The impact of Helicobacter pylori infection on gut microbiota-endocrine system axis; modulation of metabolic hormone levels and energy homeostasis

Abstract

The gut microbiota is a complex ecosystem that is involved in the development and preservation of the immune system, energy homeostasis and nutritional status of the host. The crosstalk between gut microbiota and the host cells modulates host physiology and metabolism through different mechanisms. Helicobacter pylori (H. pylori) is known to reside in the gastric mucosa, induce inflammation, and alter both gastric and intestinal microbiota resulting in a broad spectrum of diseases, in particular metabolic syndrome-related disorders. Infection with H. pylori have been shown to affect production level and physiological regulation of the gut metabolic hormones such as ghrelin and leptin which are involved in food intake, energy expenditure and body mass. In this study, we reviewed and discussed data from the literature and follow-up investigations that links H. pylori infection to alterations of the gut microbiota and metabolic hormone levels, which can exert broad influences on host metabolism, energy homeostasis, behavior, appetite, growth, reproduction and immunity. Also, we discussed the strong potential of fecal microbiota transplantation (FMT) as an innovative and promising investigational treatment option for homeostasis of metabolic hormone levels to overcome H. pylori-associated metabolic syndrome-related disorders.

Introduction

The term “gut microbiota” is referred to the microbial communities including bacteria, viruses, fungi, and protozoans inhabiting in the gut lumen [1, 2]. It has been estimated that the number of the microbiota associated genes is 150-fold higher than the host’s genes [3]; therefore, the microbiota could be considered as a distinct and functional metabolic organ [4]. During the past decade, a large amount of datasets on the gut microbial composition and diversity have been generated. As a result of the findings from the studies, the core microbiota in healthy adults consists of six dominant phyla including Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, Fusobacteria and Verrucomicrobia [5].

It was indicated that imbalance of the gut microbiota composition and diversity, so-called “dysbiosis”, may happen due to unhealthy conditions, environmental factors, diet, as well as the presence of some eukaryotic microorganisms and viruses [6–9]. Many studies showed that disruption of the gut microbiota could be the origin of a broad spectrum of disorders from psychological distress [10, 11] to obesity [12, 13]. It is also believed that microbial community of the gut can communicate with one another and their hosts through metabolically active compounds to switch genes on and off [14]. In a mutualistic manner, the colonized bacteria in the gut consume undigested materials such as dietary fibers and can produce short-chain fatty acids (SCFA), which are beneficial for the physiology of their host cells while the host provides a suitable niche for the microorganisms to reside and grow [15, 16]. Moreover, it was indicated that a couple of microbial families play an important role during the food digestion, energy harvesting and uptake [17, 18]. It was well established that the gut microbiota may affect the energy harvesting through fermentation process, breaking down the dietary fibers, and producing a complex of biomolecules such as vitamins and other essential nutrients cofactors, and small molecules that the human host cannot synthesize itself [15]. Furthermore, gut bacteria can directly interact with the host’s immune cells and provoke both innate and adaptive immune responses. Therefore, interaction between bacteria and immune cells during the early years of the life leads to development of the immune system [19–21].

Helicobacter pylori (H. pylori) is a Gram-negative microaerophilic bacterium that colonizes the human stomach and affects more than half of the world’s population [22]. In 2015, it was estimated around 4.4 billion individuals were infected with H. pylori worldwide [23]. This widespread bacterial pathogen is strongly associated with various upper gastrointestinal (GI) pathologies such as chronic gastritis, peptic ulcer disease (PUD), gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and/or gastric malignancies [24, 25]. Apart from gastric disorders, accumulating evidence suggests that at least in some subpopulations H. pylori infection may potentially correlate with the development of esophageal and colorectal neoplasms [26]. Furthermore, several studies indicated that H. pylori implicates in metabolic syndrome-related disorders including insulin resistance (IR), abdominal obesity, type 2 diabetes mellitus (T2DM), dyslipidemia, hypertension, cardio-cerebrovascular disease, the central nervous system (CNS) degenerative disorders, and nonalcoholic fatty liver disease (NAFLD) [27–30].

Although the human stomach has been regarded as the exclusive niche for H. pylori colonization, 16S rRNA sequencing of the fecal samples has revealed this bacterium at low relative abundance in GI tract [31]. Moreover, infection with H. pylori can hamper the secretion of gastric acid, induce chronic inflammation of the mucosal lining of the stomach, and thereby modulate the gastric microenvironment resulting in widespread alterations in the composition and diversity of gastric microbial community. These alterations in gut microbiota are associated with a wide range of GI diseases and systemic disorders.

In this review, we aim to explore and summarize accumulating evidence potentially linking H. pylori infection with alterations in the level of gut hormones and modulation of energy homeostasis specifically through gut microbiota-endocrine system axis. We also try to discuss some new hypotheses, and suggest areas to be further investigated in future studies.

Gut microbiota and endocrine system

Although during the recent years our knowledge on the beneficial genera of bacteria involved in the metabolic process has been improved, it is still vague that whether the endocrine system affects the gut microbiota composition or dysbiosis may indirectly affect the endocrine system. In this regard, it seems that gut bacteria and endocrine system can affect each other potentially through a cross-talk signaling mechanism. It was suggested that although sex-dependent, the gut microbiota play a crucial role in development of hippocampal serotonergic system [32]. Asano et al. [33] reported a critical role for the genus Lactobacillus in production of gamma aminobutyric acid (GABA) in an animal lab model. In addition, gut bacteria are able to modulate the levels of several host hormones and hormone-like biomolecules such as serotonin, norepinephrine, dopamine, pheromones, estrogen, androgen, prolactin, leptin, ghrelin, and insulin [34]. Therefore, the composition of gut microbiota and its diversity can significantly affect the psychological conditions and behavior of their hosts. In another words, composition of the gut microbiota via altering either the levels of pheromones, estrogen, androgen, and prolactin (gender-dependent) or serotonin, norepinephrine, and dopamine (gender-independent) may lead to anxiety or calming effects [34]. Recently, Schmidt et al. [35] documented that fecal microbiota transplantation (FMT) could be a promising and effective treatment to reduce the anxiety levels after a spinal surgery. FMT, previously known as bacteriotherapy, is the accepted terminology used to describe the process of transferring fecal infusion from a healthy donor into the colon of a patient particularly with debilitating GI infections, such as Clostridioides difficile infection (CDI), via colonoscopy, enema, nasogastric (NG) tube or in capsule form (popularly called “poop pills”) [36, 37]. Furthermore, in a small placebo-controlled clinical trial performed by Vrieze et al. [38], the effects of infusing intestinal microbiota from lean donors to the duodenal tube of male recipients with metabolic syndrome were studied on the composition of recipients’ microbiota and glucose metabolism. Based on their findings, insulin sensitivity of recipients was significantly elevated following 6 weeks of infusion of microbiota from lean donors along with levels of butyrate-producing intestinal microbiota. They also concluded that infusion of gut microbiota via FMT might be considered as an effective therapeutic option to increase insulin sensitivity in subjects with metabolic syndrome. However, further investigations using well-designed randomized placebo-controlled studies featuring FMT are required to deeply unravel the mechanisms through which gut microbiota interact with metabolic hormones, host metabolism, and immune system.

Together with the classical opinion on the role of exposure to microbes in development of the host immune system, recent studies highlighted the crucial indirect role of gut microbiota in educating the immune system [6, 14, 21]. Accordingly, it is believed that bidirectional communication and effects of gut microbiota and sex hormones via microbiota-gut-brain axis may play an important role in the changes in intestinal physiological function and immune responses [32]. Recently, Flak et al. [39] presented a novel concept termed as “microgenderome” or sexual dimorphism, which defines the bidirectional interaction and relationship between sex hormones, gut microbiota, immune system and disease susceptibility. It was also shown that certain bacterial species such as Clostridium scindens can utilize glococorticoids and convert them into androgens by side-chain cleavage [40]. On the other hand, it was demonstrated that the gut microbiota composition and abundance are sex-dependent and modulated by the sex hormones. Regarding the key role of sex hormones in immune responses, it seems that gut microbiota can modulate the immune system via alteration in the levels of sex hormones [41].

Gut microbiota and energy homeostasis

Apart from the direct impact of the gut microbiota composition on the digestion of foods, the microbial communities are able to control metabolism of energy via altering the levels of hormones through either secretion of specific hormones [42] or via gut-brain axis [43].

From the classical point of view, the gut microbiota can break down polysaccharides to monosaccharides and fermenting them to SCFAs [44]. An in vivo study conducted by Samuel et al. [45] represented that the caecal concentration of acetate in mice was significantly correlated with colonization of both B. thetaiotaomicron and M. smithii than either one of them or in germ-free mice. On the other hand, it was suggested that B. thetaiotaomicron not only increased the capacity of polysaccharides to glucose conversion [46], but also increased the expression of sodium/glucose co-transporter-1 (Slc5a1) which plays a crucial role in the glucose uptake in the ileum by the enterocytes [47].

Experimental evidence indicated that gut microbiota might be involved in the dehydroxylation and deconjugation of bile acids. Therefore, the secondary structure of the bile acids due to gut microbiota composition can lead to alteration during the lipid digestion and absorption [48–50]. Notably, the microbial community of the gut can affect the appetite and metabolism via controlling the levels of digestive hormones. It was established that gut microbiota affects the levels of leptin and ghrelin, two important appetite-related hormones. The experimental studies revealed that although the level of leptin was positively correlated with quantity of Bifidobacterium and Lactobacillus, the level of ghrelin was reported to be negatively related with these microorganisms [51].

H. pylori infection and alterations in gut microbiota

Although the stomach was traditionally considered as a sterile environment due to high acidity and a low number of cultured bacteria, the recent studies, particularly those which employed metagenomics approaches, indicated a large diverse group of colonizing bacteria in the gastric tissues [52]. Nevertheless, the density of bacteria in this organ is estimated to be significantly lower than that in the colon from 10¹ to 10² vs. 10¹⁰ to 10¹² (CFU/g) [53]. In addition, despite of differences in the richness of the bacteria between different parts of the stomach, it seems that the diversity of microbial composition through the all parts of the stomach is almost similar [52, 54].

Recent studies strongly suggested a modulator role for H. pylori on endocrine system and the gut microbiota composition [52]. It seems that there are microbe-microbe and host-microbe cross-talks between H. pylori and the other bacterial taxa residing in the human stomach [55]. The exact mechanisms in which the altered gut microbiota cooperates with H. pylori to trigger gastric carcinogenesis is not completely clarified. In this regard, several studies demonstrated that the combination between H. pylori and other bacteria may synergistically increase the risk of gastric cancer development. For instance, Lactobacillus, Staphylococcus, and Escherichia coli are among the microorganisms which can transform nitrogen compounds into carcinogenic N-nitroso compounds [54, 56, 57]. In contrast, certain commensal bacteria including Prevotella, Neisseria and Streptococcus are reported to associate with a lower risk of development of gastric carcinoma [58, 59].

Apart from the effects of H. pylori on the microbial composition of the stomach, a couple of studies reported an important role for this bacterium in the composition of microbial population through the intestine [60, 61]. Additionally, it was shown that H. pylori not only alter the gut microbiota, but also this bacterium may change the fungi composition throughout the intestine [62]. Besides, it was demonstrated that the presence of H. pylori disrupts the Firmicutes/Bacteroidetes (F/B) ratio, which may affect the physiological conditions of H. pylori-infected subjects, particularly in asymptomatic individuals [54, 63, 64]. Gut microbiota analysis of rodents revealed an increase in Staphylococcus aureus and Enterococcus spp., and decrease of Lactobacillus in gerbils, as well as an increase of E. coli, Bacteroides, and Prevotella in mice [63, 65]. However, it is strongly suggested that H. pylori alters the composition of the gut microbiota via three probable ways: 1) changing the acidity level of the stomach [66–68], 2) providing substrates favor for colonizing some other taxa of bacteria [69, 70], and 3) changes in the life style and dietary patterns of the H. pylori-positive subjects [71, 72].

H. pylori infection and its impact on gut hormones

Apart from the classical influence of H. pylori infection on the gastric microbiota composition, this bacterium may alter the composition of the microbiome of the gut via provoking or decreasing the secretion of gastrointestinal hormones. It was revealed that the release of gastrin, a peptide hormone released from G cell which stimulates acid secretion, was increased in H. pylori-positive subjects [73, 74]. It was well-studied that the presence of H. pylori can affect the metabolism in human subjects through modulating the hormones. Therefore, H. pylori can directly or indirectly modulate the energy harvesting, food metabolism, and the body weight in infected human patients.

Acbay et al. [75] showed that the colonization of H. pylori in the stomach could increase the serum level of food-stimulated insulin release probably in a gastrin-dependent manner. However, recent studies using experimental animals [76] as well as humans demonstrated that infection by H. pylori induces insulin resistance in nondiabetic subjects [77, 78]. Leptin and ghrelin are two hormones that play a central role in energy homeostasis. Ghrelin is mainly produced by the stomach and is known as hunger hormone. Ghrelin increases appetite and energy harvesting, and leads to weight gain. In contrast to ghrelin, leptin is primary produced by adipose cell and enterocytes through the small intestine. This hormone decreases appetite and fat storage, and increases weight loss [79, 80]. A couple of studies demonstrated that H. pylori may regulate the energy homeostasis via not only indirectly through alteration in the gut microbiota composition, but also by directly manipulating the secretion of leptin and ghrelin, as well [81, 82]. Khosravi et al. [83] investigated the plasma level of ghrelin in three groups of mice, germ-free, specific-pathogen germ-free (SPF), and H. pylori-infected, and showed that H. pylori-infected mice represented increased level of ghrelin in comparison to other two groups. These results were in contrast with previous studies by Tatsuguchi et al. [84], and Isomoto et al. [85] who reported an inverse correlation between the plasma level of ghrelin and presence of H. pylori. Furthermore, in a study conducted by Francoise et al., [82] the meal-associated level of ghrelin and leptin increased after successful eradication of H. pylori. In a study by Yap et al. [86], the levels of pre-prandial active amylin, total peptide YY (PYY) and pancreatic polypeptide (PP), and the levels of post-prandial gut metabolic hormones including glucagon-like peptide-1 (GLP-1), total PYY, active amylin, and PP were significantly higher 12 months post-eradication as compared to baseline levels. However, the values of body mass index (BMI) and anthropometric did not significantly alter following the H. pylori eradication therapy. The potential impact of H. pylori infection on gut microbiota dysbiosis via changes in metabolic hormone levels and induction of host inflammatory responses is shown in Fig. 1. Moreover, Pierantozzi et al. [87] demonstrated that H. pylori infection may increase the risk for Parkinson’s disease (PD) by affecting L-DOPA levels. They also suggested that H. pylori eradication may ameliorate the clinical status of infected patients with PD and motor fluctuations by modifying L-dopa pharmacokinetics. Taken together, these results demonstrate that the presence of H. pylori infection may affect the energy homeostasis in infected human subjects, but require further investigations.

Fig. 1.

Impact of H. pylori infection on gut microbiota dysbiosis through changes in metabolic hormone levels (ghrelin, leptin, amylin, GLP-1, PYY, PP) and induction of host inflammatory responses. H. pylori infection may lead to alterations of the gut microbiota and metabolic hormone levels, which could exert broad impacts on host metabolism, energy homeostasis, behavior, immune and reproduction systems

Conclusions

In conclusion, the number of studies implicating the role and impact of H. pylori infection on both gastric and intestinal microbiota is rapidly growing. This study provides further evidence that gastric H. pylori infection is involved in the alterations of gut microbiota composition and diversity, which can lead to changes in production level and physiologic regulation of the gut metabolic hormones released from the host endocrine system. Furthermore, this work supports the rationale that links H. pylori infection to hormone production and the gut microbiota composition, which can exert broad effects on host metabolism, energy homeostasis, behavior, appetite, growth, reproduction and immune system development. In our vision, we see how restoration of the gut microbiome through FMT could be a promising and effective option for homeostasis of metabolic hormone levels to overcome H. pylori-associated metabolic syndrome-related disorders. However, in order to validate such novel approaches, the accurate mechanisms of H. pylori pathogenesis, and its precise bacterial and endocrine-microbiome crosstalk must all be thoroughly deciphered in future studies.

Authors’ contributions

S.O.M. reviewed the literature and collected the relevant data. A.Y. worked on concept and design of the study. A.Y. and M.K. supervised the findings of this work. A.Y. and H.M. contributed to manuscript writing. A.Y. and F.K. critically revised the manuscript. All authors provided critical feedback, helped shape the research, and contributed to the final version of the manuscript.

Funding information

This study was supported by a PhD grant from the Department of Microbiology, Jahrom Branch, Islamic Azad University, Jahrom, Iran.

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Conflict of interest

The authors declare that they have no conflict of interests.

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