Microbots for IBS

In managing IBS and other GI conditions, the greatest challenges often lie in accessing and visualizing the problem areas within the complex network of the human body. However, the latest advancements in medical technology are transforming this landscape, bringing what once seemed like science fiction into the realm of reality. 

The exploration of the GI system has significantly advanced since the 1970s with the advent of technologies like sonde type and ropeway enteroscopy. A landmark development occurred in 2007 with the introduction of the single-balloon enteroscope (SBE) system, revolutionizing the comprehensive inspection of the small bowel. The advent of a motorized enteroscope further streamlined this process, offering the potential for complete enteroscopy in a single session.

In 2010s, "insideable" devices expanded to include an ingestible pill camera - PillCamSB -  to monitor pressure, pH and temperature, gastrointestinal motility, lesions, ulcers, early signs of tumors and bleeding within the small bowel. Proteus sensor could be attached to any pill or food item, enabling it to communicate vital health information from within our bodies.  Well Cow bovine health monitor designed to be swallowed by cows measured rumen pH and temperature to prevent health issues and ensure the production of high-quality milk.

The late 20th century witnessed the birth of microbots, a revolutionary product of the microcontroller revolution. These tiny robots, envisioned for medical use in the 1980s, now capitalize on advancements in wireless technology, including Wi-Fi, for improved communication and control. Made from synthetic, biological, or biohybrid materials, microbots are poised to redefine precision in drug delivery and targeted treatments. They could navigate the labyrinth of body's micro-paths, full of barriers that are difficult to break through, break up hard-to-reach clots or deliver drugs to even the most inaccessible tumors.

Microbots, with their capacity for direct drug delivery in the GI tract, promise to reduce systemic toxicity significantly. Xenobots can assemble themselves and motile living biobots or anthrobots can self-construct. Combining these with cutting-edge technologies like CRISPR 2.0 could herald a new era of precision in gene editing.

With a high failure rate of drug candidates in clinical trials, microbots offer a beacon of hope. These micromachines can precisely deliver drugs to disease locations, addressing the challenges of systemic delivery methods. This precision opens possibilities for reevaluating drugs previously set aside due to toxicity, and it stimulates new drug development ventures.

Hydrogel, known for its excellent biocompatibility and adaptable shape, has emerged as a focal point in biomedicine research. Its responsiveness to environmental stimuli (like pH, light, and temperature) has led to the development of "smart" responsive hydrogel micro-nano robots. These are now at the forefront of biomedical applications, including targeted drug delivery, stem cell therapy, and cargo manipulation.

Innovative uses of hydrogel technologies are continually being explored. For instance, recent advances have seen the development of soft and hard hybrid bionic hydrogel robots, adept at tasks like controllable grasping, tumor cell detection, and continuous drug/cell release. Merging these hydrogel robots with medical contrast agents enables their tracking within the body using nuclear magnetic resonance technology.

One of the most groundbreaking applications is the use of smart hydrogel structures for microbiome sampling in the GI tract. These hydrogel microbots, easily swallowable and retrievable, are poised to offer unprecedented insights into the GI microbiome, a critical aspect of IBS research and treatment.

REFERENCES

Nehme F, Goyal H, Perisetti A, Tharian B, Sharma N, Tham TC, Chhabra R. The Evolution of Device-Assisted Enteroscopy: From Sonde Enteroscopy to Motorized Spiral Enteroscopy. Front Med (Lausanne). 2021 Dec 23;8:792668. doi: 10.3389/fmed.2021.792668. PMID: 35004760; PMCID: PMC8733321.

Yoon D, Park S, Park S. Smart hydrogel structure for microbiome sampling in gastrointestinal tract. Sensors and Actuators B: Chemical. 2023 Aug 15;389:133910.

Cao Q, Chen W, Zhong Y, Ma X, Wang B. Biomedical Applications of Deformable Hydrogel Microrobots. Micromachines (Basel). 2023 Sep 24;14(10):1824. doi: 10.3390/mi14101824. PMID: 37893261; PMCID: PMC10609176.

Singeap AM, Sfarti C, Minea H, Chiriac S, Cuciureanu T, Nastasa R, Stanciu C, Trifan A. Small Bowel Capsule Endoscopy and Enteroscopy: A Shoulder-to-Shoulder Race. J Clin Med. 2023 Nov 26;12(23):7328. doi: 10.3390/jcm12237328. PMID: 38068379.

Kriegman S, Blackiston D, Levin M, Bongard J. A scalable pipeline for designing reconfigurable organisms. Proc Natl Acad Sci U S A. 2020 Jan 28;117(4):1853-1859. doi: 10.1073/pnas.1910837117. Epub 2020 Jan 13. PMID: 31932426; PMCID: PMC6994979.

Gumuskaya G, Srivastava P, Cooper BG, Lesser H, Semegran B, Garnier S, Levin M. Motile Living Biobots Self-Construct from Adult Human Somatic Progenitor Seed Cells. Adv Sci (Weinh). 2023 Nov 30:e2303575. doi: 10.1002/advs.202303575. Epub ahead of print. PMID: 38032125.

The Gut-Brain Connection: A New Horizon in Neurological Health

The human body is a complex system, and one of its most fascinating connections is the gut-brain axis. This bidirectional communication between the gastrointestinal (GI) tract and the central nervous system (CNS) has recently gained traction in the scientific community, especially concerning acute neurological diseases like stroke, multiple sclerosis, Alzheimer's disease, and migraine.

The gut-brain axis is not just a physical connection between the gut and the brain; it's a complex network involving proinflammatory cells, gut metabolites, hormones, and neural pathways. Key metabolites include trimethylamine N-oxide (TMAO) and short-chain fatty acids (SCFAs), which are believed to play a central role in gut-brain axis dysfunction. 

Over 50% of ischemic stroke survivors experience GI complications, with dysphagia, constipation, and GI bleeding being the most common. Diarrhea, constipation, and gastroesophageal reflux are also more frequent in patients with migraine. These complications are not merely side effects but may contribute to poor functional neurologic outcomes. It is postulated that the propagation of proinflammatory cells and gut metabolites (including trimethylamine N-oxide and short-chain fatty acids) from the GI tract to the central nervous system play a central role in gut-brain axis dysfunction. In fact, plasma trimethylamine N-oxide (TMAO) levels might predict early neurological deterioration (END) in individuals with acute ischemic stroke. 

Stroke itself can lead to gut dysbiosis, alterations in the normal host intestinal microbiome. This dysbiosis may further perpetuate neurological impairments, creating a vicious cycle that challenges recovery.

Cognition is one of the most evaluated neurologic subjects linked to the gut microbiome. Cognitive impairment is particularly prevalent in patients with multiple sclerosis (MS), a chronic neurological disorder.

Referenced reviews discuss the known GI complications in acute ischemic stroke and multiple sclerosis, emerging therapeutics and lifestyle modifications that target the gut-brain axis. 

REFERENCES

Yong HYF, Ganesh A, Camara-Lemarroy C. Gastrointestinal Dysfunction in Stroke. Semin Neurol. 2023 Aug 10. doi: 10.1055/s-0043-1771470. Epub ahead of print. PMID: 37562458.

Ghadiri F, Ebadi Z, Asadollahzadeh E, Moghadasi AN. Gut microbiome in multiple sclerosis-related cognitive impairment. Multiple Sclerosis and Related Disorders. 2022 Sep 7:104165.

La Rosa G, Lonardo MS, Cacciapuoti N, Muscariello E, Guida B, Faraonio R, Santillo M, Damiano S. Dietary Polyphenols, Microbiome, and Multiple Sclerosis: From Molecular Anti-Inflammatory and Neuroprotective Mechanisms to Clinical Evidence. International Journal of Molecular Sciences. 2023 Apr 14;24(8):7247.

He Q, Wang W, Xiong Y, Tao C, Ma L, Ma J, You C. A causal effects of gut microbiota in the development of migraine. The Journal of Headache and Pain. 2023 Dec;24(1):1-7.

Stealth Care System for IBS

The term "stealth care" was coined in a political context, referring to the idea of certain words being disguised or hidden and the fact that not all types of caring for someone's wellbeing are within (or approved by) traditional health care. 

This term has been also used in the computer security context - to describe the Honeynet Project. A honeynet is a network of Honeypots, computer systems set up to look like regular ones, but with a caveat. Honeypots allow themselves to be attacked by hackers in order to capture their every move, learn the tools, tactics and motives; being used to track down and stop attacks before they happen. 

A new paper from McMaster University describes a cellular delivery system that can safely carry potent antibiotics throughout the body to selectively attack and kill bacteria. Physicists at McMaster University are essentially using red blood cells to conceal this antibiotic within turning them into stealth vehicles. The platform could help to address the ongoing antibiotic resistance crisis while avoiding the toxicity and harmful side effects of antibiotics. The technology could be used to fight particularly dangerous and often drug-resistant bacteria such as E. coli, which is responsible for many serious conditions such as pneumonia, gastroenteritis and bloodstream infections.

It could be also used for conditions such as IBS since traditional antibiotics delivery systems can often bring more harm than good in some cases. Antibiotics can disrupt the balance of the microbiome, leading to further symptoms of IBS and potentially causing new health problems. Additionally, overuse of antibiotics can lead to the development of antibiotic-resistant bacteria, which can make it more difficult to treat future infections effectively.

REFERENCES

Krivic H, Himbert S, Sun R, Feigis M, Rheinstädter MC. Erythro-PmBs: A Selective Polymyxin B Delivery System Using Antibody-Conjugated Hybrid Erythrocyte Liposomes. ACS Infectious Diseases. 2022 Sep 29;8(10):2059-72.

Săndulescu O, Viziteu I, Streinu-Cercel A, Miron VD, Preoțescu LL, Chirca N, Albu SE, Craiu M, Streinu-Cercel A. Novel Antimicrobials, Drug Delivery Systems and Antivirulence Targets in the Pipeline—From Bench to Bedside. Applied Sciences. 2022 Nov 16;12(22):11615.

Săndulescu O, Streinu-Cercel A, Moțoi MM, Streinu-Cercel A, Preoțescu LL. Syndromic Testing in Infectious Diseases: From Diagnostic Stewardship to Antimicrobial Stewardship. Antibiotics. 2023 Jan;12(1):6.

Stealth-care system: Scientists test 'smart' red blood cells to deliver antibiotics that target specific bacteria (2022, October 31) retrieved 6 February 2023 from  https://phys.org/news/2022-10-stealth-care-scientists-smart-red-blood.html

Antibiotics and Bowel Disorders

Frequent use of antibiotics can increase the risk of developing microbiome-associated diseases in all age groups.

Studies have shown that antibiotic exposure in the prenatal period and during the first 2 years of life can significantly impact the risk of developing atopic and metabolic disorders later in life. The first 6 months of life appeared to be a critical period, as this is when the microbiome is most susceptible to irreversible changes. 

Studies of older children (such as 11,000 teens and pre-teens from Finland) have found that, instead of a specific age, the frequency of antibiotic use in the two years prior to the diagnosis of autoimmune disorders, was more strongly associated with risk. Exposures to cephalosporins, macrolides, and amoxicillin-clavulanic acid throughout childhood seemed to increase the likelihood of Juvenile Arthritis (JIA). Exposures to macrolides within two years before diagnosis showed minor association with other autoimmune disorders, including type 1 diabetes (DM), autoimmune thyroiditis (AIT), JIA, and inflammatory bowel diseases (IBD)). 

An article recently accepted for publication found that frequent use of antibiotics later in life also increased the risk of IBD. This study of more than 6 million individuals followed for close to 20 years analyzed 87112328 person-years including 36017 new cases of ulcerative colitis (UC) and 16881 new cases of Crohn’s disease (CD) - two primary types of IBD with different characteristics. This risk was predominantly driven by those diagnosed with CD and was strongest within the first few months of antibiotic use. In a nationwide case–control study of individuals 16-years or older in Sweden, similar results were seen for three or more antibiotic dispensations.

The authors of the study hypothesized that antibiotics contribute to the development of IBD by modulating the intestinal microbiome, but more research is needed to fully understand the mechanism behind this association.

REFERENCES

Semeh Bejaoui, Michael Poulsen, The impact of early life antibiotic use on atopic and metabolic disorders: Meta-analyses of recent insights, Evolution, Medicine, and Public Health, Volume 2020, Issue 1, 2020, Pages 279–289, https://doi.org/10.1093/emph/eoaa039

Räisänen L, Kääriäinen S, Sund R, Engberg E, Viljakainen H, Kolho KL. Antibiotic Exposures and the Likelihood of Developing Pediatric Autoimmune Diseases: a Register-based Matched Case-control Study. (2021). DOI: 10.21203/rs.3.rs-1110501/v1

Faye AS, Allin KH, Iversen AT, et al Antibiotic use as a risk factor for inflammatory bowel disease across the ages: a population-based cohort study Gut Published Online First: 09 January 2023. doi: 10.1136/gutjnl-2022-327845

Post-COVID Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that affects 9-23% of the global population. While the exact cause of IBS is unknown, it is believed to be a combination of genetic, environmental, and psychological factors. One potential trigger of IBS is infectious illness. Studies have shown that between 3% and 36% of enteric infections can lead to the development of new IBS symptoms, with post-viral IBS being more transient than post-bacterial or post-protozoal IBS. Meta-analysis of published literature found that the incidence of new IBS 12 months after infection was 10.1% (95% confidence interval (CI) 7.2–14.1). The incidence appears higher after parasitic or protozoan infections at 49% compared to 13.8% after bacterial gastroenteritis.

The COVID-19 pandemic has highlighted the potential link between infections and IBS, as many patients with COVID-19 have developed gastrointestinal symptoms, including diarrhea, nausea, vomiting, and abdominal discomfort. In fact, infection of the GI tract is thought to trigger symptoms in approximately 15% of COVID-19 patients. Post-COVID-vaccination gastrointestinal occurrences were reported in 10–20% of cases and the risk of a disease flare in IBS and IBD patients was close to 10%. 

Persistent symptoms after SARS-COV-2 infection, known as Post-acute Sequelae of COVID-19 (PASC) or long-COVID, may occur in anywhere from 10-55% of those who have had COVID-19, New study found that the most common new diagnoses caused by Long Covid were tachycardia, followed by Postural Orthostatic Tachycardia Syndrome (POTS), Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and IBS.

This chart shows the 0roportion of individuals diagnosed with various conditions by severity of mobility disability. Red are cardiopulmonary diagnoses (AF - atrial fibrillation, Blood Clot, Cardiomyopathy, Pericarditis, PE – pulmonary embolism, POTS – postural orthostatic tachycardia syndrome, Myocarditis, Tachycardia), light green are gastrointestinal (Irritable Bowel Disease, Irritable Bowel Syndrome), blue-green are neurologic diagnoses (MS – multiple sclerosis, ME – myaligic encephalomyelitis/chronic fatigue syndrome, PN – peripheral neuropathy, Stroke), and dark green are metabolic/renal diagnoses (AKD - acute kidney disease, Hyperthyroid, Hypothyroid, Type 1 Diabetes, Type 2 Diabetes). A little over 3% of IBS sufferers do not feel disabled, while over 10% are severely disabled.  

There are several risk factors for the development of PI-IBS, including female gender, previous antibiotic treatment, anxiety, depression, somatization, neuroticism, and clinical indicators of intestinal inflammation. A history of Clostridioides difficile infection (CDI) may also increase the risk of PI-IBS by up to 25%. Underlying possible mechanisms include ongoing increased permeability, abnormal serotonin metabolism, and ongoing chronic immune activation together with altered microbiota. 

REFERENCES

Chan WW, Grover M. The COVID-19 Pandemic and Postinfection Irritable Bowel Syndrome: What Lies Ahead for Gastroenterologists. Clinical Gastroenterology and Hepatology. 2022 Aug 6. 

Gabashvili IS. The Incidence and Effect of Adverse Events Due to COVID-19 Vaccines on Breakthrough Infections: Decentralized Observational Study with Underrepresented Groups. JMIR Formative Research. 2022 Nov 4;6(11):e41914. doi: 10.2196/41914. PMID: 36309347; PMCID: PMC9640199.

Ghoshal UC. Postinfection irritable bowel syndrome. Gut and Liver. 2022 May 5;16(3):331.

Lau B, Wentz E, Ni Z, Yenokyan K, Coggiano C, Mehta SH, Duggal P. Physical and mental health disability associated with long-COVID: Baseline results from a US nationwide cohort. medRxiv. 2022 Dec. 7

Lau B, Wentz E, Ni Z, Yenokyan K, Coggiano C, Mehta SH, Duggal P. Physical and mental health disability associated with long-COVID: Baseline results from a US nationwide cohort. medRxiv. 2022 Jan 1.

Nazarewska A, Lewandowski K, Kaniewska M, Rosołowski M, Marlicz W, Rydzewska G. Irritable bowel syndrome following COVID-19: underestimated consequence of infection with SARS-CoV-2. Polish archives of internal medicine.:16323.

Spiller R, Garsed K. Postinfectious irritable bowel syndrome. Gastroenterology. 2009 May 1;136(6):1979-88.

Thabane M, Marshall JK. Post-infectious irritable bowel syndrome. World journal of gastroenterology: WJG. 2009 Aug 8;15(29):3591.