3.2.1. Firmicutes
Most changes in microbial taxa were found on the level of and within the Firmicutes phylum. Six studies [
38,
55,
56,
57,
58,
59] reported a change at the phylum level, which significantly correlated with changes in the immunohistological markers of neurogenesis (
Table 3). In agreement with data pinpointing the bacterial effects on neurogenesis, results regarding BDNF levels were affirmative to neurogenesis with more than twice as many negative correlations as positive ones (
Table 4).
As already thematized in the germ-free chapter, data regarding a high-fat diet was also found in relation to the Firmicutes phylum. Ribeiro et al. [
57] and Ma et al. [
38] conducted experiments with mice fed a high-fat diet for 24 weeks. Both studies reported hippocampal neurogenesis to be reduced but found opposing results regarding the abundance of the Firmicutes phylum. High-fat diet-induced obesity has been associated with cognitive impairment and decreased neurogenesis in multiple neurogenic niches of the brain [
64,
65]. Further research has shown that offspring from obese dams had lower hippocampal DCX density [
66]. As for the Firmicutes phylum, an increase in bacterial abundance was related to obesity, partly explainable through the many SCFA-producing species belonging to this phylum which may contribute to increased energy needs and lipogenesis in the liver of obese animals [
67]. Although Ribeiro et al. did not see the increase in Firmicutes phylum, they detected higher levels of propionate metabolites in the liver of high-fat diet-fed mice. They further discovered how SCFAs induce depletion of adult neurogenic niches through the mitochondrial by-product, reactive oxygen species (ROS), adding new understanding to the regulation of neurogenesis through the gut microbiota [
57].
Major depressive disorder is a key modulator of adult neurogenesis and BDNF levels [
10,
11]. Three reports [
47,
59,
68] studied the effect of unpredictable chronic mild stress (a model of stress-induced depression) on the gut microbiota and neurogenesis or BDNF. DCX+ cells and Firmicutes abundance were reported to be reduced in one study [
59], while the other two studies found reduced BDNF levels parallel to increased Firmicutes abundance [
47,
68]. Several systematic reviews concluded that there is no consensus in the abundance of Firmicutes phylum in models of depression supporting the irregularities seen in our results [
69,
70,
71].
As reported before, adverse events during early life can result in morbidities later in life. Two studies [
58,
72] reported the effects of disrupted microbiota through gastrointestinal infection. Hennessey et al. [
58] studied infection of neonatal mice with enteropathogenic
Escherichia coli, discovering reduced Firmicutes phylum to benefit DCX+ cells and BDNF. Furthermore, Jang et al. caused gastrointestinal inflammation and disruption of the microbiota through 2,4,6-trinitrobenzene sulfonic acid (TNBS, known to cause immunogenic reactions) in adolescent mice. They found reduced Firmicutes parallel to reduced BDNF levels. Here, for the first time, the evidence is presented that not only in early life but also during adolescence, the microbiota converses with the brain. Flemer et al. [
73] studied the variation of the microbiota in healthy laboratory rats over their lifespan. They discovered that after birth, the Firmicutes phylum is rather low and peaks during adolescence. Of the studies discussing the effects of early life infections, in the study by Jang et al. [
72], Firmicutes were low during this critical window, possibly explaining the reduction of BDNF mRNA.
Five studies [
55,
74,
75,
76,
77] explored how the oral administration of antibiotics at different ages and for different time periods affected neurogenesis and Firmicutes abundance. Keogh et al. [
55] and Kayyal et al. [
77] investigated how short-term neonatal antibiotic treatment would shape the microbiome and impact the microbiota-gut-brain axis. Compared to controls, the treated mice showed higher Firmicutes abundance parallel to lowered neurogenesis [
55] and BDNF [
55,
77] in both studies. Desbonnet et al. [
74] explored the effects of antibiotic treatment in adolescent mice for 7 weeks and found BDNF and Firmicutes to be reduced, contradicting the first two studies. Another study [
76] treating adolescent mice for only 2 weeks found the same results as Desbonnet et al. The last study [
75] administered antibiotics to adult animals for 13 weeks to investigate the effects of chronic treatment. This study reported a lower abundance of Firmicutes phylum to be beneficial for BDNF levels supporting the negative correlation reported by Keogh et al. [
55] and Kayyal et al. [
77]. These studies suggest that taxonomic change affects the brain, dependent on age. Previous research has shown that the Firmicutes phylum peaks during the crucial period of adolescence and reduces with advancing age [
73,
78]. In the studies reviewed, the bacterial abundance of the Firmicutes phylum did not follow the timely pattern of a healthy rodent microbiota. In the postnatal period, a high abundance was found, whilst during adolescence, Firmicutes were reduced. Two studies sequenced the microbiota of elderly mice, but only Kundu et al. [
60] found the Firmicutes phylum to be decreased. Unexpectedly, neurogenesis and BDNF mRNA were increased in these elderly mice, although both are known to decline with age, pinpointing a possible technical error as the explanation for this discrepancy. Although the other study [
79] saw a decline in BDNF levels, the Firmicutes phylum was increased.
Table 4.
Firmicutes and BDNF.
Table 4.
Firmicutes and BDNF.
Taxa | BDNF | Reference |
---|
Firmicutes | 4 | 9 | 2 | [47,55,58,60,68,72,74,75,76,77,79,80,81,82,83] |
Bacillaceae | | 1 | | [55] |
Caldicoprobacteraceae | | | 1 | [84] |
Caldicoprobacter | | | 1 | [84] |
Clostridiaceae | | 1 | | [55] |
Candidatus Arthromitus | | | 2 | [82] |
Clostridium | | 1 | 1 | [82,85] |
Clostridiales vadin BB60 | 1 | | | [55] |
Coprobacillus | | | 1 | [82] |
Dehalobacterium | | | 1 | [82] |
Enterococcaceae | | 1 | | [55] |
Enterococcus | | 1 | 1 | [86] |
Erysipelotrichaceae | | 2 | | [55,81] |
Allobaculum | | 3 | 1 | [68,79,81,84] |
Eubacteriales Family XIII | 1 | | | [55] |
Lachnospiraceae | 2 | 4 | 1 | [55,58,72,75,76,83,87] |
Anerostipes | | 1 | | [85] |
Blautia | | 1 | 1 | [82,85] |
Eubacterium, r = rectale | | 1 (r) | | [47] |
Lachnobacterium | 2 | | | [68,76] |
Lachnospira | 1 | | | [76] |
Lachnospiraceae unspec. | 1 | 1 | 2 | [43,60,86] |
Roseburia | 1 | | 1 | [76,84] |
Lactobacillaceae | 2 | | | [55,58] |
Lactiplantibacillus, p = plantarum | 1 (p) | | | [88] |
Lactobacillus, b = brevis, h = helveticus, i = intestinalis, j = johnsonii, r = rhamnosus | 10 (+b, h, I, j, r) | 3 (+j) | 2 | [60,68,72,79,80,81,82,86,88] |
Mogibacteriaceae | | | 1 | [82] |
Paenibacillaceae | | 1 | | [55] |
Peptococcocus | | | 1 | [84] |
Peptostreptococcaceae | | | 1 | [82] |
Ruminococcaceae/Oscillospiraceae | 2 | 2 | 1 | [55,58,75,76,83] |
Eubacterium | | 1 | | [76] |
Oscillospira | 1 | | | [76] |
Ruminococcus | | | 2 | [82,83] |
Ruminococcaceae unspec. | 1 | | 1 | [86] |
Staphylococcus | | | 1 | [84] |
Streptococcus | | | 1 | [82] |
Within the order Bacillales, an increase in the abundance of family Bacillaceae [
55,
61] and family Paenibacillaceae [
55] was consistently associated with lower neurogenesis and BDNF levels. Dunphy-Doherty et al. found the same association between the genus
Bacillus and neurogenesis [
61]. Well-studied members of the
Bacillus genus,
B. anthracis,
B. cereus, and
B. thuringiensis, are known for their pathogenic characteristics, like the synthesis of anthrax and food poisoning agents [
89]. In children with celiac disease, a higher abundance of the family, Bacillaceae, was found in patients suffering from abdominal pain and diarrhea [
90]. Altogether, these findings underline the association of Bacillaceae and
Bacillus with poor health and could explain, at least partially, why neurogenesis and BDNF were negatively affected.
Within the order of Eubacteriales, the family Peptostreptococcaceae exhibited a positive correlation with neurogenesis in one study [
58]. Family Clostridiaceae was found to negatively correlate with the extent of neurogenesis [
55,
57] or BDNF levels [
55] in all but one study [
61]. Additionally, an unspecified genus of the family Defluviitaleaeceae [
61] and genus
Eubacterium [
61], both belonging to the order of Eubacteriales as well as genus
Clostridium [
85] and an unspecified genus of family Clostridiaceae [
57] supported the negative association in three studies. Although there was an overall negative correlation found at the family and genus level and the family of Clostridiaceae contains pathogenic members like
C. perfringens or
C. difficile, it is important to mention that the naturally residing Clostridia plays a beneficial role in maintaining normal gut homeostasis through modulation of metabolic and immune processes [
91]. Furthermore, studies have shown that the probiotic
Clostridium butyricum features neuroprotective properties and can increase hippocampal BDNF expression [
92,
93]. Since the family of Clostridiaceae is quite large, analysis of taxonomy at higher resolution could have possibly determined whether the microbiota contained harmful species, explaining the negative findings.
As for Enterococcaceae, the family Enterococcaceae [
55] or genus
Enterococcus [
86] was associated with low BDNF mRNA levels in the hippocampus in two studies. Congruent to these findings, fecal microbiota transplant from IBD patients with depressive disorder contained a higher abundance of family Enterococcaceae and caused a decrease of hippocampal BDNF in transplanted mice [
94]. While at the phylum level, a concise opinion on the abundance of Firmicutes phylum could not be formed, analysis at higher resolution in the case of Enterococcaceae suggests a detrimental effect on BDNF levels in the hippocampus.
Within the order of Erysipelotrichales, some studies reported lower neurogenesis and BDNF levels with an increase in family Erysipelotrichaceae [
55,
81] or genus
Allobaculum [
68,
79,
81] and family Turicibacteriaceae or genus
Turicibacter [
57]. In the study by Ribeiro et al. [
57], Turicibacteriaceae and
Turicibacter positively correlated to neurogenesis after a longer course of the high-fat diet. No studies were found explaining why these taxa of order Erysipelotrichales, especially Erysipelotrichaceae and
Allobaculum had a negative effect on the hippocampus.
The most abundant family in the murine cecum is Lachnospiraceae [
95]. At the family level, studies found a negative correlation between Lachnospiraceae and neurogenesis [
55,
58]. For BDNF, family-level studies did not show conclusive results, with Lachnospiraceae being altered in both directions (
Table 4). However, there were several positive correlations at the genus level. Gao et al. [
68] and Guida et al. [
76] found the diminishment of the genus
Lachnobacterium to be unfavorable regarding BDNF levels. These authors further found that the decrease of genus
Lachnospira and genus
Roseburia led to the same outcome. Only one study found negative correlations with elevated genus
Anaerostipes and genus
Blautia parallel to lower levels of BDNF [
85]. The family of Lachnospiraceae, especially
Roseburia, belongs to the group of strong butyrate producers, which, as previously shown, could have a beneficial effect on neurogenesis [
96]. Genus
Lachnospira, which can also produce butyrate [
97], has been associated with higher levels of BDNF [
98]. Therefore, multiple genera of the family Lachnospiraceae interact positively with the hippocampus, probably through the production of SCFAs. At the same time, there must be other members of the family hindering cell proliferation or expression of BDNF mRNA, resulting in the bidirectional results found at the family level.
There was a consistent positive correlation between neurogenesis as well as BDNF and bacterial abundance for the family Lactobacillaceae, best known as a probiotic family (
Table 3 and
Table 4). Only one study reported otherwise with an increase in DCX+ cells parallel to less abundance of species
Lactobacillus johnsonii [
60]. As for BDNF, three studies found the genus
Lactobacillus [
68,
79] or species
Lactobacillus johnsonii [
60] to lower BDNF production. Multiple studies have researched the benefits of probiotic
Lactobacillus subspecies for neurogenesis and BDNF in healthy and depressed mouse models [
63,
99,
100]. Some of the discovered pathways of interaction where the induction of nerve growth factor [
99], an increase of hippocampal endocannabinoids [
63], and modulation of neuroinflammatory pathways [
101].
On the family level, results regarding the Ruminococcaceae family were controversial since almost the same number of studies reported positive resp. negative correlations for neurogenesis [
55,
58,
63] and BDNF [
55,
58,
75,
76]. At the genus level, though, results showed exclusively positive correlations for the genus
Oscillospira [
61,
76], genus
Eubacterium [
76], genus
Ruminococcus [
37,
57], and unspecified Ruminococcaceae genus [
57,
86]. An in vitro study by Park et al. found the probiotic species
Ruminococcus albus to have neuroprotective properties on oxidatively stressed SH-SY5Y cells (human-derived neuroblastoma cells) by increasing the expression of BDNF. The genus
Oscillospira has the potential to be used as a probiotic since it is strongly associated with leanness and lower BMI, which consequently is associated with adult neurogenesis. Additionally,
Oscillospira possesses the capability of producing SCFAs, predominantly butyrate [
102]. The studies reporting negative correlations between the Ruminococcaceae family and neurogenesis or BDNF mRNA had different experimental designs, such as neonatal infection [
58], chronic exposure to stress [
63], and long-term antibiotic treatment [
75]. How these methods interact specifically with Ruminococcaceae and result in negative correlations is unclear since, at the genus level, only positive effects could mechanistically be explained so far.
3.2.2. Bacteroidetes
Like the Firmicutes phylum, studies reported both an increase and decrease in the Bacteroidetes phylum (
Table 5 and
Table 6). Interestingly, studies showing a change of Firmicutes phylum in one direction reported a change of Bacteroidetes towards the opposite direction, indicating a possible compensatory mechanism between the two phyla. Five studies reported a taxonomic change at the phylum level, of which only three correlated the bacterial abundances with changes in neurogenesis (
Table 5). As for BDNF, data varied in both directions, with the positive correlation group only being composed of decreased phylum parallel to decreased BDNF levels. However, six out of 10 studies reported a negative correlation at the phylum level (
Table 6).
Hence, results regarding neurogenesis tended towards a positive correlation with the Bacteroidetes phylum (
Table 5). On the contrary, results regarding BDNF clearly showed a negative correlation (
Table 6).
There were three studies studying neurogenesis and change of Bacteroidetes phylum [
38,
55,
57]. Interestingly the two studies experimenting with high-fat diets found opposing results, with Ribeiro et al. [
57] stating a decrease of Bacteroidetes phylum to be favorable for neurogenesis, whilst Ma et al. [
38] found a decrease at the phylum level to reduce cell proliferation. Bacteroidetes are known to be reduced in obese mice and have been associated with weight loss in humans [
103]. In a previous study, obesity led to impaired neurogenesis because of the accumulation of senescent cells in the subventricular zone [
64]; how a whole phylum associates with these findings remains unclear. One could argue that in obese animals, Bacteroidetes are reduced in relation to Firmicutes as a compensatory mechanism since increased Firmicutes abundance has been clearly associated with obesity.
Multiple studies found an increase of Bacteroidetes disadvantageous and a decrease in beneficial BDNF levels (
Table 6). Only three of a total of nine studies found a positive correlation between the two. Two of the three studies [
55,
74] had in common that in studying postnatal exposure to antibiotics, both found reduced BDNF parallel to lower bacterial abundance. In the negative correlation group, all three studies exposed adult animals to antibiotics [
75,
76,
88]. After birth, the gut microbiota of healthy laboratory rats compromises to a large part of Bacteroidetes that reduces at adolescence [
73]. The loss of Bacteroidetes in the postnatal antibiotic exposure group could be responsible for the measured dip in BDNF mRNA levels. Also, Bacteroidetes correlated negatively with BDNF in the adult group showing that this phylum has an impact on hippocampal homeostasis early in life.
All studies focusing on the phylum of Bacteroidetes reported bacterial taxa belonging to the order of Bacteroidales. Genus
Parabacteroides [
57], genus
Barnesiella and genus
Odoribacter [
85] were each reported in a single study to have a positive correlation with neurogenesis and BDNF levels. These data are awaiting confirmation by independent research groups. For four out of the five families discussed, we could not find a definite allocation to one correlation group. Unclear results were reported for the family Bacteroidaceae and genus Bacteroides, family Bacteroidales S24-7, family Prevotellaceae, and genus Prevotella and family Rikenellacceae. Differences and discrepancies between the studies are mentioned in the paragraphs following.
The correlation of the Bacteroidaceae family as well as genus
Bacteroides altered in both directions, with each correlation group having almost as many studies for neurogenesis as for BDNF (
Table 5 and
Table 6). While Kundu et al. [
60] and Li et al. [
79], who both studied age-related shifts in microbiota and its effect on cognition, found an increase of an unspecified species of
Bacteroides genus to promote neurogenesis and to heighten BDNF levels, three other studies [
47,
87,
88] found an inverse correlation between
Bacteroides genus and BDNF. In general, genus
Bacteroides contributes to the resistance against the colonization of enteric pathogens such as
Campylobacter ssp. Or
Salmonella ssp., which can produce SCFAs (propionic acid) and cross-feeds other gut residents, which as a result, produce more SCFAs like butyrate [
104]. Taken together, even though
Bacteroides are beneficial for gut homeostasis, the family Bacteroidaceae and genus
Bacteroides tended to reduce BDNF mRNA in the adult hippocampus.
As for family Bacteroidales S24-7 and genera of this family, Ribeiro et al. found that after 24 weeks of the high-fat diet, bacterial abundance and neurogenesis were low; at 14 weeks of the high-fat diet, bacterial abundance was low, but on the contrary, neurogenesis was elevated. Regarding BDNF, postnatal short-term antibiotics treatment reduced Bacteroidales S24-7 and hindered BDNF production [
55], while chronic treatment with antibiotics for 13 weeks reduced Bacteroidales S24-7 as well but led to better BDNF production [
75]. Experimental designs for this family were very heterogeneous, and clear explanations for these results could not be identified.
The available studies regarding the family Porphyromonadaceae tended towards a negative correlation with neurogenesis and BDNF levels [
57,
63,
75]. Porphyromonadaceae strongly associates with reduced visceral adipose tissue [
105,
106,
107], and the family is linked to SCFA production (propionate) [
108,
109]. The route of this apparent discrepancy is unknown since propionate-producing bacteria of the Firmicutes phylum have been associated with obesity and reduced adult neurogenesis. As a consequence, Porphyromonadaceae should have shown a positive correlation to BDNF.
At the family level of Prevotellaceae, there was a tendency towards a negative correlation between the family and BDNF levels (
Table 6). There was no data found regarding neurogenesis and the family Prevotellaceae. Genus
Prevotella and an unspecified genus of the Prevotellaceae family both showed a negative correlation in all but two mentioned studies. Less abundance of genus
Alloprevotella positively correlated with reduced BDNF. What is known is that genus
Prevotella and
Alloprevotella belong to the SCFA-producing (acetate and propionate) bacteria and, therefore, should not, at least at the genus level, lead to impaired neurogenesis or BDNF mRNA in the hippocampus [
31].
For and within the family of Rikenellaceae, results were conflicting because studies regarding neurogenesis tended towards a negative correlation, and studies regarding BDNF levels found a positive correlation with bacterial abundance (
Table 5 and
Table 6). There were two studies [
58,
72] investigating the impact of intestinal inflammation on the microbiome and alterations in the brain. Interestingly, they found opposing results regarding Rikenellaceae abundance. A major difference between these studies was the age at which experiments were carried out. The study identifying a positive correlation observed the results in adolescent mice, while the negative correlation between Rikenellaceae and neurogenesis was seen in neonatal mice. This finding is conflicting with the higher taxonomic rank, the phylum level since Bacteroidetes are more abundant after birth and subside with age [
73]. With three out of four studies, genus
Alistipes tended towards positive correlation. Previous research regarding the family Rikenellaceae and genus
Alistipes is just as contrasting as the results found in the studies reviewed. Especially genus
Alistipes has been found to parallel inflammation and depression in humans but may as well have protective effects against liver fibrosis, colitis, and cardiovascular disease [
110].
3.2.3. Proteobacteria
Phylum Proteobacteria was reported to have a negative correlation with neurogenesis and BDNF in multiple studies, but few studies also reported the opposite (
Table 7 and
Table 8). Furthermore, all studies reporting a negative correlation between phylum and neurogenesis or BDNF found an elevation of Proteobacteria to be damaging [
55,
57,
72,
74,
76].
Studies experimenting with antibiotic treatment clustered differentially. Other than mentioned before, not age but the time span of antibiotic treatment was the distinctive factor, and independent of the exposure duration, Proteobacteria abundance was increased in all four studies. Hoban et al. [
75] treating mice with antibiotics for 13 weeks showed opposite results (positive correlation), especially for BDNF, to the studies giving antibiotics for a short period of time [
55,
74,
76]. A reason for why there was a positive correlation between BDNF and Proteobacteria after chronic treatment with antibiotics was not found. All studies used a combination of antibiotics which are poorly absorbed systemically and, therefore, should not have a direct effect on brain physiology [
49]. Previous research found ampicillin exposure to suppress BDNF expression and cause neuroinflammation in the hippocampus by a Proteobacteria-dominant dysbiosis in mice [
111]. However, ampicillin has also been proven not to cross the blood–brain barrier indicating the changes in the hippocampus to be directly Proteobacteria-related [
49]. These findings show that, in antibiotic-induced dysbiosis, the abundance of Proteobacteria is increased. In addition, they suggest that, dependent on the duration of antibiotic treatment, the changes in bacterial abundances cause changes in the hippocampus. It seems plausible to assume that the longer the antibiotic therapy, the more likely it is that neurogenesis or BDNF mRNA is reduced. However, in the studies reviewed, we found even short-term treatment with antibiotics to lead to a negative correlation with BDNF.
At a higher-resolution taxonomic rank in the order of Burkholderiales, the families and genera exhibited varying associations with neurogenesis and BDNF expression. The order of Burkholderiales contains the four important families of Alcaligenaceae, Burkholderiaceae, Oxalobacteraceae, and Sutterellaceae.
At the family level, Oxalobacteraceae [
68] correlated negatively with BDNF levels, while the family Alcaligenaceae [
55] correlated positively with neurogenesis and BDNF in single studies.
Genus
Parasutterella and genus
Cupriavidus, partly specified as
Cupriavidus metallidurans and an unspecified species of order Burkholderiales, showed a positive correlation [
60] for neurogenesis and BDNF levels. However, Gao et al. [
68] stated the opposite at the genus level. Comparisons between these three studies are difficult because of the different study designs. The study designs differed in mice age and experimental methods, with one study evaluating the effects of antibiotic treatment and the other studying the impact of chronic stress on BDNF expression.
Not belonging to the order Burkholderiales is the family Enterobacteriaceae. The family and its higher taxonomic resolution had a consistent negative correlation with neurogenesis and BDNF levels in all reviewed studies. The reduction of the genus
Klebsiella and genus
Shigella [
88] led to an increase, and the increase of the species
Escherichia coli [
72] led to a decrease in BDNF levels. The members of the Enterobacteriaceae family are well known for causing various syndromes and diseases, such as foodborne diarrhea, enteritis, colitis, hemolytic-uremic syndrome, and extraintestinal diseases [
112]. A confirmation of this negative correlation was presented in a study in which increased
Shigella positively correlated with increased microglia activation (a marker of neuroinflammation) and decreased hippocampal neurogenesis in offspring from obese dams [
66].