Fecal microbiome in systemic sclerosis, in search for the best candidate for microbiota-targeted therapy for small intestinal bacterial overgrowth control

Abstract

Gastrointestinal involvement is a common complication in systemic sclerosis patients and must be suspected and investigated already in the early stages of the disease. Gastrointestinal symptoms and complications—such as gastroesophageal reflux disease, intestinal pseudo-obstruction, malnutrition, diarrhea, constipation, and small intestinal bacterial overgrowth—severely impair systemic sclerosis patients’ quality of life and affect their prognosis. Although some pathogenetic aspects of the gastrointestinal involvement in systemic sclerosis remain unclear, defining the characteristics of the microbiota and its role could help in risk stratification, selection of candidates for microbiota-targeted therapies, prediction of standard treatment efficacy, and prognosis of systemic sclerosis patients. Finally, understanding how to modify the microbiota composition may represent an important therapeutic approach to target gastrointestinal involvement in systemic sclerosis.

Editorial comment of: Levin D, De Palma G, Zou H, et al. Fecal microbiome differs between patients with systemic sclerosis with and without small intestinal bacterial overgrowth. J Scleroderma Relat Disord 2021; 6(3): 290–298. Epub ahead of print 24 July 2021. DOI: 10.1177/23971983211032808. PMID: 35382497; PMCID: PMC8922657.

Systemic sclerosis (SSc) is a chronic systemic autoimmune disorder characterized by tissue and organ fibrosis, fibro-proliferative vasculopathy, and various immunological (humoral and cellular) alterations leading to production of autoantibodies. ¹ The gastrointestinal (GI) tract is involved in up to 90% of SSc patients, and both upper and lower GI tracts can be affected since the very early disease phases. GI involvement can be characterized by several different symptoms (reflux, dysphagia, early satiety, postprandial pain/nausea, abdominal pain, distention, diarrhea, and flatulence), or it can be asymptomatic especially in the early SSc stages and detectable with instrumental findings.^1,2 GI symptoms and complications severely impair SSc patients’ quality of life and affect their prognosis. To date there are no biomarkers able to help clinicians recognizing SSc patients at higher risk of GI involvement, and the current treatments for managing this complication in SSc are limited and cannot prevent progression of symptoms. This SSc clinical aspect is a major point of interest among the experts on the topic since the human GI microbiota, and its interplay with immune system, have been extensively studied as a potential key player in rheumatic diseases’ onset and progress. In detail, the gut microbiota (GM) is crucial for the development of the human immune system and alterations of GM composition, named “dysbiosis,” can affect the host immune responses at epithelial surfaces, triggering inflammatory and autoimmune diseases in susceptible individuals. ³

Dysmotility accounts for most SSc-associated GI symptoms and complications, such as gastroesophageal reflux disease, intestinal pseudo-obstruction, malnutrition, diarrhea, constipation, and small intestinal bacterial overgrowth (SIBO). ⁴ In detail, SIBO is a clinical disorder that results from the colonization of the small bowel by increased number and/or abnormal types of microorganisms. It leads to an extension of colonic bacteria into the small bowel, usually coliforms, which are typically found in the colon, and Gram-negative aerobic and anaerobic species that ferment carbohydrates producing gas, changing the equilibrium of the microbial flora. ⁵ Of note, it is a common manifestation in SSc with a prevalence of 30%–62%. ⁶

All the three characteristic aspects of SSc (fibro-proliferative vasculopathy, immune dysfunction, and fibrosis) have been proposed as pathogenic mechanisms of the neuro-muscular impairment in the GI tract; ¹ however, the pathogenesis is complex and still poorly understood. Collective evidence suggests that the aberrant fibroproliferation observed in SSc results from an interplay between genetic factors, environmental exposures, and epigenetic modifications. ⁷ GM alterations may represent one of the key environmental factors contributing to the SSc grade. Emerging evidence suggests that certain microbial compositions are associated with specific SSc-related features ⁷ and in particular with GI symptoms, usually assessed by UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0). ⁸

In this scenario, the study from Levin and colleagues provides interesting data regarding the changes of the fecal microbiota in SSc patients with SIBO. In their cohort of 29 Canadian SSc patients, they identified unique microbiota profiles in comparison with healthy controls (HCs), and reported remarkable differences also between SIBO negative and SIBO positive SSc patients. When compared with HCs, SSc patients exhibited a greater microbial diversity while the absolute number of species in a sample (microbial richness) was similar, suggesting that healthy subjects have more homogeneous microbiomes. Also, the beta diversity between HCs and SSc patients differed, providing further support that SSc patients have distinctly different microbiomes from their healthy counterparts. In addition, the SSc patients had a higher relative abundance of Proteobacteria and Bacteroidetes and lower abundance of Firmicutes compared to HCs. The phyla Firmicutes, Bacteroidetes, and Proteobacteria include the most abundant components of the human GM, respectively, 64%, 23%, and 8%. ⁶ Dysbiosis between these phyla in the human gut has been described in previous studies in association with different disorders, for example, the dual finding of a decrease in Firmicutes (described as “protective”) associated with a parallel increase in Proteobacteria (described as “aggressive”) is one of the major themes of most of the previous studies focus on compositional GM changes in patients with inflammatory bowel disease (IBD) or colorectal cancer,^7,9,10 and lower Firmicutes/Bacteroidetes ratio was also found in a Systemic Lupus Erythematosus (SLE) patients cohort. ⁸ ,11

In this issue, Levin et al. highlighted also interesting differences in microbial composition in SIBO positive versus SIBO negative SSc patients. When compared to SIBO negative patients, SIBO positive ones had increased bacterial diversity and richness, exhibited higher relative abundance of Proteobacteria, Bacteroides, and Rikenellaceae and lower relative abundance of Erysipelotrichaceae (Figure 1).

Figure 1.

Differences in GIT microbiota in SSc SIBO negative versus SSc SIBO positive patients.

All these findings may influence the SSc development considering that the presence of these same types of bacteria has been associated with other pro-inflammatory states. In fact, an expansion of the Proteobacteria phylum has been demonstrated in IBD patients, in particular adherent-invasive species might have unique abilities that enable them to exploit host defenses and promote inflammatory change in susceptible hosts.^12,13 A higher abundance of Rikenellaceae was reported in patient with ankylosing spondylitis ¹⁴ and changes in the levels of Erysipelotrichaceae in IBD patients or animal models of IBD have been observed, but the evidence is not consistent; however, some studies report that patients who experienced new onset or recurrence of Crohn’s disease had significantly lower levels of Erysipelotrichaceae.^15,16

SSc patients in Levin’s cohort also presented some original findings compared to HCs, such as a lower relative abundance of Lactic Acid Bacteria, for example, Enterococcus and Lactococcus and higher relative abundance of commensal Bacteroides spp.; these results can be related to the inclusion of SIBO positive patients in the cohort, whose bacteria overgrowth could easily affect the composition of the lower GI tract and feces.

Even though no definitive conclusions can be made, their concomitant finding improves the existing knowledge of the fecal microbiome role in SSc, providing another puzzle piece in determining the complex SSc etiology and its associated GI symptoms.

Furthermore, recent reports aiming to characterize the lower GI tract in SSc have described depletions in beneficial commensal genera (e.g. Faecalibacterium, Clostridium, and Bacteroides), as well as enrichments in potentially pathobiont genera (e.g. Fusobacterium, Prevotella, Erwinia, Ruminococcus, and Akkermansia). In addition, some studies have linked specific genera with clinical SSc features; a recent review showed that patients with none to mild GIT involvement (based on the GIT 2.0 questionnaire) are likely to have increased abundance of Bacteroides Fragilis and Clostridium whether patients with more severe GI disease scores present higher levels of Fusobacterium and Prevotella. ¹⁷

Unfortunately, to date there are no disease-modifying drugs for GI involvement in SSc, and both the limited knowledge about pathogenesis and the lack of appropriate animal models of GI-SSc have obstructed the development of new therapies. ¹ Some studies suggest that both the neural and myogenic effects of the anti-acetylcholinreceptor (AChR) M3 autoantibodies can be reproducibly abrogated by intravenous immunoglobulin (IVIG), suggesting that SSc-associated intestinal dysfunction, at both the initial neuropathic and myopathic stages, may be potentially reversible with IVIG.^2,18 However, when the motility dysfunction and its complications are established, there is no clearly effective therapy to reduce the symptoms and improve patients’ quality of life.

The most recent EULAR recommendations for the treatment of GI manifestations on SSc patients are from 2016; the suggestion is to use prokinetics for symptomatic motility issues and rotating antibiotics for malabsorption due to SIBO. ¹⁹ Proton-pump inhibitors (PPIs)—largely used in SSc to treat esophageal aperistalsis, esophageal sphincter atony, and persistent gastroesophageal reflux—are known to increase the SIBO risk. Therefore, reducing PPIs in SSc when possible would help prevent SIBO, even if it is often impossible. ²⁰

The available data for the treatment of SIBO in SSc are limited, and guidelines have been extrapolated from SIBO in other populations. There have been recent systematic reviews showing efficacy of probiotics and rifaximin in SIBO, but these are not specific for SSc patients. ²¹ About this topic, Pittman and colleagues recently carried out an interesting meta-analysis. They revised the abstracts of 5295 publications, finding only five non-randomized studies specifically about the treatment of SIBO in patients with SSc, confirming that there is not enough information in this field. The best result to eradicate SIBO was obtained from only five patients after octreotide 50 mg/day subcutaneously for 3 weeks, in six of eight patients who received a combination of antibiotics (trimethoprim, ampicillin, ciprofloxacin, tetracycline, and erythromycin) and in 22 of 30 patients receiving rifaximin. ⁶

Good results in terms of SIBO eradication, less hydrogen production, and reduction in GI symptoms were achieved in a Mexican cohort of 40 SSc patients with SIBO treated with a combination of Metronidazole and Saccharomyces Boulardii (SB). In detail, the treatment scheme was Metronidazole 500 mg plus SB 200 mg b.i.d. for 7 days and 7 more days with SB, administered over 2 months during the first and second weeks of each month, and for the rest of the month, there was no more intervention. Their results suggest a possible role of long-term periodic administration of SB to maintain and improve GI outcomes in SSc SIBO patients. ²²

Dysmotility and slowed intestinal transit also involve the colon and are the main cause of constipation or evacuation alterations frequently reported by SSc patients. A fiber rich diet and abundant amounts of liquids are the lifestyle habits that could help improve intestinal regularity. Moreover, the use of pyridostigmine was evaluated for the treatment of GI symptoms with evidence of significant improvement in constipation in 31 SSc patients treated for 4 weeks. ²³

In addition, an open-label crossover study (PROGASS) evaluated the safety and efficacy of prucalopride for the treatment of SSc patients, reporting an improvement in the number of complete bowel movements and intestinal transit, and in the reduction of reflux and swelling in treated patients compared to placebo. ²⁴

The involvement of the ano-rectum is present in 50%–70% of cases, resulting in the dysfunction of the internal and/or external sphincter and/or the rectal inhibitory reflex, responsible for fecal incontinence in 1/3 of patients. The treatment includes biofeedback techniques, pelvic floor rehabilitation, and sacral nerve stimulation in refractory cases, and possible surgical therapy if necessary. ²⁵

However, non-invasive tests or biomarkers able to identify SSc patients at high risk of developing GI manifestations are still lacking today. Therefore, the characterization of SSc–GI microbiota and understanding its role in the pathogenesis of the disease and how it contributes to specific phenotypic dimensions of it can be a very useful tool. Future research shall be focused on understanding if the changes in the fecal microbiome in SSc are more related to inflammation (considering the similarities between SSc and IBDs’ microbiomes) or if they are the direct consequences of decreased motility/fibrosis, to comprehend what would be the mechanism causing an improvement in GI manifestation of scleroderma. Such studies may reveal important targets for disease prevention and treatment as it can be hypothesized that modifying the GI microbiota through nutritional interventions, modifying the diet, and with the integration of probiotics/prebiotics can improve the GI symptomatology. Interventional strategies may include also fecal transplantation that have been studied most extensively in IBD with mixed results, but compared with probiotics, which provide a limited scope of microbes, fecal transplantation may offer more diverse species and a greater change for restoring GI homeostasis in SSc. ¹⁵ A recent study of five SSc patients reported how fecal transplantation resulted in a reduction in swelling, fecal incontinence, and diarrhea in treated patients compared to placebo demonstrating how it can be a therapeutic option able to reduce GI symptoms by altering the intestinal microbiota. ²⁶

In conclusion, GI involvement is a common complication in SSc patients and must be suspected and investigated already in the early stages of the disease. Although some aspects of the SSc–GI pathogenesis remain unclear, defining the characteristics of the microbiota and its role could help in risk stratification, selection of candidates for microbiota-targeted therapies, prediction of standard treatment efficacy, and prognosis of SSc patients. Finally, understanding how to modify the microbiota composition may represent an important therapeutic approach to target GI involvement in SSc.