**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 gu<sup>t</sup> microbiota [9]. The gu<sup>t</sup> 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 gu<sup>t</sup> microbiota that occurs via three different pathways: neural, endocrine and immune [13]. It is worth mentioning

**Citation:** Cardona, D.; Roman, P.; Cañadas, F.; Sánchez-Labraca, N. The Effect of Multiprobiotics on Memory and Attention in Fibromyalgia: A Pilot Randomized Controlled Trial. *Int. J. Environ. Res. Public Health* **2021**, *18*, 3543. https://doi.org/10.3390/ ijerph18073543

Academic Editor: María José Benito

Received: 22 February 2021 Accepted: 23 March 2021 Published: 29 March 2021

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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 gu<sup>t</sup> 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 gu<sup>t</sup> 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 gu<sup>t</sup> 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 gu<sup>t</sup> microbiota could be involved in FMS, so modulating the gu<sup>t</sup> 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 gu<sup>t</sup> microbiota in central nervous system functions, we expect that oral intake of probiotics will have beneficial effects on memory and attention in FM.

#### **2. Materials and Methods**

#### *2.1. Study Design and Participants*

This study is part of a large, double-blinded study and a parallel group design that was registered with ClinicalTrial.gov (NCT02642289) and approved by the Human Research Ethics Committee of the University of Almeria (Spain). The study protocol and recruitment procedure have been previously described [30]. Fibromyalgia patients were recruited from the Almeria Fibromyalgia Association (AFIAL—Spain) or from El Ejido Fibromyalgia Association (AFIEL—Spain) and were diagnosed at least 1 year before entering the study according to the criteria of the American College of Rheumatology [1,32]. Exclusion criteria involved: (1) use of antibiotics and nutritional supplements, (2) allergies, (3) current participation in other psychological or medical studies, (4) being pregnan<sup>t</sup> or breastfeeding, (5) severe intestinal disease and (6) meeting the criteria for psychiatric disorders other than depression and/or anxiety. More information about the participants' characteristics can be found in the first part of the study [31].
