel object recognition test, 16S rRNA gene sequencing of feces and haematoxylineosin staining of hippocampal CA1 area were performed for all mice. The results showed that donor obese mice induced by diets high in long-chain saturated fatty acid (LCSFA), n-6 polyunsaturated fatty acid (n-6 PUFA) and trans fatty acid (TFA) had significant cognitive impairment (all Ps < 0.05) compared with that in control and n-3 polyunsaturated fatty acid (n-3 PUFA) groups. In recipient mice, the similar effect of above high-fat diets was revealed after FMT, while in absence of obesity. The donor mice in LCSFA, medium-chain saturated fatty acid (MCSFA), n-6 PUFA, and TFA groups showed more structural breakage and less nerve cells in hippocampal CA1 area than that in other groups, which was similar to corresponding recipients. According to these results it was concluded that high LCSFA, n-6 PUFA, and TFA diets may impair the cognitive function by damaging the structures of CA1 region in hippocampal through influencing intestinal microbiota in mice.

Health sciences/Diseases/Nutrition disorders/Obesity

Biological sciences/Neuroscience/Diseases of the nervous system

high-fat diet

fatty acid

gut microbiota

cognition

behavior

obesity

The association between obesity and neuropsychiatric disorder, including cognitive dysfunction in learning and memory, is now widely recognized [1]. In human subjects, obesity is related to cognitive decline, hyperlipidemic disorders, and hippocampal atro-phy [2, 3], in particular, the impaired learning and memory function induced by obesity has been widely discussed. In animals, obesity/hyperlipidemia induced by high-fat diet impaired cognitive processes and mood states, especially the functions dependent on hippocampus [4, 5]. Hidese et al. reported worse working memory, motor speed, and exec-utive function in obese subjects than that in non-obese subjects [6]. Furthermore, animal studies also demonstrated that obesity impaired spatial learning and it was associated with low-grade systemic inflammation [7, 8].

Nevertheless, recent studies indicated that the quality and type of dietary fatty acids could unequally affect cognition in obese subjects. It was demonstrated that excessive consumption of saturated fatty acid has been related to cognitive decline while polyun-saturated fatty acid intake has advantages in their prevention [9]. In one current study, high-fat diets enriched in saturated fatty acid associate with obesity and insulin resistance, which is in turn associated with cognitive decline and dementia in human population [10]. Külzow et al. showed beneficial effects of long-chain polyunsaturated n-3 fatty acids (n-3 PUFAs) on memory abilities in healthy elders [11]. Moreover, one previous research indicated that according to the maternal weight, cognition of infant was positively associ-ated with content of n-6 polyunsaturated fatty acids (n-6 PUFAs) and n-3 PUFAs in breast milk, while negatively affected by ratio of n-6/n-3 [12]. The results of Wang et al. revealed that the supplement of PUFAs could improve the disorder of cognition and mood by sleep deprivation in Sprague Dawley rats [13]. Meanwhile, results of our human study indicat-ed that high n-6 PUFA diet intake could exacerbate the cognitive decline in the obese pop-ulation [14]. Animal studies also revealed that excessive consumption of fats, in particular saturated fat and trans fat, could induce adiposity and dyslipidemia, especially lead to impaired cognitive performance [8].

Recently, the most common report is that diet-induced obesity could affect gut micro-biota [15], furthermore, some studies identified gut microbiome as one point of the mech-anistic link between diet-induced obesity and cognitive impairment in individuals [16]. Mariat and colleagues’ research demonstrated that decrease of Firmicutes/Bacteroidetes ratio in elderly consuming diet containing high-fat, pointing out that the decreased ratio might be related to the cognitive dysfunction in the elder population [17]. Similarly, Alzheimer’s disease (AD) patients have low microbial diversity, including decreased Firmicutes and increased Bacteriodetes [18]. Fava et al. showed a reduced diversity of overall intestinal mi-crobiota induced by high fat diets in the individuals who were at risk of metabolic syndrome [19]. Data of Cattaneo et al. indicated that the increased abundance of a pro-inflammatory gut microbiota taxon (Escherichia/Shigella), and the reduced abundance of an anti-inflammatory taxon (E. rectale) were possibly related to increased proinflammatory cytokines in dementia patients [20]. One associated animal study showed that altera-tions in neuroethology induced by changing n-3 PUFA in feed was clearly related to com-plicated changes in intestinal flora [21]. The study of Robertson et al. indicated that com-pared with the basal diet, early-life male C57BL/6 mice fed n-3 supplemented diet dis-played enhanced cognition, an elevated Firmicutes/Bacteroidetes ratio and blunted systemic LPS responsiveness. On the contrary, mice fed n-3 deficient diet displayed impaired communication, social and depression-related behaviors, higher Bifidobacterium and Lac-tobacillus abundance and dampened hypothalamic-pituitary-adrenal axis activity [21]. High n-6 PUFA diet was associated with reduced abundance of Bifidobacteria and de-creased immune functions [22]. Related research showed that Bifidobacteria could modu-late cognitive processes in an anxious mouse strain [23]. In addition, many studies ex-plored a possible link among diet, gut microbiota, and hippocampus injury. Tsan et al. showed that high sugar and fat diet consumption during adolescence female rats resulted in hippocampus-dependent place recognition memory impairments and intestinal mi-crobiota dysbiosis [24]. Beilharz et al. found that rats fed SFA diet were impaired on hip-pocampus-dependent memory, compared with the PUFA and CON groups [25]. Besides, researchers found that transplantation of intestinal flora from Alzheimer's disease mice into normal mice inhibited hippocampal neurogenesis and caused memory impairment [26]. Another study confirmed the effect of fecal microbiota transplantation (FMT) on the hippocampus fimbria and hence impaired spatial learning and memory [27]. Wang and colleagues transplanted fecal microbiota from patients to mice induced neuronal apopto-sis in the CA1 region of the hippocampus and cognitive impairment [28]. These results suggested that the changed intestinal microbiota induced by high fat diets may lead to cognitive decline by influencing the hippocampus, especially the CA1 region.

Therefore, current study was conducted to verify the assumption that different dietary fatty acids may regulate the cognitive function through obesity-concomitant microbiome influencing the structure of CA1 region in hippocampus.

2.1. Body weight and plasma parameters

Donor mice in CON group showed increased body weights when comparing with those mice in other groups (all Ps < 0.05) at fecal flora collection time. Detailed information was shown in our previous study [35].

The body weights of recipient mice over 18-week were shown in Fig. 2 and Supplementary Table 2. During the antibiotic treatment, the body weight of CON-0 group was significantly higher than that in most of other groups with exception of the third and the fifth week (Ps < 0.05).

The results of plasma parameters were shown in Fig. 3 and Fig. 4. In donor mice, the levels of TC and HDL-C in CON and n-3 PUFA groups were significantly lower than mice fed with other fatty acid diets’ groups (Ps < 0.05). Higher HDL-C in MCSFA group than that in n-6 PUFA and MUFA groups was also revealed (Ps < 0.05). Mice in CON group showed decreased levels of TG when comparing with other groups excepting mice fed on MCSFA containing diet (all Ps < 0.05). However, the levels of TG in the LCSFA and MCSFA groups were significantly lower than MUFA and TFA groups (Ps < 0.05). Mean-while, the levels of TG were also lower in the n-3 PUFA group comparing with TFA con-suming mice (P < 0.05). Compared with that of the CON group, the levels of LDL-C showed an increase in the mice feeding with diet high in LCSFA, MCSFA, MUFA, and TFA (Ps < 0.05). And, LDL-C in LCSFA, MCSFA, n-6 PUFA, MUFA and TFA groups also showed significant increase than n-3 PUFA mice (Ps < 0.05). Besides, glucose in the CON and LCSFA groups were lower than other groups with exception of MCSFA group (all Ps < 0.05).

In recipient mice, plasma TC levels in the + n-6 PUFA and + n-3 PUFA groups were significant decreased when comparing to the CON-0 group (all Ps < 0.05). When it is re-spect to TG, mice in + n-3 PUFA and + MUFA groups showed increased level of TG than that in CON-0, CON-1, +LCSFA, +MCSFA and + n-6 PUFA groups (Ps < 0.05). Furthermore, TG in mice of + TFA group also showed significant decline, compared with that in mice belonging to + MUFA group (P < 0.05). In addition, the TG levels of + CON group were sig-nificantly higher than that on + LCSFA group (P < 0.05). For HDL-C, its level in mice of CON-0 group was higher than that in the + MCSFA group (P < 0.05).

2.2. Novel object recognition

In the familiarity period, donor mice spent same amount of time to investigate two similar objects (object A and object B) in all groups except the n-3 PUFA group. In test pe-riod, the time to explore novel object in the mice of CON group was significantly increased comparing to explore the familiar object (P < 0.01). However, the mice fed with diet con-taining LCSFA, MCSFA, and n-6 PUFA spent shorter time to explore the novel object than that spent on the familiar object (Ps < 0.05). Furthermore, the discrimination indexes in CON and n-3 PUFA groups were significantly higher than mice in other groups (all Ps < 0.05). Besides, the discrimination index was markedly lower in the MCSFA group than the MUFA group (P < 0.05). In the familiarity period, recipient mice spent similar amount of time to investigate two similar objects in all groups except the CON-0 and CON-1 groups (Ps < 0.05). In the test period, the recipient mice of + CON and + n-3 PUFA groups spent more time to explore the novel object than the familiar object (Ps < 0.05). Compared with those in the CON-0 and + CON groups, the discrimination indexes significantly decreased in other groups with exception of + MCSFA, +n-3 PUFA and + MUFA groups (Ps < 0.05). The discrimination indexes were significantly higher in the + MCSFA and + n-3 PUFA groups than mice belonging to + n-6 PUFA and + TFA groups (Ps < 0.05). Moreover, the dis-crimination index of mice in the + TFA group was decreased comparing with that in + MUFA group (P < 0.05). Detailed information was shown in Fig. 5.

2.3. Pathological changes of hippocampal CA1 area

As showed in Fig. 6, the results of the light microscopic observation of the hippo-campal CA1 showed that the neurons in the CON, CON-0, CON-1, +CON groups were arranged neatly. Furthermore, the neurons were round and intact with clear nucleus and membrane, and without obvious necrosis. Compared with control groups, the nerve cells in all of the high fat groups of donor mice and the + LCSFA, +MCSFA, +n-6 PUFA, +TFA groups of recipient mice were irregular in size and shape. Furthermore, the hippocampal neurons in these groups were atrophied and performed reduced number, disordered ar-rangement, larger cell gap and blurred cell structure with pale cytoplasm. Compared with the donor mice in CON group, the number of neurons in hippocampus CA1 showed sig-nificant decline in other groups with exception of n-3 PUFA group (Ps < 0.05). Moreover, mice in the n-3 PUFA group obtained more neurons than mice in LCSFA, MCSFA, and n-6 PUFA groups (Ps < 0.05). In recipient mice, mice’ hippocampus CA1 in + CON and + n-3 PUFA mice obtained more never cells than that in the + LCSFA group (Ps < 0.05), which was similar to that in donor mice.

2.4. Alpha and beta diversity of gut microbiota

Totally, 1538440, 2608578, 2045767 and 2618690 usable sequence reads were ob-tained from all of fecal samples of donor mice, recipient mice before antibiotic, after anti-biotic and after FMT treatment. After subsampling each sample to an equal depth (26308 sequences per sample in donor mice, and 33282, 29919, 35412 sequences per sample in recipient mice before antibiotic, after antibiotic and after FMT respectively) and separately clustering 722, 1275, 2290 and 1360 operational taxonomic units (OTUs) at 97% identity were obtained, with OTUs ranging from 180 to 340, 427 to 686, 17 to 761 and 44 to 692 per sample in donor mice, recipient mice before antibiotic, after antibiotic and after FMT treatment.

Fecal samples collected from donor mice were analyzed with 16S rRNA gene se-quencing and inoculated into recipient mice. Then, fecal samples of three stages in recipi-ent mice were also collected for 16S rRNA gene sequencing analysis. As shown in Fig. 7, the bacterial diversity and richness in different groups were measured and presented by Shannon index, Simpson index, Chao 1 index and PD index at the OTU level. In donor mice, the Shannon index in CON group were significantly lower than that of the MCSFA and TFA groups (Fig. 7A, Ps < 0.05). Compared with that in the CON group, the Chao 1 indices showed significant increases in other groups excepting mice in LCSFA group (Ps < 0.05). Besides, the Chao 1 indices were also increased in the MUFA and TFA groups com-paring to LCSFA group (Ps < 0.05). Additionally, the mice fed with MUFA diet showed higher Chao 1 index than MCSFA group (Fig. 7C, P < 0.05). The PD indices in the high fat diet feeding groups were higher than that in the CON group with the exception of LCSFA and n-3 PUFA groups (Ps < 0.05). The PD indices were also higher in MUFA and TFA mice than mice in LCSFA group, (Fig. 7D, Ps < 0.05).

In recipient mice, before antibiotic treatment, nine groups of mice were with similar bacterial diversity and richness (Fig. 7E-H, all Ps > 0.05). After fecal transplantation, the Simpson index showed marked increase in the CON-1 group compared with those in other groups (Fig. 7J, P < 0.05), which was conversed with Shannon and PD indices (Fig. 7I, and L, Ps < 0.05). The CON-1 group performed lower Chao 1 index than those in other groups, excepting the + CON group (Ps < 0.05). Furthermore, the Chao 1 indices of + LCSFA and + MCSFA groups were obviously lower than + n-6 PUFA group (Ps < 0.05). The Chao 1 index of the + LCSFA group was also lower than that in the + MUFA group (Fig. 7K, P < 0.05).

As shown in Fig. 8, principal coordinates analysis (PCoA) of the weighted UniFrac distance metric revealed the bacterial composition of mice in different diet or colonized flora groups. In donor mice, a PCoA showed distinct clusters among different dietary groups (Fig. 8A, R = 0.403, P = 0.001). Before antibiotic treatment, bacterial composition was similar in all recipient mice (Fig. 8B, R = 0.055, P = 0.105). After FMT, a PCoA showed separated clusters of the intestinal microbiota between the CON-1 and other groups in recipient mice (Fig. 8C, R = 0.269, P = 0.001). These results indicating that the FMT influenced the composition of the intestinal flora in recipient mice.

2.5. Composition of the intestinal microbiota

The proportions of gut microbiota at the phylum and family levels in donor mice and in the three stages of recipient mice are showing in Fig. 9. After antibiotics treatment, the structure of gut bacteria in recipient mice was changed clearly. Antibiotic regimen almost depleted the recipient dominant microbiome, as shown in Supplementary Fig. 1, most of the groups performed significant decrease of Shannon, Chao1 and PD indexes and increased Simpson index after antibiotic treatment. The relative proportions of domi-nant phyla and families in intestinal microbiota were compared using Kruskal-Wallis H test in Fig. 10. In donor mice, proportions of Firmicutes phylum in the all of high fat die-tary groups were higher than that of the CON group (Ps < 0.05). Meanwhile, mice in LCSFA, MUFA and n-6 PUFA groups contained markedly higher abundance of Firmicutes than n-3 PUFA group (Ps < 0.05). Proportions of Bacteroidetes in CON, n-3 PUFA, and TFA mice were significantly higher than other groups (all Ps < 0.05). What’s more, the abun-dance of Deferribacteres was increased in the TFA groups comparing with CON group, (P < 0.05). When it respected to family, the abundances of Muribaculaceae in the CON and TFA groups were higher than those in other groups with exception of n-3 PUFA group (Ps < 0.05). The mice in CON and n-6 PUFA groups showed less abundances of Lachnospiraceae than LCSFA and TFA groups (Ps < 0.05). Proportions of Lachnospiraceae in the CON, n-3 and n-6 PUFAs, and MUFA groups were significantly decreased comparing to MCSFA group (all Ps < 0.05). The proportion of Erysipelotrichaceae in the mice feeding with MUFA containing diet was higher than the mice fed by diet high in LCSFA, MCSFA, and TFA (Ps < 0.05). The Ruminococcaceae was increased in mice of MCSFA group when comparing with the CON group (P < 0.05). It also showed higher level in the TFA group than those in the CON, LCSFA, and MUFA groups (Ps < 0.05). In addition, n-6 PUFA group had a markedly higher abundance of Lactobacillaceae compared with the other donor groups but not LCSFA and MUFA groups (Ps < 0.05). Results of Fig. 10G demonstrated that the genus level, the relative level of most abundant genus norank_f__Muribaculaceae belonging to family Muribaculaceae performed a consistent alteration with that in family Muribacula-ceae among all of the groups. Then the relative levels of genera Faecalibaculum and Lactoba-cillus belonging to family Erysipelotrichaceae and Lactobacillaceae respectively were also dif-fered among groups in the same ways as above two families in donor mice. While, for the level of genus Bacteroides containing in family Bacteroidaceae, in n-3 PUFA treated group was significantly higher than that in LCSFA, n-6 PUFA and MUFA treated mice (Ps < 0.05), which was different with trend of family Bacteroidaceae. For the genus nor-ank_f__Lachnospiraceae belonging to family Lachnospiraceae, the TFA treated mice with higher level than that in CON, n-3 PUFA and n-6 PUFA treated group (Ps < 0.05). The other genus belonging to family Lachnospiraceae, Lachnoclostridium level in n-6 PUFA group was lower than the MCSFA treated group, meanwhile its relative level in LCSFA, MCSFA and TFA treated groups were considerably higher than CON group (Ps < 0.05).

Before antibiotic treatment, no significant differences appeared at the phylum, family and genus levels in recipient mice (Fig. 10B, E and H). After FMT, the diversity and abundance of intestinal microbiome in recipient mice were recovered and even higher than that in donor mice, as shown in Supplementary Fig. 2. The abundances of Verrucomicrobia and Proteobacteria phyla were increased in the CON-1 group comparing to other groups (Ps < 0.05). The abundance of Patescibacteria phylum in CON-1 was lower than CON-0 and + CON groups (Ps < 0.05). Compared with + MUFA group, the proportions of Patescibacteria showed decreased level in the three control groups and + LCSFA groups (all Ps < 0.05). At family level, the abundances of Muribaculaceae, Prevotellaceae, and Rikenellaceae showed markedly decrease in the CON-1 group compared with other groups. On the contrary, the abundance of Akkermansiaceae showed a significant increase in the CON-1 group compared with other groups (Ps < 0.05). Additionally, the abundance of Muribaculaceae decreased in the + n-3 PUFA mice compared to the CON-0, +MCSFA, +n-6 PUFA and + TFA groups (Ps < 0.05). The Ruminococcaceae in the CON-1 recipient mice was lower than those received FMT from donor mice feeding with diets high in CON, LCSFA, n-3 PUFA and MUFA (all Ps < 0.05). Besides, the + CON group had a higher abundance of Ruminococcaceae compared with the + MCSFA group (P < 0.05). What’s more, faces from re-cipient mice in the + LCSFA, +n-3 PUFA, +n-6 PUFA, +MUFA, and + TFA groups contained higher proportion of Rikenellaceae than that in the + CON group (Ps < 0.05). When it re-spected to genus level (Fig. 10I), the variability of the most abundant genus nor-ank_f__Muribaculaceae between groups was the same as that at family Muribaculaceae. As the second abundant genus, there was no significant difference among groups for the ge-nus Lachnospiraceae_NK4A136_group, as did the family Lachnospiraceae to which it belongs. The variability of relative level of genus Prevotellaceae_UCG-001 was similar to its belonged family Prevotellaceae with exception of that n-6 PUFA group with higher level than in MCSFA group (P < 0.05). For the other genus belonging to Lachnospiraceae, relative level of unclassified_f__Lachnospiraceae was higher in all of the high fat treated group than in CON-1 group (Ps < 0.05), and its levels in n-3 PUFA, n-6 PUFA and TFA groups were sig-nificantly lower than in LCSFA group (Ps < 0.05). The differences among groups for genus alistipes was similar to its belonged family Rikenellaceae with some exceptions. Its relative abundance in n-6 PUFA, MUFA and LCSFA groups were higher than in MCSFA group (Ps < 0.05). For the genus Bacteroides, its level in CON-1 group was higher than in all of the other groups (Ps < 0.05). All of the above results suggested similar trend between groups at phyla, family and genus levels with some exceptions.

Numerous evidences suggest that obesity induced by high-fat diet can adversely af-fect the function of brain [36, 37] and a growing number of studies link gut dysbiosis to neurological and psychiatric disorders [38–40]. Our results demonstrated that different types of high dietary fatty acids might induce obesity, pathological changes in hippo-campal CA1 area, and alterations of gut microbiota in mice. Transplantation of fecal mi-crobiota shaped by multiple high dietary fatty acid diets, possibly through damage to the hippocampus CA1 area, caused marked disruption or improvement in exploratory and cognitive behavior in non-obese mice fed with normal diet.

This study revealed that the consumption of diet containing high level of LCSFA, MCSFA, n-6 PUFA, MUFA, and TFA diets led to increases plasmic level of TC, HDL-C, and LDL-C, whereas diet high in n-3 PUFA induced reverse trend compared with the CON group in donor mice. The plasma TG were also increased in high LCSFA, n-3 PUFA, n-6 PUFA, MUFA, and TFA dietary groups. These results indicated that high-fat diets led to elevated blood lipids, and n-3 PUFA might be a protective role in the regulation of plasma cholesterol. Related research conducted by Micioni et al. and Opyd, indicated increases of plasma glucose, triglycerides and cholesterol, including HDL and LDL in obese rats fed hemp oil (4% diet) or hemp seeds (12% diet) [36, 41]. Lunn et al. demonstrated that the ap-propriate ratio of n-6/n-3 PUFA in diet is associated with improvement of blood lipid pro-file [42], which might be related to the different changes in plasmic TC, HDL-C, and LDL-C of obese mice induced by diet containing much n-3 PUFA in our study. Neverthe-less, FMT did not induce increases of plasma parameters in mice receiving “obese-type” gut microbiota compared with mice receiving “lean-type” gut microbiota. So the recipient mice did not replicate the obese phenotype of the donors from the results of current study.

Furthermore, our results demonstrated that the mice in most of high fat diet groups performed decreased cognitive functions with exception of mice consuming high n-3 PUFA diet. This may be relating to damages and structural breakage, and the fewer nerve cells in hippocampal CA1 area of mice in the LCSFA, MCSFA, n-6 PUFA, and TFA groups. Besides, the high LCSFA, n-6 PUFA, and TFA diet-induced impaired learning and memory ability was inherited in recipient mice by FMT, as showed in the novel object recognition test of their corresponding recipient groups. Similarly, the recipient mice in the + LCSFA, +n-6 PUFA, and + TFA groups performed reduced number of neurons and wid-ened intercellular spaces in hippocampal CA1 area. Interestingly, the n-3 PUFA group in donor mice and the CON-0 and CON-1 group in recipient mice showed significant differ-ences for exploring the two identical objects during the familiarity period of the novel ob-ject recognition tests. The possible reason was that some mice felt uncomfortable with new environment at the beginning, which made them spent a long time exploring the first contacting place. And during the test period, all mice have sufficiently adapted to the en-vironment. Overall, our results showed that high LCSFA, n-6 PUFA, and TFA diets dam-aged the structure of the hippocampal CA1 area by modulating gut microbiota, which in turn affected cognitive function. The control and high n-3 PUFA diets showed the opposite effect with them. These results are in consistent with associated epidemiological [43] and animal [8] studies, indicating that consumption of dietary fat is one of the most important risk factors in the development of cognitive dysfunction. Specially, excessive consumption of TFA and SFA was linked to obesity [44, 45] and neurologic conditions [8, 46]. Wu et al. revealed that high-fat diet-feeding could induce neuron cell injury, structural disorder, pro-inflammatory cytokine over-expression, and serotonergic system abnormality of the hippocampus in mice [47]. Previous studies have showed that PUFAs could improve the activity of brain cells, and enhance the learning and memory abilities in humans [48, 49]. De Mello et al. demonstrated that n-3 PUFA intake partially reversed the inflammatory, oxidative damage, and inhibition of mitochondrial respiratory chain complexes in the brain structures in obesity mice [50]. Similarly, Arendash et al. stated that high level of n-6 PUFA in cortex was related to cognitive decline in APP/PS1 transgenic mice [51]. However, some studies revealed negative association between intake of n-6 fatty acids and low cog-nitive performance [52, 53], which might be associated with anti-inflammatory and anti-oxidant effects of arachidonic acid. In addition, related studies found that low ratio of die-tary n-6/n-3 PUFA might decrease the risk of cognitive dysfunction [54, 55]. These differ-ences might be due to diverse research perspectives. More likely, independent discussion of n-6 PUFA intake might be associated with a lower risk of cognitive decline in animals or humans. The study of Jiang et al. showed that midlife dietary intake of n-6 PUFA was related to a lower risk of cognitive impairment in elderly Chinese participants [56]. Thus, above all, further exploration is required to study the beneficial effects on the cognitive abilities with appropriate doses of n-6 and n-3 PUFA, and the ratio between them. Several population studies reported that higher intakes of MUFA could improve cognition and prevent cognitive decline [56, 57], whereas others showed no significant associations for MUFA [58–60]. In our study, though high-MUFA diet-intake reduced the cognitive ability compared with basal-diet and high-n-3 PUFA diet-intake of mice in our study, high-MUFA diet-intake showed better cognitive behavior than high-MCSFA diet-intake. Both of our results and above literatures underscore different dietary fatty acids induced obesity could unequally affect in cognitive phenotype. While most of related publications indicted inflammatory responses and oxidative damage play key roles in high-fat di-et-induced cognitive impairment, the role of intestinal microbiota in it was emphasized in our study.

To explore the underlying mechanism of dietary fatty acids effecting hippocampal CA1 area, even cognition, the gut microbiota induced by multiple high-fat diets was transplanted to pseudo-germ-free mice (transplantation following antibiotics treatment). Related study demonstrated that FMT from aged donor mice induced impaired learning and memory ability, altered neurotransmission in hippocampus, and reduced the abun-dances of Lachnospiraceae, Faecalibaculum, Prevotellaceae and Ruminococcaceae in young re-cipients [27]. In our study, according to the alpha diversity, beta diversity, and the overall community difference analysis, we detected the intestinal microbiota of donor mice and in the three stages of recipient mice (before antibiotic treatment, after antibiotic treatment, and after FMT) and found similar alpha diversity all of the groups. Besides, the microbiota community diversity in MCSFA and TFA groups and the community richness in MCSFA, TFA, n-3 PUFA, n-6 PUFA and MUFA groups were higher than the CON group. These da-ta are contrary to that high-fat diets decreased microbial diversity or richness in most studies [61, 62]. Our results are similar to previous research reporting that high-fat diets can increase community diversity in mice [63, 64]. In recipient mice, the community rich-ness showed increases in the + n-6 PUFA, +MUFA, and + TFA groups after FMT, which was consistent with the conclusion of transplanted community keeping most of its original diversity [65].

Compared with the control, sixteen weeks of different high-fat-diets consumption induced extensive alteration in the intestinal microbial community structure at the phy-lum level in donor mice. The increased abundance of Firmicutes and decreased level of Bacteroidetes were observed in the six high fat feeding groups. These results are consistent with previous research revealing that high-fat diets induced increased Firmicutes and a decreased Bacteroidetes or a high Firmicutes/Bacteroidetes ratio [61, 63, 66]. These studies suggest that a higher ratio of Firmicutes/Bacteroidetes enables greater efficiency of gut mi-crobiota in extracting energy from the diets, which may be one of the reasons for obesity. In addition, increased Firmicutes are known as a risk factor in AD pathogenesis [67]. Hang et al. reported that FMT could ameliorate the cognitive impairment, and reverse the in-creased Firmicutes and the decreased Bacteroidetes of AD mice [68]. Tomova et al. reported that the fecal microbiome of autistic children showed a remarkable increase of the Firmic-utes/Bacteroidetes ratio [69]. In summary, the increased Firmicutes and the decreased Bac-teroidetes are not only associated with obesity, but also with cognitive dysfunction. Dinan et al. indicated that patients with irritable bowel syndrome showed an increase ratio of Firmicutes/Bacteroidetes and elevation of the amount of Lactobacillus spp, compared with healthy controls [70], which also suggests that these altered floras may play a role in au-tism through the "gut brain axis".

At the family level, the abundance of Muribaculaceae, which is mainly composed of genus norank_f__Muribaculaceae, showed decreases in the LCSFA, MCSFA, n-6 PUFA, and MUFA groups when compared with the CON and TFA groups of donor mice. In related studies, researchers found that the decreased Muribaculaceae was associated with reduced lipid and energy metabolism in AD mice [71] and consistent with clinical manifestations of AD patients [72]. In this research, there were higher abundances of Lachnospiraceae con-taining genus norank_f__Lachnospiraceae, in the LCSFA, MCSFA, and TFA groups than those in the CON and n-6 PUFA groups. Previous studies linked decreased Lachnospiraceae to neurodegenerative impairment [73], such as Parkinson’s disease [74]. Haskell-Ramsay et al. showed that nut supplementation exhibited a protective effect on cognitive function adults with the increased Lachnospiraceae in gut [75]. However, other studies suggested that different OTUs within the family Lachnospiraceae had different effects on place memory. Thus, we need to study it more deeply at the OUT level in the further research. We found mice in the MUFA group with a higher levels of family Erysipelotrichaceae and genus Faecalibaculum belonging to it than those in the LCSFA, MCSFA, and TFA groups. The enrichment of Erysipelotrichaceae showed relationships with cognitive dysfunction in AD rats [76]. Ruminococcaceae showed a higher abundance in the MCSFA and TFA groups than mice in CON, LCSFA, and MUFA groups, which was similar to previous study that indicated an increased expression of Ruminococcaceae in high-energy diets [77]. Neverthe-less, the family Ruminococcaceae associated with short-chain fatty acids production may beneficial to the structure of hippocampus [27]. The results of Bloemendaal et al. showed that probiotic supplementation in subjects with the increased Ruminococcaceae_UCG-003 could improve negative effects of stress on working memory [78]. In addition, our results showed increased abundance of family Lactobacillaceae and genus Lactobacillus in the n-6 PUFA group compared with those in the CON, MCSFA, n-3 PUFA, and TFA groups. Many researches demonstrated that Lactobacillus, as a probiotic, enhanced memory and changed regional brain metabolites in humans and animals [79, 80]. These studies are contrary to our results, and it may be necessary to further study the relationship between them and the metabolic reactions of different fatty acids. In summary, increased richness of Firmicu-tes phylum, families of Lachnospiraceae, Erysipelotrichaceae, Ruminococcaceae, and Lactobacil-laceae, genera of norank_f__Lachnospiraceae, Faecalibaculum and Lactobacillus, and decreased level of Bacteroidetes phylum, Muribaculaceae family and norank_f__Muribaculaceae genus in gut microbiota were found in high-fat diet-induced obesity mice with low cognitive per-formance in current study. Further studies are needed to investigate the roles of these gut microbiota in their effects of high-fat diet on cognitive function.

After transplantation of donor gut microbiota, the relative abundances of phyla Ver-rucomicrobia, Proteobacteria, and family Akkermansiaceae showed significant increases, whereas families Muribaculaceae, Prevotellaceae, Ruminococcaceae, and Rikenellaceae, genera norank_f__Muribaculaceae, Prevotellaceae_UCG-001 and alistipes showed marked decreases in the CON-1 group when comparing with other groups. Related reports indicated that the increased Patescibacteria in patients with AD or mild cognitive impairment was correlated with Clinical Dementia Rating [81]. The phylum Patescibacteria is associated with cyto-kines from “gut-brain axis” including brain-derived neurotrophic factor, serotonin, and others [82]. Contrary to the donor mice, the abundance of Muribaculaceae and genus nor-ank_f__Muribaculaceae in the + n-3 PUFA group was decreased comparing with the CON-0, +MCSFA, +n-6 PUFA and + TFA groups. In one previous study, the Chitooligosaccharides has been verified to promote neuronal regeneration in hippocampus by decreasing the relative level of Muribaculaceae [83]. This reverse change might be caused by antibiotic treatment and/or FMT. The abundance of Ruminococcaceae, was decreased in the + MCSFA group when compared to CON-0 group, which was similar to the previous study finding the decreased Ruminococcaceae in young recipient mice from old donors by FMT [27]. The abundance of Rikenellaceae in the mice of + LCSFA, +n-3 PUFA, +n-6 PUFA, +MUFA and + TFA groups, meanwhile the genus alistipes which is assigned to Rikenellaceae in + LCSFA, +n-6 PUFA and + MUFA groups, showed increases compared to the + CON group. The finding of Ren et al. indicated a higher abundance of Rikenellaceae in Parkinson’s disease patients with mild cognitive impairment compared with healthy subjects [84]. Lee et al. indicated that Rikenellaceae was correlated with cognitive function and blood and fecal LPS levels in mice [85] which showed the changes in intestinal flora might change cogni-tive function by stimulating inflammatory response.

Our results suggested that this binary distinction did not sufficiently reflect the com-plex influence of diet-induced gut microbiome on cognition, as reported in the previous study of Bruce-Keller and his colleagues [1]. These deviations could be induced by the dif-ferent sequencing depth between fecal samples collected from donor mice and recipient mice in different time points. Moreover, the CON-0 and CON-1 group could express the effects of repeated gavage and antibiotic treatment respectively. Other groups were treated equally to minimize the potential artifacts. Appropriate animal models are indispensable in exploring the association between the host and the intestinal flora [86]. However, germfree animals have notably underdeveloped immune systems, decreased cardiac output [87] as well as delay gastric emptying and gastrointestinal transit [88]. Therefore, antibiotic-treated mice are more suitable than germ-free mice for the current study because it can resemble the human condition.

According to our results, the similar behavioral phenotype between donor mice and recipient mice combined with the transplantation of diet-induced intestinal microbiota supported the concept of a “microbiome-gut-brain axis”. Khan et al. reported that mice were exposed to the increase of social defeat stress, which caused the higher attenuation of Lactobacillus [89]. Moreover, some studies indicated that probiotic intake is linked to posi-tive changes in behavior and mood [90]. “Gut microbiota, gut, and brain could interact via the central nervous system, either through the enteric nervous system, via spinal and va-gal nerves, or via blood circulation” [91, 92]. But the detailed mechanism of the gut micro-biota’s effects on cognitive function in mice needs to be further studied.

Taken together, high LCSFA, MCSFA, n-6 PUFA, MUFA, and TFA diets induced obe-sity, increased plasmic cholesterol, and the reverse regulation of high n-3 PUFA diet were evident in the donor mice. However, these obesity phenotypes were not induced in recipi-ent mice by FMT. The high LCSFA, n-6 PUFA, and TFA diet-induced impaired spatial learning and memory ability in donor mice was inherited in recipient mice by FMT. On the contrary, the high n-3 PUFA diet might be a protective factor of cognitive function. High LCSFA, MCSFA, n-6 PUFA, and TFA diets induced structural breakage and reduced nerve cells in hippocampal CA1 area in donor mice, which was also showed in corresponding groups (+ LCSFA, +MCSFA, +n-6 PUFA, and + TFA groups) of recipients. In addition, increased phylum Firmicutes, family Erysipelotrichaceae and genus Faecal-ibaculum, and decreased phylum Bacteroidetes, family Muribaculaceae and genus nor-ank_f__Muribaculaceae in gut microbiota of donor mice might be positively correlated with low cognitive performance in high-fat diet-induced obesity donor mice. In the same way, increased phylum Patescibacteria, family Rikenellaceae and genus alistipes, and decreased family Ruminococcaceae in recipient mice might be associated with cognitive impairment.

Our study has strong limitations by using mice as study subjects and the different sequencing depth may lead to unexpected results for microbiota analysis. The results in mice studies do not always extend into human studies and relevant population studies are very necessary. Thus, in-depth study of which bacteria in the intestinal flora play a role in the process of FMT causing similar phenotypes between recipient mice and donor mice should be the focus of future research. Besides, this study suggested that the therapeutic manipulation of the microbiome in humans should be deeply studied and utilized in neuropsychiatric diseases.

4.1. Animal characteristics

The Ethics Committee approved all experimental protocols on the use and care of laboratory animals of Capital Medicine University (Ethics Review No: AEEI-2018-061 & No: AEEI-2018-131). Donor mice, 8 week-old male C57BL/6 mice (Beijing, China, SCXK-(Jing) 2016-0006), were randomly divided into seven groups of 10 mice each according to weight. After 16 weeks of dietary intervention with diet containing different types of high fatty acids (Table 1). The dietary composition for donor mice was shown in supplementary Table 1. Feces of donor mice were collected with sterile material under specified pathogen-free (SPF) conditions for subsequent FMT. The fecal samples were stored at -80℃ immediately until use.

Table 1

Groups’ information of donor mice and corresponding recipient mice
Donor mice		Recipient mice
Group names	Fat type in diet	Group names	Treatment
		CON-0	physiological saline
		CON-1	+ antibiotic mixture + physiological saline
control (CON)	lard + soybean oil	+CON	+ antibiotic mixture + FMT from CON group
long-chain saturated fatty acid (LCSFA)	lard	+LCFSA	+ antibiotic mixture + FMT from LCSFA group
medium-chain saturated fatty acid (MCSFA)	coconut oil	+MCSFA	+ antibiotic mixture + FMT from MCSFA group
n-3 polyunsaturated fatty acid (n-3 PUFA)	flaxseed oil	+n-3 PUFA	+ antibiotic mixture + FMT from n-3 PUFA group
n-6 polyunsaturated fatty acid (n-6 PUFA)	soybean oil	+n-6 PUFA	+ antibiotic mixture + FMT from n-6 PUFA group
monounsaturated fatty acid (MUFA)	olive oil	+MUFA	+ antibiotic mixture + FMT from MUFA group
trans fatty acid (TFA)	lard + hydrogenated soybean oil	+TFA	+ antibiotic mixture + FMT from TFA group

3 weeks-old male C57BL/6 recipient mice (Beijing, China, SCXK-(Jing) 2016-0011) ac-climated for 2 weeks and then were randomly divided into nine groups with 10 mice. The group information and intervention methods in recipient group are also shown in Table 1. Except the CON-0 group drinking ordinary water, the mice in other eight groups were provided antibiotic mixture of metronidazole, ampicillin, neomycin sulfate (1g/L; ACMEC, Shanghai, China) and vancomycin (500mg/L; HEOWNS, Tianjin, China) in drinking water for 4 weeks according to existing reports [29–31]. Fecal samples were collected from 5-week-old and 9-week-old recipient mice separately. After the antibiotic treatment, recipient mice in the + CON, +LCSFA, +MCSFA, +n-3 PUFA, +n-6 PUFA, +MUFA, and + TFA groups were subjected to FMT with corresponding donor microbiota from the CON, LCSFA, MCSFA, n-3 PUFA, n-6 PUFA, MUFA, and TFA groups in donor mice, once per week for ten consecutive weeks. And two control groups (CON-0 and CON-1) in recipient mice were given equal volume of physiological saline. Fecal samples were collected from 19-week-old recipient mice again. All fecal samples collected in donor and recipient mice were analyzed with 16S rRNA gene sequencing.

All animals were housed in SPF Laboratory Animal Center with controlled laboratory conditions (controlled temperature, humidity and inverted 12-h light-dark cycle). All mice were had ad libitum access to feed and water, and weighed weekly. After the last fecal collection, behavioral tests were performed for the two batches of mice. The mice were anesthetized with 5% chloral hydrate followed by blood collection for detection of indices. The brain tissues were carefully removed, and the hippocampus was used for histological analysis. Experiment design is shown in Fig. 1.

4.2. Fecal microbiota transplantation (FMT)

The fecal pallets from seven groups of donor mice were collected on seven discontinuous days with sterile material. Fecal pallets were homogenized in glycerol extender (0.5 g/mL) containing 0.9 wt% NaCl, 0.5 ~ 2.0 wt% Vitamin C, 20 ~ 50 wt% glycerol, and sterile purified water, then stored at -80℃ for subsequent oral gavage. Fecal bacteria preservation solutions were resuspended in germ-free normal saline (4 mL/10 mL) and homogenized, following by centrifugation at 800× g for 3 min. Then the supernatant was collected and 200 µL was introduced orally to the antibiotic treated mice for 10 consecutive weeks. CON-0 and CON-1 groups were given normal saline as control during this period.

4.3. Behavioral testing

Novel object recognition test was conducted in four dimly lit 50 × 50 ×50 cm boxes in parallel, using heavy bright plastic cubes (2 × 2 × 2 cm), cones (2 cm diameter, 2 cm height), and spheres (2 cm diameter) as objects. The test consisted of an adaptive phase, a familiarity period and a test period. For the adaptive phase, the mice were placed into a box, faced to the wall and had 5 minutes to explore the open field to eliminate the stress and anxiety caused by unfamiliar environment. For the familiarity phase, two identical cubes were placed in the box with 10 cm from the wall, and mice had 10 min to explore them. After 24 h, one cube was replaced by one novel object (a cone or a sphere), and the mice were permitted to investigate them for 5 min [32].

Automatic tracking of mice was performed with Super Maze+ (Xinruan, China) software and the behaviors of each animal during the test was recorded; meanwhile, the time spent to explore objects by mice was calculated. Exploration time was measured as the nose close to the object within 2 cm, or contact the object with nose, mouth, or front paw. Climbing, sitting, or learning on top of the objects was not considered. A discrimination index (time spent on novel object – time spent on familiarizing object) / (total time to explore both objects) was calculated for each mouse [21].

4.4. Analysis of plasma indicators

The levels of glucose, triglyceride (TG) and total cholesterol (TC) in plasma were detected using oxidase method by an AU480 automatic biochemical analyzer (OLYMPUS, Japan). Low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) content in plasma were also analyzed using direct method on an AU480 automatic biochemical analyzer. All of the measurements were conducted according to the direction of reagent producer (Xiamen Intec PRODUCTS, INC). In addition, non-esterified fatty acids (NEFA) were assessed using enzyme method by C501 automatic biochemical analyzer (Cobas, Germany). All of the reagents used in this study were pur-chased from Beijing Strong Biotechnologies, INC.

4.5. Hematoxylin-eosin (HE) Staining

After the behavioral experiment, brain of donor and recipient mice were collected fol-lowing by fixation using 4% paraformaldehyde for histological analysis. The specimens were dehydrated and embedded in paraffin followed by staining in HE solutions as previously described [33], and then mounted with coverslips. Finally, the morphology and quantity of neurons, including neurons irregular shape, neurons arrangement, and neuronal death etc., in the hippocampal CA1 area were observed under 400× microscopes.

4.6. 16S rRNA sequencing

Fecal samples of mice from donors and recipients were collected with sterile materials. After defecation, feces were collected directly in a sterilized eppendorf tubes, frozen at -80℃ immediately. Then 16S rRNA gene sequencing were used to analyze the intestinal microbiota. Total DNA of bacteria was isolated using the E.Z.N.A. ® Soil DNA Kit (Omega BioTek, Norcross, GA, U.S.). DNA concentration and purification were determined using the NanoDrop 2000 UV-vis spectrophotometer (Thermo Scientific, Wilmington, USA), and the final DNA integrity was assessed by 1% agarose gel electrophoresis. V3-V4 hypervariable regions of bacterial 16S rRNA gene were amplified using polymerase chain reaction (PCR) with primers 338F (5’-ACTCCTACGGGAGGCAGCAG − 3’) and 806R (5’-GGACTACHVGGGTWTCTAAT-3’) (GeneAmp 9700, ABI, USA). The reaction conditions were 95°C for 3 min, with 27 cycles of 95°C for 30 s, 55°C for 30 s, 72°C for 40 s, and 72°C for 10 min. All reactions were conducted in triplicate, with a 20 µL mixture containing 4 µL of 5 × FastPfu Buffer, 2 µL of 2.5 mM dNTPs, 0.8 µL of each primer (5 µM), 0.4 µL of FastPfu Polymerase, and 10 ng of template DNA. PCR amplicons were confirmed by 2% agarose gels, purified with the AxyPrep DNA Gel Extraction Kit (Axygen Biosciences, Un-ion City, CA, USA), and quantified with QuantiFluor™-ST (Promega, USA). After purification, the amplicon was sequenced on an Illumina MiSeq platform (Illumina Inc., San Die-go, CA, USA). The raw reads were deposited into the National Center for Biotechnology Information (NCBI) Sequence Read Archive database (Sequence Read Archive accession: PRJNA714181 & PRJNA713515). The Operational Taxonomic Units (OTUs) were obtained by clustering the reads with 97% similarity by UPARSE (version 7.1 http://drive5.com/uparse/). Chimeric OTUs were screened and removed using UCHIME. RDP Classifier (http://rdp.cme.msu.edu/) was used to analyze the phylogenetic affiliation of each 16S rRNA gene sequence, which was based on the Silva (SSU132) 16S rRNA database with confidence threshold of 70%.

4.7. Statistical analyses

SPSS 23.0 software were to analyze data and the data were presented as mean ± standard error (SEM). The normality of the data was checked using Kolmogorov-Smirnov normality test. One-way ANOVA were used to compare data of different groups following by least significant difference (LSD) or Dunnett T3.

The relative proportions of dominant phyla and families in gut microbiota were compared using Kruskal-Wallis H test followed by Welch’s test among groups. The mothur software (version 13.0) and GraphPad Prism (version 6.0) were used to calculate and visualize alpha-diversity, including community diversity (Shannon and Simpson) and community richness (Chao 1 and Phylogenetic Diversity, PD) of the intestinal flora. For beta diversity analysis, principal coordinates analysis (PCoA) was used to assess the intestinal microbiota composition of different samples based on OTU level using the R package software [34]. The overall community difference was statistically analyzed and visualized by R stats and Python scipy package software. The statistical two-sided significance level was 0.05.

All data generated or analyzed during this study are included in this published article.

Author Contributions

W.M. conceived and designed the study; Y.H. and R.F. carried out major experiments; Y.H. and J.S. performed the statistical analyses; C.Z. and R.F. collected the data; Y.H. and C.Z. wrote the manuscript. S.B. revised the language of the manuscript. W.M. and R.X. interpreted the data and revised the manuscript. All authors have read and approved the final manuscript.

Competing interests

The authors declare no conflict of interest.

Funding

The work was supported by the grants from the National Natural Science Foundation of China (grant NO. 81773406).

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Altered intestinal microbiota in mice consuming high-fat diets influence cognitive function

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Abstract

Figures

1. Introduction

2. Results

2.1. Body weight and plasma parameters

2.2. Novel object recognition

2.3. Pathological changes of hippocampal CA1 area

2.4. Alpha and beta diversity of gut microbiota

2.5. Composition of the intestinal microbiota

3. Discussion

4. Research Design And Methods

4.1. Animal characteristics

4.2. Fecal microbiota transplantation (FMT)

4.3. Behavioral testing

4.4. Analysis of plasma indicators

4.5. Hematoxylin-eosin (HE) Staining

4.6. 16S rRNA sequencing

4.7. Statistical analyses

5. Data Availability

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References

Additional Declarations

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