The present study firstly investigated whether migraine-related cephalic allodynia could induce microbial composition alteration in a rat model. Our results showed that repeated dural IS infusions induced cephalic allodynia, nociception-related behaviors and microbiota community alterations in rats, which could be ameliorated by preconditioning with topiramate. The biomarker genera and the indicator metabolites were also detected in the altered microbiota profile and microbial metabolism.

Migraine is a condition characterized by a moderate to severe throbbing headache, reduction of routine physical activity and lack of movement. Previous studies have shown that activation of the trigeminovascular system and neurogenic inflammation play pivotal roles in the pathophysiology of migraine [2]. Infusing IS to the dura mater could induce meningeal nociception and activate the trigeminovascular pathway, mimicking onset of headache in migraine [19]. Melo-Carrillo et al. reported decreased exploratory activity and increased resting behavior in IS-induced migraine rats [29]. Consistent with this study, we found that rats in the IS group presented more immobility and less movement, similar to the avoidance of routine activity in migraineurs during attacks [30]. In clinical trials, topiramate has been proved effective for migraine prevention [22]. Also, topiramate can attenuate both acute and chronic hyperalgesia in an NTG-induced migraine model [31]. Our results showed that rats treated with topiramate showed significant reductions in the IS-induced allodynia and nociception-related behaviors.

Recent studies have demonstrated that bidirectional interactions of the gut-brain axis are involved in the pathophysiology of neuropsychiatric disorders as well as gastrointestinal diseases [32]. Migraineurs often suffer from gastrointestinal comorbidities, including Helicobacter pylori infection, IBS, IBD and celiac disease [3]. Patients with IBS have a higher prevalence odd of migraine, while migraineurs with a long headache history and high headache frequency have a higher chance of being diagnosed with IBS [33, 34]. The roles of intestinal microbiota and gut-brain axis may provide plausible explanations for migraine and its gastrointestinal comorbidities [5]. Host-microbiota interactions participate in various physiological and pathological events, including host homeostasis, energy metabolism, cognition, behavior and nociception [35, 36]. In a study of 108 elderly women, discrepancy was found in the gut microbiota composition between migraineurs and healthy controls [37]. But in humans, daily diet and lifestyle also have an impact on the gut microbiota, indicating the complexity and diversity of microbial profiles [38]. Here, we found microbial composition alteration in the IS group compared with the VEH group. However, in the IS-TO group, prophylactic treatment with topiramate could prohibit IS-induced alteration in the gut microbiota. These results led us to hypothesize that migraine-related cephalic allodynia induced alteration in the gut microbiota composition.

Although little research demonstrated the association between microbial dysbiosis and migraine, some studies have reported that migraineurs benefit from a 10–12 week probiotic mixture containing strains of Lactobacillus and Bifidobacterium [39, 40]. In our research, the relative abundances of both the Lactobacillaceae family and Lactobacillus genus were significantly decreased in the IS group compared with the VEH group, indicating reduced probiotic strains and intestinal dysbiosis. However, more research is needed to confirm the association between the reduction of beneficial bacteria and the probiotic supplement treatment in migraine. Among the five biomarker genera, four were increased in the IS group, including Colidextribacter, Lachnoclostridium, Monoglobus and Anaerovorax, while Lactobacillus was not. Previous studies have shown that Colidextribacter is positively correlated with antidepressive-like behavior and that Monoglobus may participate in pectin degradation [41, 42]. Both Lachnoclostridium and Anaerovorax are butyrate-producing genera [43, 44]. The highest LDA score as well as MDA score for Lactobacillus indicated that reduced Lactobacillus was the most prominent biomarker genus in the IS-induced alteration of microbiota composition.

For microbial functional predictions, we found that in comparison with the VEH group, the butanoate, propanoate, and tryptophan metabolic pathways were enhanced in the IS group. Microbiota-related products in these pathways, including SCFAs and tryptophan metabolites, have been reported to participate in pain modulation [12, 15].

Short-chain fatty acids, mainly acetate, propionate and butyrate, are fermentation products of undigested carbohydrates produced by intestinal microbiota. Propionate can affect fatty acid content as well as food intake, and also inhibit inflammation in the gastrointestinal tract [45]. Kukkar et al. reported that a 14-day administration of butyrate attenuates neuropathic pain in a chronic constriction injury rat model [12]. Recent research has shown that both propionate and butyrate can reduce pain attacks in an NTG-induced migraine model [17]. The anti-inflammatory effects of SCFAs can down-regulate the levels of proinflammatory mediators in the trigeminal nucleus, including cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) [17]. Thus, SCFAs are likely to be involved in alleviating NTG-induced neuroinflammatory response and inhibiting nociceptive transmission. Although enhanced butanoate and propanoate metabolic pathways were predicted in the IS group, we failed to detect any significantly different SCFAs in either feces or sera.

Tryptophan is an essential amino acid for humans, and its metabolites are crucial in host-microbiota interactions. On one hand, the gut microbiota could directly utilize tryptophan, reducing its availability to the host [46]. On the other hand, microbiota-related tryptophan metabolites can enter the circulation, distributing to target sites with diverse biological activities [46]. The migraineurs suffer from a low central 5-HT disposition associated with an increase in 5-HT release during attacks, indicating disturbances of tryptophan metabolism in migraine [47]. Kiss et al. reported that cortical KYNA level is augmented in a migraine model of cortical spreading depression, seeming to decrease the sensitivity in the cerebral cortex [48]. Additionally, LC–MS/MS analysis revealed that serous KYNA level is significantly decreased in chronic migraine patients compared with healthy controls [49]. However, in our study, neither serotonin nor kynurenine-related metabolites were found significantly different between the IS and VEH groups. A possible explanation could be that 7 times of IS infusion were not enough to mimic an abnormal serotonin or kynurenine metabolic state in rats. Interestingly, we found that the indole-related derivatives IAM and IEt were significantly increased in feces of the IS group compared with the VEH group. These results revealed that elevated IAM and IEt in feces could be the indicators in the IS-induced alteration of microbial metabolism.

In our previous study, we have found that eradication of gut microbiota leads to increased basal mechanical sensitivity and hyporesponsiveness to NTG administration in mice, which could be reversed by restoring the gut microbiota [16]. However, Tang et al. reported that gut microbiota deprivation dramatically prolongs NTG-induced migraine-like orofacial pain in mice [50]. Despite these results are not entirely consistent, the gut microbiota seems to be associated with pain modulation in rodent models of migraine. In addition, these two studies have demonstrated that upregulation of tumor necrosis factor alpha (TNF-α), especially in the trigeminal nucleus caudalis, influences NTG-induced acute hyperalgesia [16, 50]. As an important proinflammatory cytokine, TNF-α is involved in the innate immune response [51]. In pathological conditions, microglia can release large amounts of TNF-α, which contributes to neuroinflammatory response [52]. Erny et al. discovered that deprivation of gut microbiota causes microglia function defects in mice, affecting the release of TNF-α [53]. This may provide a plausible explanation for our previous observations that NTG could not induce elevation of TNF-α in both germ-free and antibiotic-treated mice. Several studies have revealed that microbiota-derived SCFAs play important roles in modulating microglia homeostasis as well as inhibiting neuroinflammatory response [17, 53, 54]. Wen et al. reported that Gastrodia elata Blume and Uncaria rhynchophylla, a Chinese medicine pair, can affect the microbial composition and amino acid metabolism, and alleviate NTG-induced thermal allodynia in rats [55]. These findings have shown potential therapeutic targets for migraine by regulating the gut microbiota and its metabolites.

In this study, we mainly investigated that IS-induced cephalic allodynia caused the alteration of gut microbiota composition. Although the exact mechanism is still unknown, there are several hypotheses to explain how the CNS modulates gut microbiota. On one hand, the CNS can influence intestinal microbiota by sending efferent signals from the sympathetic and parasympathetic systems [9]. On the other hand, physical or psychological stress factors can act on the hypothalamic-pituitary-adrenal (HPA) axis and induce cortisol secretion, causing alterations of the microbiota profile and intestinal permeability [56]. It is worth noting that stress factors can induce microbial composition alteration in a short time. In one animal model of depression, the mice are exposed to a different CD1 aggressor mouse for 10 min on 10 consecutive days, and then alteration in the gut microbiota is found [57]. In another animal model of depression, the gut microbiota composition alters when the rats have been subjected to inescapable electric foot shocks for two days (30 times per day) [58]. In our research, we found the alteration of gut microbial composition after 7 times of IS dural infusion. However, the underlying mechanisms through which cephalic allodynia influences the gut microbiota have not yet been defined and future research is needed.

Based on the above, we speculated that when the host confronts with stress factors or environmental changes, such as migraine attacks, the adaptive alterations occur in the gut microbiota. To some degree, these alterations might be beneficial for the host adapting itself to migraine. As migraine progresses, gut microbial dysbiosis and altered microbiota-related metabolites emerge. Reversely, these changes might affect the progression of migraine through the gut-brain axis. Therefore, the bidirectional host-microbiota crosstalk might be involved in the migraine pathophysiology.

It should be noted that migraine is highly prevalent in women, with a female-to-male ratio of 3:1 [1]. There is a strong relationship between migraine and female hormones, and the fluctuations of estrogen have an impact on intensity and duration of the headaches in migraineurs [59, 60]. Additionally, accumulating evidence suggests that there also exists bidirectional crosstalk between estrogen and the intestinal microbiota [61, 62]. Considering the effects of female hormones on pain processing and gut microbiota, only male rats were used in our study. Whether cephalic allodynia would influence the gut microbiota in female rats needs to be further explored. There are still some limitations in the present study. This animal model induced by repeated dural IS infusions may partially simulate the pathophysiology of migraine. Due to the limited times of IS administration, the microbial composition alteration might be a stress-induced phenomenon. Hence, it is inconclusive whether recurrent headaches would induce alterations of the microbiota profile and microbial metabolic pathways in migraineurs. Clinical study is needed to investigate the mechanism of host-microbiota interactions in the future.

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