1. Introduction
Fibromyalgia syndrome (FMS) is a chronic, generalized and diffuse pain disorder accompanied by symptoms such as morning stiffness, fatigue, depression and sleeping disorders [
1]. Another prevalent complaint is cognitive deficits such as forgetfulness, concentration difficulties, loss of vocabulary and mental slowness, among others [
2,
3]. Some previous research found that FMS patients show poor performance in some executive functions [
4], such as concentration, working memory deficits [
5] and reduced ability to inhibit irrelevant information [
6], as well as low cognitive flexibility and poor decision-making [
4]. Likewise, in these patients, there is also less brain activation in the cortical structures of the inhibition network (specifically in the areas involved in response selection/motor preparation) and the attention network [
7].
Recently, FMS has been associated with altered intestinal microbiota [
8], as well as with chronic widespread musculoskeletal pain, a symptom of FMS which has shown reduced diversity in the microbiome, particularly of
Coproccocus, indicating the involvement of the gut microbiota [
9]. The gut microbiota plays an important role in different physiological functions, exerting effects from energy metabolism to psychiatric well-being [
10]. Research has documented lower levels of
Bifidobacterium and higher levels of
Enterococcus spp. in these patients [
11]. Furthermore, it has been stated that the higher the aerobic enterococcal count, the worse the neurological and cognitive deficits, such as nervousness, memory loss, forgetfulness and confusion [
12]. This is related to the gut–brain axis pathway, which is a bidirectional communication network between the brain and the gut microbiota that occurs via three different pathways: neural, endocrine and immune [
13]. It is worth mentioning that neural communication takes place through the vagus nerve and the enteric nervous system (ENS), while endocrine communication occurs via the production of hormones such as cortisol, and immune system communication takes place via the modulation of cytokines [
14,
15]. In this context, bacterial products activate the ENS [
16] and stimulate primary afferent nerves, as well as bacterial metabolites that cause behavioral changes [
17]. For these reasons, the gut–brain axis, which allows gut bacteria to affect the central nervous system (for example, with probiotic administration), has been used as a treatment option for a variety of health and mental disorders [
18].
Probiotics are defined as live microorganisms which, when administered in adequate amounts, confer a health benefit on the host [
19]. Probiotics have been shown to specifically catalyze oligosaccharides, increasing short-chain fatty acid (SCFA) production [
20]. SCFAs are metabolic byproducts of the anaerobic fermentation of dietary carbohydrates and some amino acids, and they play a variety of roles in health maintenance, not only in the intestine as an energy source that improves transit, but also in the immune system [
21]. Fibromyalgia (FM) patients have an altered composition of SCFAs, and
Parabacteroides merdae increases neurotransmitters in FMS patients, which could explain the cognitive dysfunction [
22].
In fact, FMS and irritable bowel syndrome (IBS) are common co-occurring disorders [
23] for which modulation of the gut microbiota is a treatment strategy [
24]. Moreover, FMS is frequently associated with other immuno-rheumatic diseases, such as chronic fatigue syndrome [
25], which appears to improve after probiotics administration [
26], or rheumatoid arthritis, in which probiotics also improve symptoms [
27]. However, even though the gut microbiota may play a role in FMS, according to a recent systematic review, the data are insufficient [
28], and more research is required to obtain conclusive answers in relation to the effectiveness of dietary interventions [
29].
According to all of the above, changes in gut microbiota could be involved in FMS, so modulating the gut microbiota is a therapeutic treatment that needs to be explored. Therefore, we carried out a pilot study on the effect of multispecies probiotics on the cognitive and emotional symptoms of FMS [
30]. In the first part of this study, we showed the beneficial effects of probiotics on impulsivity [
31]. In this context, the current study aims to continue exploring the role of probiotics in cognitive processes in patients with FMS, specifically the effects of a multispecies probiotic on attention and memory function in FMS patients. Given the role of gut microbiota in central nervous system functions, we expect that oral intake of probiotics will have beneficial effects on memory and attention in FM.
4. Discussion
The purpose of the present study was to continue exploring the beneficial effects of treatment with a multispecies probiotic in patients diagnosed with FMS. For this, a group of patients with a mean time of 8 and a half years since diagnosis and a mean age of 52 years were treated for 8 weeks with a multispecies probiotic or with a placebo substance and evaluated immediately for its effects on attention and memory.
To our knowledge, the only study evaluating the role of probiotics in cognition in FMS patients is our previous study, which showed a reduction in impulsivity after treatment [
31]. In the current research, we found no significant differences in memory after treatment. Although no other studies have used probiotics to improve memory in FMS, a recent systematic review and meta-analysis of preclinical and clinical studies indicates that probiotics could be a useful strategy to improve dementia and cognitive decline [
35] in both healthy [
36] and elderly populations [
40]. Similarly, a probiotic-treated Alzheimer’s experimental model demonstrated an improvement in learning [
41] and memory [
42]. In clinical studies of elderly people with mild cognitive impairment, an improvement in cognitive function (memory and attention) and an increase in brain-derived neurotrophic factor (BDNF) were reported after treatment with
Lactobacillus plantarum C29-fermented soybean (DW2009) for 12 weeks [
43]. Similar data were collected after the administration of
Bifidobacterium A1 for 12 weeks in older adults with memory deficits, although the data are not conclusive and further research is required in this regard [
44]. According to these studies, one possible explanation for the lack of positive results in our study could be the short length of treatment; studies demonstrating memory benefits were of significantly longer duration.
Regarding the attentional tasks, no differences in the Stroop effect or the negative priming effect (Stroop Task with Negative Priming) were observed among the participants after the treatment, implying that the probiotic treatment used did not affect the inhibitory mechanisms of attention. However, patients with FMS treated with the probiotic showed a tendency towards reduced errors of omission (Go trials) during the Go/No-Go Task and the group that received the placebo presented a number of errors that was slightly higher than those registered in the pre-treatment phase. This type of error occurs when there is an absence of response to a relevant stimulus, and it is assumed that it reflects symptoms of inattention [
45]. Therefore, FMS patients treated and not treated with the probiotic showed similar levels of inhibitory motor control and similar ability to inhibit information irrelevant to the task objective, but they differed in their ability to maintain attention for an extended period with the objective of responding to specific stimuli. This difference could be attributed to the effect that probiotics produced in these patients, which improved their ability to maintain attention, as evidenced by the results obtained in the Go/No-Go Task in the post-treatment phase.
Despite studies finding that the effects of probiotics on attention are reduced, similar results have been observed in other populations. In this regard, after 8 weeks of treatment with
Lactobacillus plantarum 299v, patients with major depression showed an improvement in attention and work speed on the attention and perceptivity test, but no significant effects on the Stroop test [
46]. Similarly,
Lactobacillus plantarum DR7 treatment for 12 weeks improved basic attention and memory in healthy adults, as measured by the computerized CogState Brief Battery [
47].
A recent systematic review and meta-analysis showed a positive effect of probiotics on cognition in both humans and animals [
48]. Human studies showed an improvement in attention and memory in patients with Alzheimer’s, in the healthy elderly individuals or those with depression. The only FMS study included in this analysis was the first part of our current research [
31]. Most included studies used
Lactobacillus and
Bifidobacterium probiotic strains, but it is worth noting that the meta-analysis found that using just one probiotic was more effective than using a combination. In the same manner, the 12-week treatment was more effective than the 8-week treatment, implying that our findings on FM cognition could be significant after additional weeks of treatment.
The putative mechanisms of action of probiotics in cognitive function, as suggested by Lv and collaborators [
48], are related to neuroinflammation. In this regard, the decline in cognitive function associated with aging is related to changes in brain immunoregulation, including decreases in IL-4 [
49]. Several studies suggest a decrease in the diversity of microbiota with cognition and inflammatory markers [
50], in which changes in the intestinal metagenome appear to be associated with cognitive function and brain iron deposition [
51]. In this context, factors associated with aging, such as oxidative stress and inflammation, are related to the intestinal microbiota [
52], which influences the different sequences of cognitive impairment [
53], and probiotic treatment could reverse this cognitive impairment via cytokine systems.
Interestingly, elevations of proinflammatory chemokines/cytokines could negatively impact symptoms of FMS. Proinflammatory cytokines have been shown to have an important modulatory role in pain transmission and perception. It is not surprising that high levels of them have been found, specifically of interleukins 1, 2, 6 and 8, in patients with FMS [
54]. Therefore, probiotic administration could be an effective approach to treat cognitive deficits in FMS, as can be seen in our results. In other words, a multispecies probiotic treatment can improve some cognitive functions in FMS patients, such as impulse control, sustained attention and the ability to maintain attentional control in a context of change. The clinical relevance of microbiota modulation in FMS patients should be considered as an adjuvant treatment.
However, these results must be taken with caution, given that this study had several limitations. First of all, we had a limited number of subjects, since this was a pilot randomized controlled trial. Secondly, the nutritional habits of the participants should have been registered because they could influence or interfere with the results—for example, the effect of the consumption of other fermented foods. Finally, measuring the gut microbiota would have given us more information about probiotic modulation. In this manner, future studies should be designed with a large sample size while keeping these limitations in mind.